Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice to infection with virulent Mycobacterium tuberculosis

The superior resistance of some strains of mice over others to infection with certain intracellular pathogens, including the vaccine strain of Mycobacterium bovis, bacillus Calmette Guerin (BCG), is determined by a gene associated with a small segment of chromosome 1 designated by Ity/Lsh/Bcg locus, referred to here as the Bcg locus. DBA/2 mice containing the dominant resistant allele of the Bcg gene (Bcgr), major histocompatibility complex-compatible BALB/c mice containing the recessive susceptible allele (Bcgs), and congenic C.D2- N20 Bcgr, which are genetically the same as BALB/c mice except for possessing a small piece of DBA/2 chromosome 1 containing the Bcg locus, were used to determine whether the Bcg gene determines resistance to infection with the virulent H37Rv strain of Mycobacterium tuberculosis (Mtb). According to the survival times of Bcgr and Bcgs mice infected via either the intravenous or respiratory route, Bcgr mice proved much less, rather than more, resistant to Mtb infection than Bcgs mice. Shorter survival times of Bcgr mice were associated with an inferior capacity to control Mtb growth in their lungs and to retard the development of Mtb-induced pathology in this organ. Resistance to Mtb infection was a dominant trait in the F1 progeny of Bcgr and Bcgs mice. The results show that resistance to Mtb is not determined by the resistance allele of the Bcg gene nor by the recently isolated candidate Bcg gene Nramp1, located in the Bcg locus.
Life-event stress induced by the Great East Japan Earthquake was associated with relapse in ulcerative colitis but not Crohn's disease: a retrospective cohort study

Objective Stress is thought to be one of the triggers of relapses in patients with inflammatory bowel disease (IBD). We examined the rate of relapse in IBD patients before and after the Great East Japan Earthquake. Design A retrospective cohort study. Settings 13 hospitals in Japan. Participants 546 ulcerative colitis (UC) and 357 Crohn's disease (CD) patients who received outpatient and inpatient care at 13 hospitals located in the area that were seriously damaged by the earthquake. Data on patient's clinical characteristics, disease activity and deleterious effects of the earthquake were obtained from questionnaires and hospital records. Primary outcome We evaluated the relapse rate (from inactive to active) across two consecutive months before and two consecutive months after the earthquake. In this study, we defined ‘active’ as conditions with a partial Mayo score=2 or more (UC) or a Harvey-Bradshaw index=6 or more (CD). Results Among the UC patients, disease was active in 167 patients and inactive in 379 patients before the earthquake. After the earthquake, the activity scores increased significantly (p<0.0001). A total of 86 patients relapsed (relapse rate=15.8%). The relapse rate was about twice that of the corresponding period in the previous year. Among the CD patients, 86 patients had active disease and 271 had inactive disease before the earthquake. After the earthquake, the activity indices changed little. A total of 25 patients experienced a relapse (relapse rate=7%). The relapse rate did not differ from that of the corresponding period in the previous year. Multivariate analyses revealed that UC, changes in dietary oral intake and anxiety about family finances were associated with the relapse. Conclusions Life-event stress induced by the Great East Japan Earthquake was associated with relapse in UC but not CD.
EyeTab: model-based gaze estimation on unmodified tablet computers

Despite the widespread use of mobile phones and tablets, hand-held portable devices have only recently been identified as a promising platform for gaze-aware applications. Estimating gaze on portable devices is challenging given their limited computational resources, low quality integrated front-facing RGB cameras, and small screens to which gaze is mapped. In this paper we present EyeTab, a model-based approach for binocular gaze estimation that runs entirely on an unmodified tablet. EyeTab builds on set of established image processing and computer vision algorithms and adapts them for robust and near-realtime gaze estimation. A technical prototype evaluation with eight participants in a normal indoors office setting shows that EyeTab achieves an average gaze estimation accuracy of 6.88° of visual angle at 12 frames per second.
Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.

