List of Top 25 Articles of Bioinformatics

Jul Sep 2014

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Sr. No
1

Title
Hallmarks of Cancer: The Next Generation
Summary:
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks
constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling,
evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and
metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and
inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of
potential generality to this listreprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors
exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition
of hallmark traits by creating the tumor microenvironment. Recognition of the widespread applicability of these concepts will
increasingly affect the development of new means to treat human cancer.

Development and Applications of CRISPR-Cas9 for Genome Engineering

Recent advances in genome engineering technologies based on the CRISPR-associated RNA-guided endonuclease Cas9 are enabling the
systematic interrogation of mammalian genome function. Analogous to the search function in modern word processors, Cas9 can be
guided to specific locations within complex genomes by a short RNA search string. Using this system, DNA sequences within the
endogenous genome and their functional outputs are now easily edited or modulated in virtually any organism of choice. Cas9-mediated
genetic perturbation is simple and scalable, empowering researchers to elucidate the functional organization of the genome at the
systems level and establish causal linkages between genetic variations and biological phenotypes. In this Review, we describe the
development and applications of Cas9 for a variety of research or translational applications while highlighting challenges as well as future
directions. Derived from a remarkable microbial defense system, Cas9 is driving innovative applications from basic biology to
biotechnology and medicine.
Comparison of aroma active and sulfur volatiles in three fragrant rice cultivars using GC-Olfactometry and GC-PFPD
Abstract
Aroma volatiles from three cooked fragrant rice types (Jasmine, Basmati and Jasmati) were characterised and identified using SPME GCO,
GCPFPD and confirmed using GCMS. A total of 26, 23, and 22 aroma active volatiles were observed in Jasmine, Basmati and Jasmati
cooked rice samples. 2-Acetyl-1-pyrroline was aroma active in all three rice types, but the sulphur-based, cooked rice character impact
volatile, 2-acetyl-2-thiazoline was aroma active only in Jasmine rice. Five additional sulphur volatiles were found to have aroma activity:

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dimethyl sulphide, 3-methyl-2-butene-1-thiol, 2-methyl-3-furanthiol, dimethyl trisulphide, and methional. Other newly-reported aroma
active rice volatiles were geranyl acetate, -damascone, -damascenone, and -ionone, contributing nutty, sweet floral attributes to
the aroma of cooked aromatic rice. The first two principal components from the principal component analysis of sulphur volatiles
explained 60% of the variance. PC1 separated Basmati from the other two cultivars and PC2 completely separated Jasmine from Jasmati
cultivars.
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Single-Cell Phenotyping within Transparent Intact Tissue through Whole-Body Clearing

Summary
Understanding the structure-function relationships at cellular, circuit, and organ-wide scale requires 3D anatomical and phenotypical
maps, currently unavailable for many organs across species. At the root of this knowledge gap is the absence of a method that enables
whole-organ imaging. Herein, we present techniques for tissue clearing in which whole organs and bodies are rendered macromoleculepermeable and optically transparent, thereby exposing their cellular structure with intact connectivity. We describe PACT
(passive clarity technique), a protocol for passive tissue clearing and immunostaining of intact organs; RIMS
(refractive index matching solution), a mounting media for imaging thick tissue; and PARS (perfusion-assisted agent release in situ), a
method for whole-body clearing and immunolabeling. We show that in rodents PACT, RIMS, and PARS are compatible with endogenousfluorescence, immunohistochemistry, RNA single-molecule FISH, long-term storage, and microscopy with cellular and subcellular
resolution. These methods are applicable for high-resolution, high-content mapping and phenotyping of normal and pathological
elements within intact organs and bodies.

YAP/TAZ Incorporation in the @b-Catenin Destruction Complex Orchestrates the Wnt Response
Summary
The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying
mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of
the -catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from
the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are
required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are
essential for -TrCP recruitment to the complex and -catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is
instrumental for Wnt/-catenin signaling. In line, the -catenin-dependent maintenance of ES cells in an undifferentiated state is
sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and
tumor suppression.

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CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling

Summary
CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of
Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using
adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells.
Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung
adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homologydirected repair-mediated KrasG12D mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results
suggest that Cas9 mice empower a wide range of biological and disease modeling applications.

