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Bioinformatics in MicroRNA Research 1st Edition Coll.
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Methods in
Molecular Biology 1617

Jingshan Huang · Glen M. Borchert

Dejing Dou · Jun (Luke) Huan
Wenjun Lan · Ming Tan · Bin Wu
Editors

Bioinformatics
in MicroRNA
Research
Methods in Molecular Biology

Series Editor:
John M. Walker
School of Life and Medical Sciences
University of Hertfordshire
Hatfield, Hertfordshire, AL10 9AB, UK

For further volumes:

http://www.springer.com/series/7651
 Bioinformatics in MicroRNA
Research
Editors

Jingshan Huang
School of Computing, University of South Alabama, Mobile, AL, USA

Glen M. Borchert
Department of Pharmacology, University of South Alabama, Mobile, AL, USA;
Department of Biology, University of South Alabama, Mobile, AL, USA

Dejing Dou
Department of Computer and Information Science, University of Oregon, Eugene, OR, USA

Jun (Luke) Huan

Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, KS, USA

Wenjun Lan
School of Bio-Engineering, Qilu University of Technology, Jinan, Shandong, China

Ming Tan
Mitchel Cancer Institute, University of South Alabama, Mobile, AL, USA

Bin Wu
Department of Endocrinology, First Affiliated Hospital, Kunming Medical University, Kunming, Yunnan, China
Editors
Jingshan Huang Glen M. Borchert
School of Computing Department of Pharmacology
University of South Alabama University of South Alabama
Mobile, AL, USA Mobile, AL, USA
Department of Biology
Dejing Dou
University of South Alabama
Department of Computer
Mobile, AL, USA
and Information Science
University of Oregon
Jun (Luke) Huan
Eugene, OR, USA
Department of Electrical Engineering
and Computer Science
Wenjun Lan
University of Kansas
School of Bioengineering
Lawrence, KS, USA
Qilu University of Technology
Jinan, Shandong, China
Ming Tan
Mitchel Cancer Institute
Bin Wu
University of South Alabama
Department of Endocrinology
Mobile, AL, USA
First Affiliated Hospital
Kunming Medical University
Kunming, Yunnan, China

ISSN 1064-3745     ISSN 1940-6029 (electronic)

Methods in Molecular Biology
ISBN 978-1-4939-7044-5 ISBN 978-1-4939-7046-9 (eBook)
DOI 10.1007/978-1-4939-7046-9

Library of Congress Control Number: 2017937362

© Springer Science+Business Media LLC 2017

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Preface

As a special class of noncoding RNAs, microRNAs (miRNAs or miRs for short) have been
reported to perform important roles in various biological and pathological processes by
regulating respective target genes. To completely understand and fully delineate miR func-
tions, besides performing biological experiments and querying PubMed and TarBase for
biologically validated miR targets, biologists can also query various miR target prediction
databases/websites for computationally predicted targets. More often than not, biologists
need to extract additional information for each and every miR target, either validated or
putative, with regard to its related information such as protein functions and affiliated sig-
naling pathways. In short, biologists are facing significant barriers in fully delineating miR
functions and the following effective bio-curation. Therefore, there is an urgent need for a
comprehensive book focusing on miR target genes, miR regulation mechanisms, miR func-
tions performed in various human diseases, and miR databases/knowledge bases.
This book is intended to give an in-depth introduction to and discussion of miRs and
their targets, miR functions, and computational techniques applied in miR research. The
primary audience includes, but is not limited to, computational biologists, computer scien-
tists, bioinformaticians, bench biologists, and clinical investigators. No prior knowledge of
computer science, databases, semantic technologies, or molecular biology is assumed. But we
do assume that readers have some biology background knowledge at the high-school level.
A brief overview of the book structure is as follows. Chapter 1 introduces the concepts of
miRs and long noncoding RNAs (lncRNAs) as well as some recent advances in miR/lncRNA
biology. Chapters 2, 3, and 4 discuss protein participants in miR regulation; viral microRNAs,
host miRs regulating viruses, and bacterial miR-like RNAs; and biomarkers, diagnostics, and
therapeutics aspects of miRs, respectively. Chapter 5 introduces basic concepts of relational
databases and biomedical big data. Chapter 6 provides an overview of semantic technologies
and bio-ontologies. Chapter 7 discusses genome-wide analysis of miR-regulated transcripts.
Chapters 8 and 9 describe in detail computational prediction of miR target genes, regulatory
interactions between miRs and their targets, as well as an introduction of various miR target
prediction databases and relevant Web resources. Chapter 10 discusses some limitations of
existing approaches that aim to improve miR target prediction accuracy. Chapters 11 and 12
introduce genomic regulation of miR expression in disease development and next generation
sequencing for miR expression profile. Chapters 13 through 16 discuss advanced topics in
computational/bioinformatics approaches in miR research, including the handling of high-
dimension data, identification and removal of noisy data, logical reasoning, and machine
learning techniques. Finally, Chapters 17–19 introduce some advances of miR research in
three human diseases: diabetes, obesity, and thyroid carcinoma.

Mobile, AL, USA Jingshan Huang

Mobile, AL, USA  Glen M. Borchert
Eugene, OR, USA  Dejing Dou
Lawrence, KS, USA  Jun (Luke) Huan
Jinan, Shandong, China  Wenjun Lan
Mobile, AL, USA  Ming Tan
Kunming, Yunnan, China  Bin Wu

v
Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 MicroRNAs, Long Noncoding RNAs, and Their Functions

in Human Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Min Xue, Ying Zhuo, and Bin Shan
2 MicroRNA Expression: Protein Participants in MicroRNA Regulation . . . . . . . . . . 27
Valeria M. King and Glen M. Borchert
3 Viral MicroRNAs, Host MicroRNAs Regulating Viruses,
and Bacterial MicroRNA-Like RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Sara-Elizabeth Cardin and Glen M. Borchert
4 MicroRNAs: Biomarkers, Diagnostics, and Therapeutics . . . . . . . . . . . . . . . . . . . . 57
Weili Huang
5 Relational Databases and Biomedical Big Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
N.H. Nisansa D. de Silva
6 Semantic Technologies and Bio-Ontologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Fernando Gutierrez
7 Genome-Wide Analysis of MicroRNA-Regulated Transcripts . . . . . . . . . . . . . . . . . 93
David Chevalier and Glen M. Borchert
8 Computational Prediction of MicroRNA Target Genes,
Target Prediction Databases, and Web Resources . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Justin T. Roberts and Glen M. Borchert
9 Exploring MicroRNA::Target Regulatory Interactions
by Computing Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Yue Hu, Wenjun Lan, and Daniel Miller
10 The Limitations of Existing Approaches in Improving MicroRNA
Target Prediction Accuracy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Rasiah Loganantharaj and Thomas A. Randall
11 Genomic Regulation of MicroRNA Expression
in Disease Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Feng Liu
12 Next-Generation Sequencing for MicroRNA Expression Profile . . . . . . . . . . . . . . . 169
Yue Hu, Wenjun Lan, and Daniel Miller
13 Handling High-Dimension (High-Feature) MicroRNA Data . . . . . . . . . . . . . . . . . 179
Yue Hu, Wenjun Lan, and Daniel Miller
14 Effective Removal of Noisy Data Via Batch Effect Processing . . . . . . . . . . . . . . . . . 187
Ryan G. Benton
15 Logical Reasoning (Inferencing) on MicroRNA Data . . . . . . . . . . . . . . . . . . . . . . . 197
Jingsong Wang

vii
viii Contents

16 Machine Learning Techniques in Exploring MicroRNA Gene Discovery,

Targets, and Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Sumi Singh, Ryan G. Benton, Anurag Singh, and Anshuman Singh
17 Involvement of MicroRNAs in Diabetes and Its Complications . . . . . . . . . . . . . . . 225
Bin Wu and Daniel Miller
18 MicroRNA Regulatory Networks as Biomarkers in Obesity:
The Emerging Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Lihua Zhang, Daniel Miller, Qiuping Yang, and Bin Wu
19 Expression of MicroRNAs in Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Gaohong Zhu, Lijun Xie, and Daniel Miller