IMPORTANCE Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95% CI, 1.93%-3.48%] vs human controls, 7.17% [95% CI, 5.91%-8.44%] vs elephants, 14.64% [95% CI, 10.91%-18.37%]; P < .001; doxorubicin exposure: human controls, 8.10% [95% CI, 6.55%-9.66%] vs elephants, 24.77% [95% CI, 23.0%-26.53%]; P < .001). CONCLUSIONS AND RELEVANCE Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.
Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma

Purpose: Inhibition of the proteasome leads to the activation of survival pathways in addition to those that promote cell death. We hypothesized that down-regulation of interleukin-6 (IL-6) signaling using the monoclonal antibody CNTO 328 would enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance. Experimental Design: The cytotoxicity of bortezomib, CNTO 328, and the combination, along with the associated molecular changes, was assessed in IL-6–dependent and IL-6–independent multiple myeloma cell lines, both in suspension and in the presence of bone marrow stromal cells and in patient-derived myeloma samples. Results: Treatment of IL-6–dependent and IL-6–independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion. This effect was additive to synergistic and was preserved in the presence of bone marrow stromal cells and in CD138+ myeloma samples derived from patients with relative clinical resistance to bortezomib. CNTO 328 potentiated bortezomib-mediated activation of caspase-8 and caspase-9 and the common downstream effector caspase-3; attenuated bortezomib-mediated induction of antiapoptotic heat shock protein-70, which correlated with down-regulation of phosphorylated signal transducer and activator of transcription-1; and inhibited bortezomib-mediated accumulation of myeloid cell leukemia-1, an effect that was associated with down-regulation of phosphorylated signal transducer and activator of transcription-3. Conclusions: Taken together, our results provide a strong preclinical rationale for the clinical development of the bortezomib/CNTO 328 combination for patients with myeloma.
How bank business models drive interest margins: evidence from US bank-level data

The two decades prior to the credit crisis witnessed a strategic shift from a traditional, relationships-oriented model (ROM) to a transactions-oriented model (TOM) of financial intermediation in developed countries. A concurrent trend has been a persistent decline in average bank interest margins. In the literature, these phenomena are often explained using a causality that runs from increased competition in traditional segments to lower margins to new activities. Using a comprehensive data set with bank-level data on over 16,000 Federal Deposit Insurance Corporation-insured US commercial banks for a period ranging from 1992 to 2010, this paper qualifies this chain of causality. We find that a bank's business model, measured using a multi-dimensional proxy of relationship banking activity, exerts a strong, positive effect on interest margins. Our results suggest that the strategic shift from ROM to TOM has transformed banks’ balance sheets and reduced interest rate margins as a by-product.
Violation of Kirchhoff's Laws for a Coherent RC Circuit

What is the complex impedance of a fully coherent quantum resistance-capacitance (RC) circuit at gigahertz frequencies in which a resistor and a capacitor are connected in series? While Kirchhoff's laws predict addition of capacitor and resistor impedances, we report on observation of a different behavior. The resistance, here associated with charge relaxation, differs from the usual transport resistance given by the Landauer formula. In particular, for a single-mode conductor, the charge-relaxation resistance is half the resistance quantum, regardless of the transmission of the mode. The new mesoscopic effect reported here is relevant for the dynamical regime of all quantum devices.
Effect of acute acid-base disturbances on the phosphorylation of phospholipase C-γ1 and Erk1/2 in the renal proximal tubule

The renal proximal tubule (PT) plays a major role in whole‐body pH homeostasis by secreting H+ into the tubule lumen. Previous work demonstrated that PTs respond to basolateral changes in [CO2] and [ HCO3− ] by appropriately altering H+ secretion—responses blocked by the ErbB inhibitor PD168393, or by eliminating signaling through AT1 angiotensin receptors. In the present study, we analyze phosphorylation of three downstream targets of both ErbBs and AT1: phospholipase C‐γ1 (PLC‐γ1), extracellular‐regulated kinase 1 (Erk1), and Erk2. We expose rabbit PT suspensions for 5 and 20 min to our control (Ctrl) condition (5% CO2, 22 mmol/L HCO3− , pH 7.40) or one of several conditions that mimic acid‐base disturbances. We found that each disturbance produces characteristic phosphorylation patterns in the three enzymes. For example, respiratory acidosis (elevated [CO2], normal [ HCO3− ]) at 20 min decreases PLC‐γ1 phosphorylation at tyrosine‐783 (relative to Ctrl). Metabolic acidosis (normal [CO2], decreased [ HCO3− ]) for 5 min increases Erk1 phosphorylation (p‐Erk1) but not p‐Erk2, whereas metabolic alkalosis (normal [CO2], elevated [ HCO3− ]) for 5 min decreases p‐Erk1 and p‐Erk2. In the presence of CO2/ HCO3− , PD168393 blocks only two of eight induced decreases in phosphorylation. In two cases in which disturbances have no remarkable effects on phosphorylation, PD168393 unmasks decreases and in two others, increases. These drug effects provide insight into the roles of PD168393‐sensitive kinases. Our results indicate that PLC‐γ1. pY783, p‐Erk1, and p‐Erk2 in the PT change in characteristic ways in response to acute acid‐base disturbances, and thus presumably contribute to the transduction of acid‐base signals.
The New Perspectives on Genetic Studies of Type 2 Diabetes and Thyroid Diseases