KRAS and YAP1 Converge to Regulate EMT and Tumor Survival

Summary
Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular
basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic
RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an
inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional
coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell
transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling.
KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelialmesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of
oncogenic RAS signaling.

Metal-organic coordination polymers based on imidazolyl- and benzimidazolyl-containing 4,4'-bipy typeligands

Abstract
Two new semirigid ligands 2,2-bis(imidazol-1-ylmethyl)-4,4-bis(4-pyridyl)biphenyl(L1) and 2,2-bis(benzimidazol-1-ylmethyl)-4,4bis(4-pyridyl)biphenyl(L2) were designed and synthesized. Six new coordination compounds, {Cd(L1)Br2}n (1), {Cd(L1)(1,2bdc)(H2O)H2O}n (2), {Zn(L1) (1,3-bdc)2.7H2O}n(3), {Co(L1)(1,3-bdc)H2O}n (4), (1,2-bdc = 1,2-benzenedicarboxylate, 1,3-bdc = 1,3benzenedicarboxylate, {Cd(L2)2(NO3)22H2O}n (5) and, [Ni(L2)2(H2O)2](ClO4)23H2O (6) based on them were obtained and characterized
by single-crystal X-ray diffraction methods. 1 is a 2D infinite spongy cushion-like network. In 2, two bridging 1,2-bdc anions chelate two
neighboring Cd(II) atoms with their carboxylate groups to form a 1D double chain. 3 displays a 2D network in which the wavelike {Zn(1,3bdc2)}n chains are linked to each other by bidentate L1. 4 adopts a unique 3D framework, in which the coplanar {Co(1,3-bdc2)}n chains
are connected to each other through tridentate L1. 5 features a 1D double chain motif composed of a square bimetallic ring as the

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building block. 6 is mononuclear nickel complex. The photoluminescence properties of L1L2, 13 and 5 were investigated, and all of them
exhibit intense fluorescent emissions in the solid state at room temperature.
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Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors

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Summary
Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with
embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent
stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture
conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the
morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice
resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to
mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by
the addition of only a few defined factors.
The Hallmarks of Cancer
After a quarter century of rapid advances, cancer research has generated a rich and complex body of knowledge, revealing cancer to be a
disease involving dynamic changes in the genome. The foundation has been set in the discovery of mutations that produce oncogenes
with dominant gain of function and tumor suppressor genes with recessive loss of function; both classes of cancer genes have been
identified through their alteration in human and animal cancer cells and by their elicitation of cancer phenotypes in experimental models
(Bishop and Weinberg 1996).
Some would argue that the search for the origin and treatment of this disease will continue over the next quarter century in much the
same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex almost
beyond measure. But we anticipate otherwise: those researching the cancer problem will be practicing a dramatically different type of
science than we have experienced over the past 25 years. Surely much of this change will be apparent at the technical level. But
ultimately, the more fundamental change will be conceptual.

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A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation
Summary
DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme
A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional
in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis
of acetyl-CoA and acetylation of core histones. Nuclear PDC levels increased in a cell-cycle-dependent manner and in response to serum,
epidermal growth factor, or mitochondrial stress; this was accompanied by a corresponding decrease in mitochondrial PDC levels,

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suggesting a translocation from the mitochondria to the nucleus. Inhibition of nuclear PDC decreased acetylation of specific lysine
residues on histones important for G1-S phase progression and expression of S phase markers. Dynamic translocation of mitochondrial
PDC to the nucleus provides a pathway for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.
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Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis
Summary
Circulating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not
well defined. Using mouse models with tagged mammary tumors, we demonstrate that CTC clusters arise from oligoclonal tumor cell
groupings and not from intravascular aggregation events. Although rare in the circulation compared with single CTCs, CTC clusters
have 23- to 50-fold increased metastatic potential. In patients with breast cancer, single-cell resolution RNA sequencing of CTC clusters
and single CTCs, matched within individual blood samples, identifies the cell junction component plakoglobin as highly differentially
expressed. In mouse models, knockdown of plakoglobin abrogates CTC cluster formation and suppresses lung metastases. In breast cancer
patients, both abundance of CTC clusters and high tumor plakoglobin levels denote adverse outcomes. Thus, CTC clusters are derived from
multicellular groupings of primary tumor cells held together through plakoglobin-dependent intercellular adhesion, and though rare, they
greatly contribute to the metastatic spread of cancer.

