snu-aidas/HVMap-dataset huggingface dataset:
Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectal cancer.

PURPOSE The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer. EXPERIMENTAL DESIGN Three colorectal cancer cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examine changes in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-based regimens. RESULTS Bmal1 overexpression inhibited colorectal cancer cell proliferation and increased colorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P = 0.043). The progression-free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; P = 0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2-M arrest by activating the ATM pathway. CONCLUSION Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.
Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape

Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.
The Effect of Submaximal Exercise Preceded by Single Whole-Body Cryotherapy on the Markers of Oxidative Stress and Inflammation in Blood of Volleyball Players

The aim of the study was to determine the effect of single whole-body cryotherapy (WBC) session applied prior to submaximal exercise on the activity of antioxidant enzymes, the concentration of lipid peroxidation products, total oxidative status, and the level of cytokines in blood of volleyball players. The study group consisted of 18 male professional volleyball players, who were subjected to extremely cold air (-130°C) prior to exercise performed on cycloergometer. Blood samples were taken five times: before WBC, after WBC procedure, after exercise preceded by cryotherapy (WBC exercise), and before and after exercise without WBC (control exercise). The activity of catalase statistically significantly increased after control exercise. Moreover, the activity of catalase and superoxide dismutase was lower after WBC exercise than after control exercise (P < 0.001). After WBC exercise, the level of IL-6 and IL-1β was also lower (P < 0.001) than after control exercise. The obtained results may suggest that cryotherapy prior to exercise may have some antioxidant and anti-inflammatory properties. The relations between the level of studied oxidative stress and inflammatory markers may testify to the contribution of reactive oxygen species in cytokines release into the blood system in response to exercise and WBC.
Incidence of childhood distal forearm fractures over 30 years: a population-based study.

CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth. Changes in physical activity or diet may therefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present. Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase.
Aluminum fluoride stimulates surface protrusions in cells overexpressing the ARF6 GTPase

To study the effector function of the ADP- ribosylation factor (ARF) 6 GTP-binding protein, we transfected HeLa cells with wild-type, epitope-tagged ARF6. Previously shown to indirectly activate the ARF1 GTPase, aluminum fluoride (AIF) treatment of ARF6-transfected cells resulted in a redistribution of both ARF6 and actin to discrete sites on the plasma membrane, which became increasingly protrusive over time. The effects of AIF were reversible, specific to cells transfected with wild-type ARF6, and resembled the cellular protrusions observed in cells expressing the GTPase defective mutant of ARF6. Importantly, the protrusions observed in cells transfected with ARF6 were distinct from the enhanced stress fibers and membrane ruffles observed in cells transfected with RhoA and Rac1, respectively. In cells forming protrusions, there was an apparent stimulation of macropinocytosis and membrane recycling within the protrusive structures. In contrast, no block in transferrin uptake or alteration of the distribution of clathrin AP-2 complexes was detected in these cells. The AIF-induced, ARF6- dependent formation of protrusive structures was blocked by cytochalasin D and inhibitors of the lipoxygenase pathway. These observations support a novel role for the ARF6 GTPase in modeling the plasma membrane and underlying cytoskeleton.
HIV–1 Infects Multipotent Progenitor Cells Causing Cell Death and Establishing Latent Cellular Reservoirs

HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.
The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage

It is well known that upon stress, the level of the tumor suppressor p53 is remarkably elevated. However, despite extensive studies, the underlying mechanism involving important inter-players for stress-induced p53 regulation is still not fully understood. We present evidence that the human lincRNA-RoR (RoR) is a strong negative regulator of p53. Unlike MDM2 that causes p53 degradation through the ubiquitin-proteasome pathway, RoR suppresses p53 translation through direct interaction with the heterogeneous nuclear ribonucleoprotein I (hnRNP I). Importantly, a 28-base RoR sequence carrying hnRNP I binding motifs is essential and sufficient for p53 repression. We further show that RoR inhibits p53-mediated cell cycle arrest and apoptosis. Finally, we demonstrate a RoR-p53 autoregulatory feedback loop where p53 transcriptionally induces RoR expression. Together, these results suggest that the RoR-hnRNP I-p53 axis may constitute an additional surveillance network for the cell to better respond to various stresses.
Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock).

The increase in lactate (L) and pyruvate (P) content of arterial blood during experimental and clinical shock states and the extent to which such increases serve as measures of oxygen deficit and irreversible injury were investigated on an empirical basis. A standardized method for production of hemorrhagic shock in the Wistar rat was employed. During a 4-hour bleeding period, oxygen consumption of the rat was reduced to approximately 40% of control value, pH was reduced from 7.39 to 7.08, and a concurrent increase in L from 0.80 to 6.06 mm and in P from 0.07 to 0.18 mm were observed. Cumulative oxygen debt correlated with log L (r = 0.50; P < 0.0005) and both were significantly related to survival. Correlation of cumulative oxygen debt and survival, both with P and with computed values of the lactate pyruvate ratio (L/P) and excess lactate (XL), were of no higher magnitude. Partial correlation analysis demonstrated that neither the measurement of P nor the computation of L/P or XL improved predictability...
Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis

The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2.
position-specific gap penalties

The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.
Pedestrian Detection via Periodic Motion Analysis