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Contributors

Ryan G. Benton • Department of Computer Science, University of South Alabama

School of Computing, Mobile, AL, USA
Glen M. Borchert • Department of Pharmacology, University of South Alabama,
Mobile, AL, USA; Department of Biology, University of South Alabama, Mobile, AL,
USA
Sara-Elizabeth Cardin • Department of Biology, University of South Alabama,
Mobile, AL, USA
David Chevalier • Department of Biology, East Georgia State College, Swainsboro,
GA, USA
N.H. Nisansa D. de Silva • Department of Computer and Information Science,
University of Oregon, Eugene, OR, USA
Fernando Gutierrez • Department of Computer and Information Science,
University of Oregon, Eugene, OR, USA
Yue Hu • College of Bioengineering, Qilu University of Technology, Jinan, Shandong,
People’s Republic of China
Weili Huang • Miracle Query, Incorporated, Eugene, OR, USA
Valeria M. King • Department of Biology, University of South Alabama, Mobile, AL, USA
Wenjun Lan • School of Bioengineering, Qilu University of Technology, Jinan,
Shandong, People’s Republic of China
Feng Liu • National Research Center for Translational Medicine (Shanghai), Rui-Jin
Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Rasiah Loganantharaj • Bioinformatics Research Lab, The Center for Advanced
Computer Studies, University of Louisiana, Lafayette, LA, USA
Daniel Miller • School of Computing, University of South Alabama, Mobile, AL, USA
Thomas A. Randall • Integrative Bioinformatics, National Institute of Environmental
Health Sciences, National Institutes of Health, Research Triangle Park, Durham,
NC, USA
Justin T. Roberts • Department of Biology, University of South Alabama,
Mobile, AL, USA
Bin Shan • Elson S. Floyd College of Medicine, Washington State University, Spokane,
WA, USA
Anshuman Singh • School of Computer Science and Mathematics, University of
Central Missouri, Warrensburg, MO, USA
Anurag Singh • Center for Advanced Computer Studies, University of Louisiana,
Lafayette, LA, USA
Sumi Singh • School of Computer Science and Mathematics, University of Central
Missouri, Warrensburg, MO, USA
Jingsong Wang • Oracle Corporation, Redwood Shores, CA, USA
Bin Wu • Department of Endocrinology, First Affiliated Hospital, Kunming Medical
University, Kunming, Yunnan, China

ix
x Contributors

Lijun Xie • Department of Nuclear Medicine, First Affiliated Hospital of Kunming

Medical University, Kunming, Yunnan, China
Min Xue • Xuzhou College of Medicine, Xuzhou, Jiangsu, China
Qiuping Yang • Department of Geriatrics, First Affiliated Hospital of Kunming
Medical University, Kunming, Yunnan, China
Lihua Zhang • Department of Geriatrics, First Affiliated Hospital of Kunming
Medical University, Kunming, Yunnan, China
Gaohong Zhu • Department of Nuclear Medicine, First Affiliated Hospital
of Kunming Medical University, Kunming, Yunnan, China
Ying Zhuo • Kadlec Regional Medical Center, Richland, WA, USA
 Chapter 1

MicroRNAs, Long Noncoding RNAs, and Their Functions

in Human Disease
Min Xue, Ying Zhuo, and Bin Shan

Abstract
Majority of the human genome is transcribed into RNAs with absent or limited protein-coding potential.
microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two major families of the non-protein-­
coding transcripts. miRNAs and lncRNAs can regulate fundamental cellular processes via diverse mecha-
nisms. The expression and function of miRNAs and lncRNAs are tightly regulated in development and
physiological homeostasis. Dysregulation of miRNAs and lncRNAs is critical to pathogenesis of human
disease. Moreover, recent evidence indicates a cross talk between miRNAs and lncRNAs. Herein we
review recent advances in the biology of miRNAs and lncRNAs with respect to the above aspects. We
focus on their roles in cancer, respiratory disease, and neurodegenerative disease. The complexity, flexibil-
ity, and versatility of the structures and functions of miRNAs and lncRNAs demand integration of experi-
mental and bioinformatics tools to acquire sufficient knowledge for applications of these noncoding
RNAs in clinical care.

Key words MicroRNA, Long noncoding RNA

1 Introduction

Majority of the human genome is transcribed although only ~2%

of the human genome encodes proteins [1]. The transcribed
RNAs with absent or limited protein-coding potential are named
noncoding RNAs and operationally divided into small RNAs and
long noncoding RNAs (lncRNA) with a boundary set at 200
nucleotides in length. The small RNA family includes microR-
NAs (miRNA), small nuclear RNAs, and piwi-interacting RNAs.
miRNAs and lncRNAs are critical regulators of development,
physiology, and disease. Herein we review recent advances in the
biology of miRNAs and lncRNAs and their functions in human
disease.

Jingshan Huang et al. (eds.), Bioinformatics in MicroRNA Research, Methods in Molecular Biology, vol. 1617,
DOI 10.1007/978-1-4939-7046-9_1, © Springer Science+Business Media LLC 2017

1
2 Min Xue et al.

2 Functions of miRNAs and Human Disease

2.1 Biogenesis miRNAs are ~22-nucleotide long single stranded RNAs that regu-
of miRNAs late gene expression via diverse mechanisms [2]. Since discovery of
the first miRNA lin-4 in Caenorhabditis elegans in 1993, 35,828
mature miRNAs have been catalogued in 223 species in the latest
release of miRBase (www.mirbase.org) [3, 4]. Biogenesis of miR-
NAs starts with transcription from a miRNA-hosting gene, which
yields a long primary transcript named primary miRNA (pri-­
miRNA) [5]. Then the pri-miRNA is cleaved by the ribonulease
III-type protein Drosha in the nucleus to produce a ~70-­nucleotide
long hairpin structure named precursor miRNA (pre-miRNA) [6].
The pre-miRNA is exported to the cytoplasm by exportin-5 and
subsequently cleaved by another ribonulease III-type protein Dicer
to generate a miRNA:miRNA* duplex of ~22 nucleodtides [7].
The miRNA:miRNA* duplex binds to an argonaute (AGO) pro-
tein to form an effector RNA-induced silencing complex (RISC)
complex. A mature miRNA is produced when miRNA* is peeled
off from the duplex. It is noteworthy that a miRNA* is not simply
a nonfunctional byproduct of miRNA biogenesis but rather a func-
tional miRNA on many occasions [8].
Besides their canonical destination in the cytoplasm miRNAs
exist and function in the nucleus and secretary microvesicles called
exosomes [9, 10]. Exosomes are small extracellular membrane ves-
icles with sizes of 30–100 nm in diameter and secreted by various
types of cells in the body [11–14]. miRNAs packaged in exosomes
can be taken up by neighboring cells or distant recipient cells via
transportation in body fluids and function in their recipient cells,
which serve as an important tool for proximal and distant intercel-
lular communications [15–18].
Biogenesis of miRNAs can be regulated at every step of their
production by physiological and pathological signals. For instance
the miRNA-200 family is transcriptionally suppressed by ZEB1
during epithelial–mesenchymal transition (EMT) [19]. In another
example type I collagen posttranscriptionally upregulates the
expression of miR-21 by promoting maturation of pre-miR-21 to
miR-21 without alteration in the amount of pri-miRNA-21 and
pre-miR-21 [20].