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H3K4me3 Breadth Is Linked to Cell Identity and Transcriptional Consistency

Summary
Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to mark the transcription start sites of active genes.
Here, we show that H3K4me3 domains that spread more broadly over genes in a given cell type preferentially mark genes that are
essential for the identity and function of that cell type. Using the broadest H3K4me3 domains as a discovery tool in neural progenitor
cells, we identify novel regulators of these cells. Machine learning models reveal that the broadest H3K4me3 domains represent a distinct
entity, characterized by increased marks of elongation. The broadest H3K4me3 domains also have more paused polymerase at their
promoters, suggesting a unique transcriptional output. Indeed, genes marked by the broadest H3K4me3 domains exhibit enhanced
transcriptional consistency rather than increased transcriptional levels, and perturbation of H3K4me3 breadth leads to changes in
transcriptional consistency. Thus, H3K4me3 breadth contains information that could ensure transcriptional precision at key cell
identity/function genes.

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Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development

Summary
Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited
success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated

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gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events
were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients
bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal
complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of
expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our
findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development
and enteric innervation.
15

CellNet: Network Biology Applied to Stem Cell Engineering

Summary
Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages
represent powerful approaches to engineer cells for research and regenerative medicine. We have developed CellNet, a network biology
platform that more accurately assesses the fidelity of cellular engineering than existing methodologies and generates hypotheses for
improving cell derivations. Analyzing expression data from 56 published reports, we found that cells derived via directed differentiation
more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell-type
gene regulatory networks (GRNs). Furthermore, we discovered that directly converted cells fail to adequately silence expression programs
of the starting population and that the establishment of unintended GRNs is common to virtually every cellular engineering paradigm.
CellNet provides a platform for quantifying how closely engineered cell populations resemble their target cell type and a rational strategy
to guide enhanced cellular engineering.

16

MicroRNA Directly Enhances Mitochondrial Translation during Muscle Differentiation

Summary
MicroRNAs are well known to mediate translational repression and mRNA degradation in the cytoplasm. Various microRNAs have also
been detected in membrane-compartmentalized organelles, but the functional significance has remained elusive. Here, we report that
miR-1, a microRNA specifically induced during myogenesis, efficiently enters the mitochondria where it unexpectedly stimulates, rather
than represses, the translation of specific mitochondrial genome-encoded transcripts. We show that this positive effect requires specific
miR:mRNA base-pairing and Ago2, but not its functional partner GW182, which is excluded from the mitochondria. We provide evidence
for the direct action of Ago2 in mitochondrial translation by crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq),
functional rescue with mitochondria-targeted Ago2, and selective inhibition of the microRNA machinery in the cytoplasm. These findings
unveil a positive function of microRNA in mitochondrial translation and suggest a highly coordinated myogenic program via miR-1mediated translational stimulation in the mitochondria and repression in the cytoplasm.

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17

Starvation-Induced Transgenerational Inheritance of Small RNAs in C. elegans

Summary
Evidence from animal studies and human famines suggests that starvation may affect the health of the progeny of famished individuals.
However, it is not clear whether starvation affects only immediate offspring or has lasting effects; it is also unclear how such epigenetic
information is inherited. Small RNA-induced gene silencing can persist over several generations via transgenerationally inherited small
RNA molecules in C. elegans, but all known transgenerational silencing responses are directed against foreign DNA introduced into the
organism. We found that starvation-induced developmental arrest, a natural and drastic environmental change, leads to the generation of
small RNAs that are inherited through at least three consecutive generations. These small, endogenous, transgenerationally transmitted
RNAs target genes with roles in nutrition. We defined genes that are essential for this multigenerational effect. Moreover, we show that
the F3 offspring of starved animals show an increased lifespan, corroborating the notion of a transgenerational memory of past
conditions.

18

Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Summary
Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human
pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for
sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms
of KrasG12Dindependent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of
KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the
transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12Dindependent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and
DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of
escape from oncogenic Kras addiction in PDAC.