We describe algorithms for detecting pedestrians in videos acquired by infrared (and color) sensors. Two approaches are proposed based on gait. The first employs computationally efficient periodicity measurements. Unlike other methods, it estimates a periodic motion frequency using two cascading hypothesis testing steps to filter out non-cyclic pixels so that it works well for both radial and lateral walking directions. The extraction of the period is efficient and robust with respect to sensor noise and cluttered background. In order to integrate shape and motion, we convert the cyclic pattern into a binary sequence by Maximal Principal Gait Angle (MPGA) fitting in the second method. It does not require alignment and continuously estimates the period using a Phase-locked Loop. Both methods are evaluated by experimental results that measure performance as a function of size, movement direction, frame rate and sequence length.
Changing geographic ranges of ticks and tick-borne pathogens: drivers, mechanisms and consequences for pathogen diversity

The geographic ranges of ticks and tick-borne pathogens are changing due to global and local environmental (including climatic) changes. In this review we explore current knowledge of the drivers for changes in the ranges of ticks and tick-borne pathogen species and strains via effects on their basic reproduction number (R 0), and the mechanisms of dispersal that allow ticks and tick-borne pathogens to invade suitable environments. Using the expanding geographic distribution of the vectors and agent of Lyme disease as an example we then investigate what could be expected of the diversity of tick-borne pathogens during the process of range expansion, and compare this with what is currently being observed. Lastly we explore how historic population and range expansions and contractions could be reflected in the phylogeography of ticks and tick-borne pathogens seen in recent years, and conclude that combined study of currently changing tick and tick-borne pathogen ranges and diversity, with phylogeographic analysis, may help us better predict future patterns of invasion and diversity.
Trimmomatic: a flexible trimmer for Illumina sequence data

MOTIVATION Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. RESULTS The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. AVAILABILITY AND IMPLEMENTATION Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic   CONTACT usadel@bio1.rwth-aachen.de   SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
The Public Health Responsibility Deal: brokering a deal for public health, but on whose terms?

UNLABELLED Coalitions of multinational food and drink businesses have pledged to reformulate their products and to market them responsibly. Largely business-led and self-regulated, the integrity of these voluntary initiatives has been questioned. The Public Health Responsibility Deal in England is an example of a voluntary initiative that is government-led. Does this approach provide evidence that with public leadership there is potential for voluntary actions to deliver meaningful results for public health? METHODS The subject of the research is the calorie reduction initiative of the Responsibility Deal. Source material was obtained primarily through a series of UK Freedom of Information requests and comprises previously unpublished Department of Health documentation relating to relevant meetings held during 2011 and 2012. RESULTS The Responsibility Deal approach to calorie reduction deliberately involves the food industry in the specification of the measures it is to implement (reformulation and portion control). Finding the common ground between private and public interests has resulted in the deflection of public health objectives and the preclusion of adequate monitoring and evaluation. CONCLUSIONS The Responsibility Deal approach is fundamentally flawed in its expectation that industry will take voluntary actions that prioritise public health interests above its own. Being government-led counts for little in the absence of sanctions to drive compliance. Instead the initiative affords private interests the opportunity to influence in their favour the public health policies and strategies that affect their products.
Thawing Frozen Robust Multi-array Analysis (fRMA)

BACKGROUND A novel method of microarray preprocessing--Frozen Robust Multi-array Analysis (fRMA)--has recently been developed. This algorithm allows the user to preprocess arrays individually while retaining the advantages of multi-array preprocessing methods. The frozen parameter estimates required by this algorithm are generated using a large database of publicly available arrays. Curation of such a database and creation of the frozen parameter estimates is time-consuming; therefore, fRMA has only been implemented on the most widely used Affymetrix platforms. RESULTS We present an R package, frmaTools, that allows the user to quickly create his or her own frozen parameter vectors. We describe how this package fits into a preprocessing workflow and explore the size of the training dataset needed to generate reliable frozen parameter estimates. This is followed by a discussion of specific situations in which one might wish to create one's own fRMA implementation. For a few specific scenarios, we demonstrate that fRMA performs well even when a large database of arrays in unavailable. CONCLUSIONS By allowing the user to easily create his or her own fRMA implementation, the frmaTools package greatly increases the applicability of the fRMA algorithm. The frmaTools package is freely available as part of the Bioconductor project.
Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance

T cell homeostasis is crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatory T cells or an inability to shut down immune responses can lead to inflammation and autoimmune pathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of terminal B cell differentiation, was expressed in a subset of antigen-experienced CD4+ and CD8+ T cells. Mice reconstituted with fetal liver stem cells expressing a mutant Blimp-1 lacking the DNA-binding domain developed a lethal multiorgan inflammatory disease caused by an accumulation of effector and memory T cells. These data identify Blimp-1 as an essential regulator of T cell homeostasis and suggest that Blimp-1 regulates both B cell and T cell differentiation.
Nuclear repositioning of the VSG promoter during developmental silencing in Trypanosoma brucei

Interphase nuclear repositioning of chromosomes has been implicated in the epigenetic regulation of RNA polymerase (pol) II transcription. However, little is known about the nuclear position–dependent regulation of RNA pol I–transcribed loci. Trypanosoma brucei is an excellent model system to address this question because its two main surface protein genes, procyclin and variant surface glycoprotein (VSG), are transcribed by pol I and undergo distinct transcriptional activation or downregulation events during developmental differentiation. Although the monoallelically expressed VSG locus is exclusively localized to an extranucleolar body in the bloodstream form, in this study, we report that nonmutually exclusive procyclin genes are located at the nucleolar periphery. Interestingly, ribosomal DNA loci and pol I transcription activity are restricted to similar perinucleolar positions. Upon developmental transcriptional downregulation, however, the active VSG promoter selectively undergoes a rapid and dramatic repositioning to the nuclear envelope. Subsequently, the VSG promoter region was subjected to chromatin condensation. We propose a model whereby the VSG expression site pol I promoter is selectively targeted by temporal nuclear repositioning during developmental silencing.