2.2 Functions The classic mode of a miRNA’s action is to inhibit gene expression
of miRNA via binding to its complementary sequences (6–8 nucleotides)
within the 3′ untranslated region (3′ UTR) of its target mRNAs.
This partial complementarity causes inhibition of expression of a
miRNA’s target via degradation or repression of translation of the
bound mRNAs [21]. Because of the need of only a 6–8 nucleotide
complementarity a miRNA can potentially targets hundreds of
mRNAs and most mammalian mRNAs are conserved targets of
 MicroRNAs, Long Noncoding RNAs, and Their Functions in Human Disease 3

miRNAs [22]. Bioinformatic tools such as TargetScan have been

widely used to guide prediction and validation of a miRNA’s target
mRNAs [23].
The cytoplasmic miRNAs inhibit their target genes expression
via degradation of mRNAs or inhibition of translation at initiation
and post-initiation steps [21, 24–31]. miRNA-mediated decrease
of their target mRNA levels is proposed as a major mechanism of
miRNA-mediated repression of a target gene expression [32]. This
action can be achieved through miRNA-induced rapid deadenyl-
ation of target mRNA as exemplified by the actions of miR-125b,
a miRNA that is linked to chemoresistance in breast cancer [31,
33, 34]. miRNA-mediated suppression of translation initiation is
exemplified in let-7-mediated repression of its target mRNAs as
let-7-bound AGO2 represses the translation initiation by binding
to the m7G cap of the mRNA targets and thereby prevents the
recruitment of eIF4E, an essential translation initiation factor [35].
The post-initiation inhibition of translation by miRNAs is accom-
plished through rapid degradation of the peptide product encoded
by the targeted mRNA, which is mediated by high rate of ribo-
some drop-off during translation elongation [36].
In addition to their canonical actions in the cytoplasm miR-
NAs are expressed in abundance in the nucleus and regulate vari-
ous nuclear events such as transcription and RNA splicing via
diverse mechanisms. For instance miR-320 recruits AGO1 and
EZH2 to the POLR3D locus through complete complementary
binding, which results in heterochromatinization and silencing of
the POLR3D promoter [37]. miRNA-mediated silencing of the
gene promoters harboring their target sites controls a variety of
fundamental cellular processes, such as cellular senescence and
neuroregeneration [38–40]. On the other hand, a few nuclear
miRNAs have been reported to activate gene expression via epi-
genetic mechanisms. For instance miR-373 activates the expres-
sion of CDH1 and CSDC2 via AGO-miRNA complexes-mediated
recruitment of positive epigenetic regulators to the target promot-
ers [41]. Lastly nuclear miRNAs can regulate splicing of the com-
plement pre-mRNA. In miR-122-mediated repression of splicing
of the hepatitis C viral RNA a ternary complex formed between the
target transcript, miRNA, and RISC masks splicing recognition
motifs and thereby prevents binding of the splicing factors [42].

2.3 miRNAs miRNAs govern fundamental biological processes, such as cell pro-
and Human Disease liferation, death, differentiation, and development [43]. As a
­feedback tool with profound effects on gene expression miRNAs
are the main tool to fine-tune gene expression and biological
homeostasis. Dysregulation of miRNAs contributes to pathogen-
esis of a wide variety of human disease. In this section we review
actions of miRNAs in cancer, respiratory disease, and neurodegen-
erative disease.
4 Min Xue et al.

2.3.1 miRNAs in Cancer The first documented association between miRNAs and cancer is
frequent deletion and downregulation of miR-15 and miR-16 at
13q14 in chronic lymphocytic leukemia [44]. Since then, thou-
sands of miRNAs have been reported to act as either oncogenes or
tumor suppressors depending on a miRNA’s targets in a particular
biological context. miRNAs have been linked to each hallmark of
cancer that is established by Hanahan and Weinberg [45].
Representative miRNAs associated with each hallmark of cancer
are listed in Table 1 [46–62].
Genetic alterations are a common cause of dysregulation of
miRNAs in cancer. More than 50% of miRNA genes are located in
cancer associated genomic regions or in fragile sites [63]. One
prime example is amplification of the oncogenic miR-17~92 clus-
ter and its consequent overexpression in small cell lung cancer
[47]. Deletion and loss of expression of miRNAs in cancer are
exemplified in frequent deletion of the miR-15a and miR-16a

Table 1
Association between miRNA and hallmarks of cancer

Hallmarks of cancer Representative miRNAs

Sustaining proliferative signaling miR-17~92-mediated suppression of PTEN in lung cancer and
B-cell lymphoma [46, 47]; Loss of let-7-­mediated suppression of
Ras by in lung cancer [48, 49]
Evading growth suppressors Interference of cell cycle arrest by miR-675-mediated suppression
of pRB in colorectal cancer [50]
Avoiding immune destruction Enhancement of resistance to cytotoxic T-lymphocytes by
miR-222 mediated suppression of ICAM-1 [51]
Enabling replicative immortality Loss of miR-34a-mediated senescence in colon cancer [52]
Tumor promoting inflammation miR-155-mediated inflammation in the tumor microenvironment
[53, 54]
Activating invasion and metastasis miR-10b-mediated migration, invasion, and metastasis in breast
cancer [62]; Loss of miR-200-mediated suppression of EMT
[55, 56]
Inducing angiogenesis Enhanced angiogenesis by miR-296-mediated suppression of
HGS in tumor associated endothelial cells in gliomas [57]
Genome instability and mutation Impairment of DNA repair by miR-21-mediated suppression of
H2AX, a histone variant essential to repair [58, 59]
Resisting cell death Inhibition of caspase activation by miR-21-­mediated suppression
of PDCD4 in glioblastoma [60]
Deregulating cellular energetics Loss of miR-99a/100-­mediated suppression of mTOR in
childhood adrenocortical tumors [61]
A summary of representative miRNAs associated with the hallmarks of cancer. PTEN phosphatase and tensin homolog,
pRB retinoblastoma protein, EMT epithelial–mesenchymal transition, HGS hepatocyte growth factor-regulated tyrosine
kinase substrate, PDCD4 programmed cell death protein 4, mTOR mechanistic target of rapamycin
MicroRNAs, Long Noncoding RNAs, and Their Functions in Human Disease 5