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Natural Neural Projection Dynamics Underlying Social Behavior

Summary
Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological
studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity
during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record
natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in
mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc)
projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic

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control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1
dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a
fundamental and previously inaccessible dimension of mammalian circuit dynamics.
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Using Targeted Chromatin Regulators to Engineer Combinatorial and Spatial Transcriptional Regulation
Summary
The transcription of genomic information in eukaryotes is regulated in large part by chromatin. How a diverse array of chromatin regulator
(CR) proteins with different functions and genomic localization patterns coordinates chromatin activity to control transcription remains
unclear. Here, we take a synthetic biology approach to decipher the complexity of chromatin regulation by studying emergent
transcriptional behaviors from engineered combinatorial, spatial, and temporal patterns of individual CRs. We fuse 223 yeast CRs to
programmable zinc finger proteins. Site-specific and combinatorial recruitment of CRs to distinct intralocus locations reveals a range of
transcriptional logic and behaviors, including synergistic activation, long-range and spatial regulation, and gene expression memory.
Comparing these transcriptional behaviors with annotated CR complex and function terms provides design principles for the engineering
of transcriptional regulation. This work presents a bottom-up approach to investigating chromatin-mediated transcriptional regulation
and introduces chromatin-based components and systems for synthetic biology and cellular engineering.

21

Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors
Summary
In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic
and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship
links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in
mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the
nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition
onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that
different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific
striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology.

22

Genome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia
Summary
Notch signaling is a key developmental pathway that is subject to frequent genetic and epigenetic perturbations in many different human
tumors. Here we investigate whether long noncoding RNA (lncRNA) genes, in addition to mRNAs, are key downstream targets of

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oncogenic Notch1 in human T cell acute lymphoblastic leukemia (T-ALL). By integrating transcriptome profiles with chromatin state maps,
we have uncovered many previously unreported T-ALL-specific lncRNA genes, a fraction of which are directly controlled by the
Notch1/Rpbj activator complex. Finally we have shown that one specific Notch-regulated lncRNA, LUNAR1, is required for efficient TALL growth in vitro and in vivo due to its ability to enhanceIGF1R mRNA expression and sustain IGF1 signaling. These results confirm that
lncRNAs are important downstream targets of the Notch signaling pathway, and additionally they are key regulators of the oncogenic
state in T-ALL.
23

Drug Resistance via Feedback Activation of Stat3 in Oncogene-Addicted Cancer Cells

Summary
Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We
found that many drug-treated oncogene-addicted cancer cells engage a positive feedback loop leading to Stat3 activation,
consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated
kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via
the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These
findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of
oncogene addiction.

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A Systematic Analysis of Biosynthetic Gene Clusters in the Human Microbiome Reveals a Common Family of Antibiotics
Summary
In complex biological systems, small molecules often mediate microbe-microbe and microbe-host interactions. Using a systematic
approach, we identified 3,118 small-molecule biosynthetic gene clusters (BGCs) in genomes of human-associated bacteria and studied
their representation in 752 metagenomic samples from the NIH Human Microbiome Project. Remarkably, we discovered that BGCs for a
class of antibiotics in clinical trials, thiopeptides, are widely distributed in genomes and metagenomes of the human microbiota. We
purified and solved the structure of a thiopeptide antibiotic, lactocillin, from a prominent member of the vaginal microbiota. We
demonstrate that lactocillin has potent antibacterial activity against a range of Gram-positive vaginal pathogens, and we show that
lactocillin and other thiopeptide BGCs are expressed in vivo by analyzing human metatranscriptomic sequencing data. Our findings
illustrate the widespread distribution of small-molecule-encoding BGCs in the human microbiome, and they demonstrate the bacterial
production of drug-like molecules in humans.

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25

Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man
Summary
Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and
the molecular determinants of healthy versus unhealthy obesity remain ill-defined. Chronic metabolic inflammation
(metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the
development of metabolic disease. Surprisingly, in matched biopsies from healthy versus insulin-resistant obese subjects we find HO1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional
HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease
such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing
and NF-B amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential
therapeutic strategy for metabolic disease.

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