hosting locus in chronic lymphocytic leukemia [44]. Single nucle-

otide polymorphism (SNP) is another common cause of dysregula-
tion of miRNAs in cancer. In a common G/C polymorphism
(rs2910164) within the pre-miR-146a coding region the C allele
results in a decrease of mature miR-146a and less efficient inhibi-
tion of the miR-146a targets, which increases risk of papillary thy-
roid carcinoma [64]. Variation within the miRNA target site of a
miRNA-targeted 3′UTR is another important source of genetic
predisposition in cancer risk. In the oncogenic HMGA2 locus the
open reading frame and the 3′UTR harboring the let-7 target sites
are separated by chromosomal rearrangements in cancer, which
leads to escape of HMGA2 from let-7-mediated repression [65, 66].
SNP in a miRNA target site can result in loss of miRNA-­mediated
repression in cancer. In the let-7 target site within the 3′UTR of
the KRAS oncogene SNP causes elevated KRAS expression and
increased risk of non-small cell lung cancer [67].
Transcriptional dysregulation of miRNA expression is another
critical mechanism in tumorigenesis. The oncogenic miRNAs are
often transcriptionally activated in cancer [68]. For instance the
oncogenic miR-17~92 cluster is transcriptionally activated by the
MYC oncogene via a MYC binding site in the promoter of the
miR-17~92 cluster [69]. In contrast the tumor suppressive miR-
NAs are often transcriptionally repressed in cancer [70]. The pro-
moter of the miR-200 cluster that encodes miR-200a, miR-200b,
and miR-429 is transcriptionally repressed by ZEB1 and SIP1 dur-
ing EMT, a process through which cancer cells acquire invasive
and metastatic competency [19, 55]. More importantly the miR-­
200 cluster members repress the expression of ZEB1 and SIP1 via
the miR-200 target sites in their 3′ UTR and this reciprocal repres-
sion between the miR-200 cluster and ZEB1/SIP1 establishes a
double-negative feedback loop in regulation of EMT [19, 55].
miRNA expression can also be regulated by the signals from the
tumor microenvironment, such as extracellular matrix, and in turn
mediates cancer cell’s responses to the tumor microenvironment
[20, 56, 71, 72].
Because of the critical roles of miRNAs in cancer biology miR-
NAs have emerged as a family of promising targets in diagnosis and
treatment of cancer. Because miRNAs are more stable than mRNAs
and released by a solid tumor into the body fluids via exosomes
miRNAs have emerged as promising biomarkers in tissue biopsies,
blood, urine, etc. [73–75]. For instance a host of circulating miR-
NAs including miR-141, miR-21, and miR-92a have been tested
as diagnostic biomarkers of colorectal cancer in whole plasma or
serum [76–81]. miRNAs have also been developed as molecular
signatures of subtypes of breast cancer and thus guide the treat-
ment that is tailored for each molecular subtype. The miRNA sig-
natures of ER+ and HER+ can guide anti-ER and anti-HER2
therapies, respectively [82–84]. miRNAs can potentially predict
6 Min Xue et al.

responses to chemotherapy and thus guide the choice of treat-

ments as illustrated in the miRNA signatures that can predict
response to tamoxifen and anti-HER2 monoclonal antibody
Herceptin in breast cancer [85–87].
Current development of miRNA-based therapies mainly
employs antagonist and oligonucleotide mimics of a miRNA of
interest. miRNA mimics are used to restore tumor suppressive
miRNAs that are deficient in cancer. On the contrary antagomiRs
are single-stranded oligonucleotides that complement and inhibit
the oncogenic miRNAs in cancer. To increase efficiency of a
miRNA antagonist, miRNA sponge technology has been ­developed
to synthesize a single stranded RNA containing multiple binding
sites of a targeted miRNA to efficiently neutralize a miRNA [88].
miRNA sponges have been validated in xenograft mouse model of
human breast cancer cell lines in that inhibition of miRNA-9 and
miR-150 using a synthetic RNA containing several miR-9 or miR-
150 binding sites reduced lung metastases [89, 90]. The miRNA
targeting therapies have entered clinical trials as exemplified by a
miR-34a mimics in phase I study (http://clinicaltrials.gov/ct2/
show/NCT01829971). Preliminary results from the translational
studies of miRNA-based therapies against cancer suggest that
miRNA mimics or antagomiRs can be easily administered through
local or parenteral injection routes with sufficient uptake of the
agents to achieve sustained and desired effects in the targeted tis-
sues and organs.

2.3.2 miRNAs miRNAs have emerged as critical regulators in the control of nervous
in Neurodegenerative system-specific gene expression during development, aging, and dis-
Disease ease. We review the role of miRNAs in two devastating neurodegen-
erative diseases, Parkinson’s disease and Alzheimer’s disease.
Parkinson’s disease is a chronic and progressive movement dis-
order that is caused by a gradual loss of midbrain dopaminergic
neurons [91]. Investigation of miRNAs has shed light on patho-
genesis of Parkinson’s disease. miR-133b is specifically expressed in
the midbrain dopaminergic neurons and regulates maturation and
function of the midbrain dopaminergic neurons as a node of a neg-
ative feedback circuit by targeting the paired-like homeodomain
transcription factor Pitx3 [92]. Importantly, miR-133b is deficient
in the midbrain tissues from patients with Parkinson’s disease [92].
Gain-of-function mutations in leucine-rich repeat kinase-2
(LRRK2) cause familial and sporadic Parkinson’s disease. The
pathogenic LRRK2 associate with RISC to interfere the miRNA
pathway and such interference leads to overproduction of E2F1/DP,
a target of let-7 and miR-184* [93]. Moreover, antagomiR-­
mediated blockage of let-7 or miR-184* can recapitulate the toxic
effects of the pathogenic LRRK2 and conversely forced expression
of let-7 or miR-184* can attenuate the toxic effects of the patho-
genic LRRK2 [93].
Exploring the Variety of Random
Documents with Different Content
Mashonaland in the southeast, Matabeleland in the
southwest, Barotseland in the northwest, and in the
northeast a portion of the now separately administered
protectorate of Nyasaland. Practically the whole country
is an elevated veldt, or plateau, ranging from three
thousand five hundred to five thousand feet above sea-
level; studded with granite kopjes which in the south
attain to the dignity of a mountain chain; well watered
by tributaries of the Congo, the Zambezi, and the
Limpopo; and covered with a luxuriant vegetation. Like
California, Southern Rhodesia has a unique and
hospitable climate, free from the dangerous heats of an
African summer and from cold winds in winter. Though
the climate of nearly all of Southern Rhodesia is suitable
for Europeans, much of the trans-Zambezi provinces,
especially along the river valleys and in the low-lying,
swampy regions near the great equatorial lakes, reeks
with malaria, while in certain other areas, now carefully
delimited and guarded by governmental regulation, the
tsetse-fly commits terrible ravages among cattle and
horses and the sleeping-sickness among men. The
climate as a whole, however, is characterised by a
rather remarkable equability of temperature, especially
when it is remembered that Rhodesia extends from the
borders of the temperate zone to within a few degrees
of the equator. At Salisbury, the capital, for example,
the mean July temperature is 57.5° and for January
70.5°, the extremes for the year ranging from 34° to
93°. It is a significant fact, however, that the glowing
prospectuses of the chartered company touch but lightly
on the climatic conditions which prevail north of the
Zambezi, a region from which, it struck me, the
European settler who does not possess a system that is
proof against every form of tropical fever, a head that is
proof against sunstroke, and a mind which is proof
against that oftentimes fatal form of homesickness
which the army surgeons call nostalgia, is much more
likely to go home in a coffin than in a cabine de luxe.
In mines of gold, of silver, and of diamonds Rhodesia
is very rich; agriculturally it is very fertile, for in addition
to the native crops of rice, tobacco, cotton, and india-
rubber, the fruits, vegetables, and cereals of Europe and
America are profitably grown. The great fields of maize,
or “mealies,” as all South Africans call it, through which
my train frequently passed, constantly reminded me of
scenes in our own “corn belt”; but in the watch-towers
which rise from every corn-field, atop of which an
armed Kaffir sits day and night to protect the crops from
the raids of wild pigs and baboons, Rhodesia has a
feature which she is welcome to consider exclusively her
own.
Though Rhodesia is distinctly a frontier country, with
many of a frontier's defects, her towns—Salisbury,
Bulawayo, Umtali, and the rest—are not frontier towns
as we knew them in Butte, Cheyenne, Deadwood, and
Carson City. There are saloons, of course, but they are
not of the “gin palace” variety, nor did it strike me that
intoxication was particularly common; certainly nothing
like what it used to be during the gold-rush days in
Alaska or in our own West. This may be due to the
fantastic prices charged for liquor—a whiskey-and-soda
costs sixty cent—and then again it maybe due to the
fact that most of the settlers have brought their families
with them, so that, instead of spending their evenings
leaning over green tables or polished bars, they devote
them to cricket, gardening, or a six-weeks-old English
paper. Though nearly every one goes armed, the streets
of the Rhodesian towns are as peaceable as
Commonwealth Avenue, in Boston, on a Sunday
morning. Indeed, the commandant of police in
Bulawayo assured me that he had had only one
shooting affray during his term of office. In Rhodesia,
should a man draw his gun as the easiest means of
settling a quarrel, his companions, instead of
responding by drawing theirs, would probably call a
constable and have him bound over to keep the peace.
Even the rights of the natives are rigidly safeguarded by
law, an American settler in Umtali complaining to me
most bitterly that “it's more dangerous for a white man
to kick a nigger down here than it is for him to kill one
in the States.” Now, all this was rather disappointing for
one who, like myself, was on the lookout for the local
colour and picturesqueness and whoop-her-up-boys
excitement which one naturally associates with life on a
frontier; but I might have expected just what I found,
for wherever the flag of England flies, whether over the
gold-miners of the Yukon, the ivory-traders of Uganda,
or the settlers of Rhodesia, there will be found the
deep-seated respect of the Englishman for English order
and English law.
In my opinion the country club, more than any other
single factor, has contributed most to the making,
socially and morally, of Rhodesia. Though the American
West is dotted with just such towns as Salisbury,
Bulawayo, Gwelo, and Umtali, with the same limitations,
pitfalls, and possibilities, the men's centre of interest,
after the day's work is over, is the saloon, the dance-
hall, or the barber-shop with a pool-room in the rear.
They do things differently in central Africa. In every
Rhodesian town large enough to support one—and the
same is true of all Britain's colonial possessions—I found
that a “sports club” had been established on the edge of
the town. Often it was nothing but a ramshackle shed
or cottage that had been given a coat of paint and had
a veranda added, but files of the English newspapers
and illustrated weeklies were to be found inside, while
from the tea tables on the veranda one overlooked half
a dozen tennis courts, a cricket ground, and a foot-ball
field. It is here that the settlers—men, women, and
children—congregate toward evening, to discuss the
crop prospects, the local taxes, the latest gold
discoveries, and, above all else, the news contained in
the weekly mail from home. Why have not our own
progressive prairie towns some simple social system like
this? It was in speaking of this very thing that the
mayor of Salisbury—himself an American-remarked: “In
the little, every-day things which make for successful
colonisation of a new country, you fellows in the States
are twenty years behind us.”
Living is expensive in Rhodesia, the prices of
necessaries usually being high and of luxuries ofttimes
fantastic. To counterbalance this, however, wages are
extraordinarily high. It is useless to attempt to quote
wages, for the farther up-country a man gets the higher
pay he can command, so I will content myself with the
bare statement that for the skilled workman, be he
carpenter, blacksmith, mason, or wheelwright, larger
wages are to be earned than in any part of the world
that I know. The same is true of the man who has had
practical experience in agriculture or stock-raising, there
being a steady demand for men conversant with
dairying, cattle-breeding, and irrigation. Let me drive
home and copper-rivet the fact, however, that in
Rhodesia, as in nearly all new countries, where there is
a considerable native population to draw upon, there is
no place for the unskilled labourer.
For the man with resource and a little capital there
are many roads to wealth in British Africa. I know of
one, formerly a laundry employee in Chicago, who
landed in Rhodesia with limited capital but unlimited
confidence. Recognising that the country had arrived at
that stage of civilisation where the people were tired of
wearing flannel shirts, but could not afford to have
white ones ruined by Kaffir washermen, he started a
chain of sanitary up-to-date laundries, and is to-day one
of the wealthy men of the colony. If you ever had to pay
one of his laundry bills you would understand why.
Another American, starting business as a hotel-keeper
in Salisbury, soon perceived that the people were ripe
for some form of amusement other than that provided
by the cricket fields and saloons; so he built a string of
cinematograph and vaudeville theatres combined, and
to-day, on the very spot where Lobenguela's medicine-
men performed their bloody rites a dozen years ago,
you can hear the whir of the moving-picture machine
and see on the canvas screen a military review at
Aldershot or a bathing scene at Asbury Park. Still
another American whom I met has increased the
thickness of his wallet by supplying prospectors and
settlers with sectional houses which are easily portable
and can be erected in an hour. Taking the circular,
conical-roofed hut of the Matabele as his model, he
evolved an affair of corrugated iron which combines
simplicity, portability, and practicability with a low price,
so that to-day, as you travel through Rhodesia, you will
see these American-made imitations of Kaffir huts
dotting the veldt.
Though Rhodesia has a black population of one
million six hundred thousand, as against twenty
thousand whites, there has thus far been no such thing
as race troubles or a colour question, due in large
measure, no doubt, to the firm and just supervision
exercised by the British resident commissioners. Arms,
ammunition, and liquor excepted, natives and
Europeans are under the same conditions. Land has
been set apart for tribal settlements, the mineral rights
being reserved to the company, but, if the native
occupation is disturbed, new lands must immediately be
assigned, all disputes being ultimately referrible to the
British high commissioner. Those natives living near the
towns are segregated in settlements of their own, a
native under no circumstances being permitted to
remain within the town limits after nightfall, or to enter
them in the day-time without a pass signed by the
commandant of police. Though possessing many of the
temperamental characteristics of the American negro,
and in particular his aversion for manual work, the
Rhodesian native is, on the whole, honest and
trustworthy, a well-disciplined and efficient force of
native constabulary having been recruited from the
warlike Barotse and Matabele.
 MORE WORK FOR THE PIONEER.
In the heart of the jungle in Northeastern Rhodesia near the Congo
border. This is the sort of country through which portions of the
“Cape-to-Cairo” railway will pass.

Highways of steel bisect Rhodesia in both directions.

From Plumtree, on the borders of Bechuanaland, the
Rhodesian section of the great Cape-to-Cairo system
stretches straight across the country to Bwana
M'kubwa, on the Congo frontier, while another line, the
Rhodesia, Mashonaland, and Beira, links up, as its name
indicates, the transcontinental system with the East
Coast. Though the much-advertised Zambezi Express is
scarcely the “veritable train de luxe” which the railway
folders call it, it is a comfortable enough train
nevertheless, with electric-lighted dining and sleeping
cars, the latter being fitted, as befits a dusty country,
with baths. The dining-car tariff is on a sliding scale; the
farther up-country you travel the higher the prices
ascend. Between Cape Town and Mafeking the charges
for meals seemed to me exceedingly reasonable (fifty
cents for breakfast, sixty cents for luncheon, and
seventy-five cents for dinner); between Mafeking and
Bulawayo they are only moderate; between Bulawayo
and the Zambezi they are high; and north of the
Zambezi—when you can get any food at all—the
charges for it are exorbitant. When the section to Lake
Tanganyika is completed only a millionaire can afford to
enter the dining-car. It speaks volumes for the
development of British South Africa, however, that one
can get into a sleeping-car in Cape Town and get out of
it again, six days later, on the navigable head-waters of
the Congo, covering the distance of nearly two
thousand five hundred miles at a total cost of eighty
dollars—and much of it through a country which has
been opened to the white man scarcely a dozen years.
Just as every visitor to the United States heads
straight for Niagara, so every visitor to South Africa
purchases forthwith a ticket to the Victoria Falls of the
Zambezi, the mighty cataract in the heart of Rhodesia
which is the greatest natural wonder in the Dark
Continent and, perhaps, in the world. The natives call
the falls Mosi-oa-tunya, which means “Thundering
Smoke,” and you appreciate the name's significance
when your train halts at daybreak at a wayside station,
sixty miles away, and you see above the tree-tops a
cloud of smoky vapour and hear a low humming like a
million sewing-machines. It is so utterly impossible for
the eye, the mind, and the imagination to grasp the
size, grandeur, and beauty of the Victoria Falls that it is
futile to attempt to describe them. If you can picture an
unbroken sheet of water forty city blocks in width, or as
long as from the Grand Central Station, in New York, to
Washington Square, hurtling over a precipice twice as
high as the Flatiron Building, you will have the best idea
that I can give you of what the Victoria Falls are like.
They are unique in that the level of the land above the
falls is the same as that below, the entire breadth of the
second greatest river in Africa falling precipitately into a
deep and narrow chasm, from which the only outlet is
an opening in the rock less than one hundred yards
wide. From the Boiling Pot, as this seething caldron of
waters is called, the contents of the Zambezi rush with
unbridled fury through a deep and narrow gorge of
basaltic cliffs, which, nowhere inferior to the rapids at
Niagara, extends with many zigzag windings for more
than forty miles. My first glimpse of the falls was in the
early morning, and the lovely, reeking splendour of the
scene, as the great, placid river, all unconscious of its
fate, rolls out of the mysterious depths of Africa, comes
suddenly to the precipice's brink, and plunges in one
mighty torrent into the obscurity of the cavern below,
the rolling clouds of spray, the trembling earth, the
sombre rain-forest on the opposite bank, and a rainbow
stealing over all, made a picture which will remain sharp
and clear in my memory as long as I live.
The Outer Lands are almost all exploited; the work of
the pioneer and the frontiersman is nearly finished, and
in another decade or so we shall see their like no more.
Rhodesia is the last of the great new countries open to
colonisation under Anglo-Saxon ideals of government
and climatically suitable for the propagation of the
Anglo-Saxon race. Though the handful of hardy settlers
who have already made it their home speak with the
burr of the shires instead of the drawl of the plains;
though they wear corded riding-breeches instead of
leather “chaps”; and stuff Cavendish into their pipes
instead of rolling their cigarettes from Bull Durham, they
and the passing plainsmen of our own West are, when
all is said and done, brothers under their skins.
With the completion of the Cape-to-Cairo trunk line
and its subsidiary systems to either coast, with the
exploitation of the mineral deposits which constitute so
much of Rhodesia's wealth, and with the harnessing of
the great falls and the utilisation of the limitless power
which will be obtainable from them, this virgin territory
in the heart of Africa bids fair to be to the home and
fortune seekers of to-morrow what the American West
was to those of yesterday, and what northwestern
Canada is to those of to-day. A few years more and it
will be a developed and prosperous nation. To-day it is
the last of the world's frontiers, where the hardy and
adventurous of our race are still fighting the battles and
solving the problems of civilisation.
 CHAPTER X
THE COUNTRY OF BIG THINGS
HE most significant thing I saw in South Africa was
an old-fashioned gabled, whitewashed house. The
name of it is Groote Schuur, and it stands in very
beautiful grounds on the slopes of Table Mountain, a
mile or so at the back of Cape Town. That house was
the home of Cecil John Rhodes, who, more than any
other man, was responsible for the Boer War and for
the resultant British predominance south of the Congo,
and in his will he directed that it should be used as the
official residence of the prime minister of that South
African confederation which his prophetic mind foresaw.
The welding of the Boer republics of the Transvaal and
the Orange Free State with the British colonies of Natal
and the Cape of Good Hope produced the great
antipodal commonwealth of which the empire-builder
dreamed, but the man who, as prime minister, dwells
under Groote Schuur's gabled roof and directs the
policies of the new nation is a member of that Boer race
which Rhodes hated and feared and whose political
power he firmly believed had been broken forever.
Fortune never doubled in her tracks more completely
than when she made General Louis Botha, the last
leader of Boer troops in the field, the first prime
minister of a united South Africa.
Strange things have happened in South Africa in the
dozen years that have passed since the musketry
crackled along the Modder and the Tugela, for the
country that the world believed had been won for good
and all by British arms is being slowly but surely rewon
by Boer astuteness. Already the bonds which hold the
new Union of South Africa to the British Empire have
become very loose ones. The man who, as prime
minister, is the virtual ruler of the young nation, is a far-
sighted and sagacious Dutchman, while seven out of
the eleven portfolios in his cabinet are held by men of
the same race. The Union not only makes its own laws
and fixes its own tariffs, but the leading Dutch organ of
the country recently went so far as to urge that, in case
Great Britain should become engaged in a European
war, it would be possible and might be proper for South
Africa to declare its neutrality and take no part in it. Not
only is the white population of the Union
overwhelmingly Dutch, but in many parts of the country
English is becoming merely a subsidiary tongue, while it
is not at all unlikely, in view of the bill recently passed
by the Parliament making Dutch compulsory in the
schools, that the language of the Netherlands will
eventually become the predominant tongue throughout
all South Africa. Most suggestive of all, perhaps, the
Orange River Colony, upon entering the Union, promptly
reverted to its old name of the Orange Free State,
which it bore before the war with England. Indeed, it
may sadly perplex the historians of the future to decide
who won the Boer War.
If South Africa is to become a union in fact as well as
in name its people will have to face and solve the great
national problems of race and colour. Of these, the
former are, if not the more important, certainly the
more pressing. Two of the four provinces of the Union,
remember, are British solely by right of conquest; a
third is bound by the closest ties of blood and tradition
to the Dutch people; while only one of the four is British
in sentiment and population. Many intelligent people
with whom I talked, both in England and in Africa,
assured me that the formation of the Union was the first
step toward cutting the bonds which join South Africa to
the mother country. While most Englishmen scoff at any
such suggestion, swaggeringly asserting that they “have
whipped the Dutch once and can do it again,” the Dutch
retort, on the other hand, that it took England, with all
her financial and military resources, four years, and cost
her tens of thousands of lives and millions of pounds, to
conquer the two little Boer republics, and that she
would not have beaten them then if their money had
held out. Though there is certainly no love lost between
the English and the Boers, I think that the majority of
the latter are convinced that it is to their own best
interests to be loyal to the new government, in the
direction of which they have, after all, the greatest say.
The attitude which the British Government has
adopted in its treatment of the Boer population since
the close of the war has been remarkable for its
generosity and far-sightedness. In all its colonial history
it has done few wiser things than the recognition of the
military, as well as the civic, ability of General Botha.
Not only is this sagacious Dutchman, who led the forces
of the embattled Boers until dispersed by the
tremendously superior might of England, and then
inaugurated a guerilla warfare by which the conflict was
prolonged for two years with victories which will go
down in history as notable, now prime minister of the
new nation, but, early in 1912, he was appointed to the
rank of general in that very army which he so long and
so valorously defied. This is, I believe, an almost
unprecedented instance of the wise and politic exercise
of imperial authority in the strengthening of imperial
power and can hardly fail to result in increasing the
loyalty of South Africa's Boer population.
 The men who planned and brought the Union into
being have had to pick their steps with care, and more
than once their ingenuity has been taxed to the utmost
to avoid the outcropping of racial jealousies and
enmities. The white population of South Africa, you
should understand, consists of three classes: the Boers,
which means simply “tillers of the soil,” and which is the
name applied by the South African Dutch to themselves;
the Colonials, or British immigrants, most of whom have
come out with the intention of returning to England as
soon as they have made their fortunes; and, lastly, the
Africanders, men whose fathers were British
immigrants, but who were themselves born and bred in
South Africa and who have intermarried with the Boers
so often that it is almost impossible to draw the line
between the races. Given these three factions,
therefore, with their different customs, ideals, and
aspirations, and it needs no saying that the task
confronting those who are responsible for the smooth
working of the governmental machinery is no easy one.
The political jealousy existing between Briton and Boer
in South Africa to-day is comparable only to that which
existed between Northerners and Southerners during
reconstruction days. The racial antagonism which arose
over the location of the Federal capital, and which
threatened at one time to upset the whole scheme of
federation, was only overcome by the novel expedient
of creating two capitals instead of one, Pretoria, the old
capital of the Transvaal, where Krüger held sway, being
made the residence of the Governor-General and the
seat of the executive power, while the Parliament sits in
Cape Town.
The Union Parliament consists of a Senate having
forty members—eight of whom are appointed by the
Governor-General, the other thirty-two being elected,
eight by each province—and a House of Assembly with
121 members chosen as follows: Cape of Good Hope
51, Natal 17, Transvaal 36, and Orange Free State 17.
No voter is disqualified by race or colour, but the
members of Parliament must be English subjects of
European descent who have lived in the colony for at
least five years. Now, a very great deal, so far as the
well-being of the native races of South Africa are
concerned, depends upon the interpretation that is
given to the words “European descent.” In Cuban
society every one who is not absolutely black is treated
as white, whereas in the United States every one who is
suspected of having even a “touch of the tar brush” is
treated as black. Though the Federal constitution is very
far from giving the native races a standing equal to that
of the whites, intelligent government of the natives is
promised by a clause which provides that four of the
Senate, out of a total of forty, shall be appointed
because of their special knowledge of the wants and
wishes of the coloured population.
If the racial problem is the most pressing, the colour
problem is by far the most serious question before the
people of South Africa, for the blacks not only
outnumber the whites four to one, but there is the ever-
present danger that rebellion may spring up among
them without the slightest warning. Apart from all other
considerations, the very numbers of the natives in South
Africa form a dangerous element in the problem, for
there are close on five million blacks south of the
Limpopo as against a million and a quarter Europeans.
If, in our own South, where the blacks are only half as
numerous as the whites, there exists a problem of
which no satisfactory solution has been offered, how
much more serious is the state of affairs in a country
where a handful of white men—themselves split into
two camps by racial and political animosities—are face
to face with a vast, warlike, and constantly increasing
native population! In fact, the colour problem which has
arisen would be strikingly similar to that in our Southern
States were it not that there is a vast difference in type
and temperament between the South African native and
the Southern darky. The native races are three in
number: the Bushmen, the aborigines of South Africa, a
race of pygmy savages of a very low order of
intelligence, who are fast becoming extinct; the
Hottentots, a people considerably more advanced
toward civilisation but rapidly decreasing from
epidemics; and the Kaffirs, as the various sections of
the great Zulu race are commonly known, a warlike,
courageous, and handsome people who, since the
British Government ended their inter-tribal wars, are
rapidly multiplying, having increased fifteen per cent in
the last seven years. Although the Europeans in South
Africa universally regard the Kaffirs with contempt, it is
not altogether unmixed with fear, for a nation of fighting
men, such as the Zulus, who organised a great military
power, enacted a strict code of laws, and held the white
man at bay for a quarter of a century, will not always
remain in a state of subjection, nor will they tamely
submit to being driven into the wilderness north of the
Zambezi, a solution of the colour problem which has
frequently been proposed.
That the attitude of Great Britain toward the colour
question in South Africa is similar to that of the
Northern States toward the same problem in the South,
while the attitude of the European settlers is almost
identical with that of the Southerners, is strikingly
illustrated by a case which recently occurred in South
Africa, in which a European jury found a native guilty of
attempting to assault a white woman, a crime as
unknown under the old régime in South Africa as it was
in our own South before the Civil War. Though the judge
sentenced the man to death, the Governor-General
promptly commuted the sentence on the ground that
the “fact of crime” had not been established.
Immediately a storm of protest and indignation arose
among the white population which swept the country
from the Zambezi to the Cape, the settlers asserting
that if the decree of commutation were to form a
precedent, no white woman would be safe in South
Africa. The echoes of this controversy had not yet died
away before two other cases occurred which intensely
aggravated the situation. One was the case of a settler
named Lewis, who shot a native for an insult to his
daughters, while the other was that of the Honourable
Galbraith Cole, a son of the Earl of Enniskillen, who
killed a native on the alleged charge of theft. Both men
were tried by white juries on charges of murder, and
both were promptly acquitted, though Mr. Cole, in spite
of his acquittal, was deported from South Africa by the
government. As though to emphasise their colour
prejudice, the lawyers of the Union about this time took
concerted action to prevent native attorneys from
practising among them. How, then, can the natives,
who form three fourths of the population of the new
Union, and who are far more children of the soil than
the Europeans, be said to have protection of their most
elementary rights if they are to be debarred from having
men of their own colour and race to defend them, and if
no white jury can be trusted to do justice where a
native is concerned?
The imperial government deserves the greatest
credit, however, for the steps it has taken to preserve
his lands to the native. In the native protectorates and
reservations of Basutoland, Swaziland, Bechuanaland,
Griqualand, Tembuland, and Pondoland the government
has reserved for the exclusive use and benefit of the
natives territories considerably larger than the combined
area of our three Pacific-coast States. Though these
territories are under the control of British resident
commissioners, the native chiefs are allowed to exercise
jurisdiction according to tribal laws and customs in all
civil matters between natives, special courts having
been established to deal with serious civil or criminal
matters in which Europeans are concerned. Though
certain small areas of land in these rich territories are
held by whites, the bulk of the country is reserved for
the exclusive use and benefit of the natives, and it is
not at all likely that any more land will be alienated for
purposes of settlement by Europeans. (Could anything
be in more striking contrast to our disgraceful treatment
of the Indian?) Though South Africa has much in
common with Canada, and with Australia, and with our
own Southwest, it is, when all is said and done, a black
man's country ruled by the white man, and it is upon
the justice, liberality, and intelligence of this rule that
the peace and prosperity of the young nation must
eventually depend.
Two great obstacles will always stand in the way of
the white man having an easy row to hoe in South
Africa: the climate and the lack of water. Though the
climate of the uplands is pleasant and makes men want
to lead an outdoor life, I am not at all certain that it
tends to develop or maintain the keenness and energy
characteristic of dwellers in the north temperate zone.
The climate of the coastal regions is, moreover,
distinctly bad, the sharply cold nights and the misty,
steaming days producing the coast fever, which is a
combination of rheumatism, influenza, dysentery, and
malaria, and is very debilitating indeed. The white man
who intends to make his permanent home in South
Africa has, therefore, two alternatives: he can submit to
the exactions of the climate, take life easily, leave the
black bottle severely alone, and live a long but
unprogressive life, or he can exhaust his energies and
undermine his health in fighting the climate and die of
old age at sixty. If the climate is not all that is desirable
for men, it is infinitely worse for animals, for every
disease known to the veterinarian abounds. Time and
again the herds of the country have been almost
exterminated by the hoof-and-mouth disease, or by the
rinderpest, a highly contagious cattle distemper which is
probably identical with that “murrain” with which Moses
smote the herds of ancient Egypt and which helped to
bring Pharaoh to terms. In the low-lying regions along
the East Coast, and in the country north of the Limpopo
it is necessary to keep horses shut up every night until
the poisonous mists and dew have disappeared before
the sun lest they contract the “blue-tongue,” a disease
characterised by a swollen, purplish-hued tongue which
kills them in a few hours by choking; while in certain
other districts, especially in the vicinity of the Zambezi
and of the Portuguese territories, the deadly tsetse-fly
makes it impossible to keep domestic animals at all.
The other great obstacle to the prosperity of South
Africa is the lack of water, for less than one-tenth of the
country is suitable for raising any kind of a crop without
water being led onto it—and irrigation by private
enterprise is out of the question, as even the
indomitable Rhodes was forced to admit. The
government is fully alive to the crying need for water,
however, and a scheme for a national system of
irrigation is filling a large part of the Ministry of
Agriculture's programme. If carried out, this scheme will
enormously enlarge the area of tillage, for some of the
regions now hopelessly arid, such as the Karroo, have a
soil of amazing fertility and need only water to make
them produce luxuriant crops. Were the rains of the wet
season conserved by means of the great tanks so
common in India, or were artesian wells sunk like those
which have transformed the desert regions of Algeria
and Arizona, the vast stretch of the Karroo, instead of
being yellow with sand, might be yellow with waving
corn.
Though agriculture is, and probably always will be,
the least important of the country's great natural
sources of wealth, the development of rural industries
is, thanks to governmental assistance, steadily
progressing. Roads and bridges are being built,
experimental farms organised on a large scale, the
services of scientific experts engaged, blooded live-
stock imported, agricultural banks established, and
literature dealing with agricultural problems is being
distributed broadcast over the country. The exports of
fruit are steadily increasing; sugar is being grown on the
hot lands of Natal and might be grown all the way to
the Zambezi; tea has lately been introduced in the
coastal regions and would probably also flourish in the
north; the tobacco of the Transvaal is as good a pipe
tobacco as any grown, and those who have become
accustomed to it will use no other; with the exception of
the olive, which does not thrive, and of the vine, which
succeeds only in a limited area around Cape Town,
nearly all of the products of the temperate zone and of
subtropical regions can be grown successfully. Though
South Africa unquestionably presents many promising
openings in farming, in fruit-growing, and in truck
gardening, it is folly for a man to attempt any one of
them unless he possesses practical experience, a
modest capital, and a willingness to work hard and put
up with many inconveniences, for in no other English-
speaking country are the necessities of life so dear and
so poor in quality, nowhere is labour so unsatisfactory,
and nowhere is lack of comfort so general.
South Africa's chief source of wealth is, and always
will be, its minerals. It was, strangely enough, the latest
source to become known, for nobody suspected it until,
in 1867, a Boer hunter, his eye caught by a sparkle
among the pebbles on the Orange River, picked up the
first diamond. The diamonds found in that region since
then have amounted in value to nearly a billion dollars.
Fifteen years after the great diamond finds which sent
the adventurers and fortune-seekers of the world
thronging to South Africa, came the still greater gold
discoveries on the Witwatersrand, or “The Rand,” as the
reef of gold-bearing quartz in the Transvaal is commonly
called. The total value of the gold production of the
Rand for the twenty-five years ending in June, 1910,
was nearly one and a half billion dollars. But though the
Rand produces more gold than America and Australia
put together; though Kimberley has a virtual monopoly
of the world's supply of diamonds; though seams of
silver, iron, coal, copper, and tin are only waiting for
capital and skill to unlock their treasures, South Africa
is, in the midst of this stupendous wealth, poor, for she
is as dependent on foreign sources for her food supply
as England. In other words, a region as large as all the
States west of the Rocky Mountains, in which flourish
nearly all the products of every zone from the Equator
to the Pole, is unable to supply the wants of a white
population which is less than that of Connecticut. In
California, on the other hand, which is strikingly similar
to South Africa in many respects, the cultivation of the
land kept pace with the production of gold and
eventually outstripped it. Until the mining industry of
South Africa is likewise put upon a solid agricultural
foundation, the country can never hope to be self-
supporting.
In many respects Johannesburg, the “golden city,” is
the most interesting place I have ever seen. In 1886 it
was nothing but a collection of miserable shanties. To-
day “Joburg,” as it is commonly called, is a city of a
quarter of a million people, with asphalted streets,
imposing office buildings, one of the best street-railway
systems that I know, the finest hotel south of the
Equator, and one of the most beautiful country clubs in
the world. It is a city of contrasts, however, for you can
stand under the porte-cochère of the palatial Carlton
Hotel and hear the click of roulette balls, the raucous
scrape of fiddles, and the shouts of drunken miners
issuing from a row of gambling-hells, dance-halls, and
gin palaces still housed in one-story buildings of
corrugated iron; a beplumed and bepainted Zulu will
pull you in a 'rickshaw, over pavements as smooth and
clean as those of Fifth Avenue, to a theatre where you
will have the privilege of paying Metropolitan Opera
House prices to witness much the same sort of a
performance that you would find in a Bowery music-
hall; in the Rand Club you can see bronzed and booted
prospectors, fresh from the mining districts of Rhodesia
or the Congo, leaning over the bar, cheek-by-jowl with
sleek, immaculately groomed financiers from London
and Berlin and New York. Johannesburg is a spendthrift
city, a place of easy-come and easy-go, for the mine-
workers are paid big wages, the mine-managers receive
big salaries, and the mine-owners make big profits, and
they all spend their money as readily as they make it.
The English miner averages five dollars a day, which he
spends between Saturday night and Monday morning in
a drunken spree, while a native labourer will save
enough in a few months to keep him in idleness and his
conception of comfort for the rest of his life.
There is pleasant society in Johannesburg and much
hospitality to a stranger. I took nearly a score of letters
of introduction with me to the Rand, but one would
have done as well, for you present one letter, and at the
dinner which the man to whom it is addressed promptly
gives for you at the Rand Club or at the Carlton you will
meet several of the other people to whom you bear
introductions. Through their club life and their business
relations the English and Americans in South Africa are
linked together in acquaintance like rings in a shirt of
chain-mail, so that if a man in Bulawayo or Kimberley or
Johannesburg gets to living beyond his income, or loses
heavily at cards, or pays undue attention to another
man's wife, they will be discussing his affairs in the club
bars or on the hotel verandas of Cape Town and Durban
within a fortnight. I found that nearly all of the mines
on the Rand are managed by Americans, and that the
mine-owners, who are nearly all English or German,
preferred them to any other nationality, which struck me
as being very complimentary to the administrative and
mechanical abilities of our people. One of these
American mine-managers drove forty miles in his motor-
car so as to shake hands with me, merely because he
had learned in a roundabout way that I came from the
same part of New York State as himself, while another
fellow-countryman, who had made a great fortune
during the Boer War by contracting to wash the clothes
of the British army, and received war-time prices for his
work, kidnapped me from the hotel where I was
staying, and landed me, baggage and all, in his home,
and actually felt affronted when I tried to leave after a
week.
 Few places could be more unlike Johannesburg than
Pretoria, the new capital of the Union, only thirty miles
away. It is as different from the “golden city” as sleepy
Bruges is from bustling Antwerp; as Tarrytown, New
York, is from Paterson, New Jersey. At first sight I was
surprised to find so English a town, but after I had
strolled in the shade of the wooden arcades formed by
the broad verandas of the shops I decided that the
atmosphere of the city was Indian; the rows of mud-
bespattered saddle-horses tied to hitching-posts along
the main streets and the rural produce being sold from
wagons in the central market-place recalled our own
West; but the substantial, white-plastered houses, with
their old-fashioned stoeps, their red-brick sidewalks,
and their prim and formal gardens, finally convinced me
that the town was, after all, Dutch. Every visitor to
Pretoria goes to see Krüger's house, the low,
whitewashed dwelling with the white lions on the stoep,
where the stubborn old President used to sit, smoking
his long pipe and drinking his black coffee and giving
parental advice to his people. Across the way is the old
Dutch church where he used to hold forth on Sundays,
with the gold hands still missing from the clock-face on
its steeple, for in the last days of the South African
Republic they were melted down and went to swell the
slender war-chest of the Boer army. In the cemetery
hard by the crafty, indomitable old man lies buried,
while the hated flag against which he fought so long
flies over the capital where he collected his guns and
hatched his schemes of conquest, and within sight of
his black-marble tomb there are rising in brick and stone
the great new buildings which mark Pretoria as the
capital of a united South Africa.
Thirty miles northward across the veldt from Pretoria
is the great hole in the ground known as the Premier
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