Recently, genome-wide association studies (GWAS) have led to the discovery of hundreds of susceptibility loci that are associated with complex metabolic diseases, such as type 2 diabetes and hyperthyroidism. The majority of the susceptibility loci are common across different races or populations; while some of them show ethnicity-specific distribution. Though the abundant novel susceptibility loci identified by GWAS have provided insight into biology through the discovery of new genes or pathways that were previously not known, most of them are in introns and the associated variants cumulatively explain only a small fraction of total heritability. Here we reviewed the genetic studies on the metabolic disorders, mainly type 2 diabetes and hyperthyroidism, including candidate genes-based findings and more recently the GWAS discovery; we also included the clinical relevance of these novel loci and the gene-environmental interactions. Finally, we discussed the future direction about the genetic study on the exploring of the pathogenesis of the metabolic diseases.
Deciding Hyperproperties

Hyperproperties, like observational determinism or symmetry, cannot be expressed as properties of individual computation traces, because they describe a relation between multiple computation traces. HyperLTL is a temporal logic that captures such relations through trace variables, which are introduced through existential and universal trace quantifiers and can be used to refer to multiple computations at the same time. In this paper, we study the satisfiability problem of HyperLTL. We show that the problem is PSPACE-complete for alternation-free formulas (and, hence, no more expensive than LTL satisfiability), EXPSPACE-complete for exists-forall-formulas, and undecidable for forall-exists-formulas. Many practical hyperproperties can be expressed as alternation-free formulas. Our results show that both satisfiability and implication are decidable for such properties.
Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism

The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased β-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.
Consensus-degenerate hybrid oligonucleotide primers for amplification of distantly related sequences.

We describe a new primer design strategy for PCR amplification of unknown targets that are related to multiply-aligned protein sequences. Each primer consists of a short 3' degenerate core region and a longer 5' consensus clamp region. Only 3-4 highly conserved amino acid residues are necessary for design of the core, which is stabilized by the clamp during annealing to template molecules. During later rounds of amplification, the non-degenerate clamp permits stable annealing to product molecules. We demonstrate the practical utility of this hybrid primer method by detection of diverse reverse transcriptase-like genes in a human genome, and by detection of C5DNA methyltransferase homologs in various plant DNAs. In each case, amplified products were sufficiently pure to be cloned without gel fractionation. This COnsensus-DEgenerate Hybrid Oligonucleotide Primer (CODEHOP) strategy has been implemented as a computer program that is accessible over the World Wide Web (http://blocks.fhcrc.org/codehop.html) and is directly linked from the BlockMaker multiple sequence alignment site for hybrid primer prediction beginning with a set of related protein sequences.
Prevalence and Risk Factors Associated with Prehypertension by Gender and Age in a Korean Population in the KNHANES 2010–2012

Background: Prehypertension frequently progresses into hypertension and is related to an increased risk of cardiovascular disease. We studied the prevalence of prehypertension and their determinants by gender and age. Methods: The study used nationally representative data from 11,754 participants aged 20–91 years collected between 2010–2012 Korea National Health and Nutrition Examination Surveys (KNHANES). Results: Prehypertension was more prevalent in men than women (aOR = 2.48, CI = 2.11–2.92). Aging was positively associated with prehypertension (40–59 vs. 20–39, aOR = 1.79, CI = 1.55–2.05; 60+ vs. 20–39, aOR = 2.89, CI = 2.35–3.56). In women aged ≥60, prehypertension was associated with WC (aOR = 1.04, CI = 1.00–1.07), whereas in both men and women aged 20–39, it was associated with BMI (men, aOR = 1.14, CI = 1.04–1.24; women, aOR = 1.08, CI = 1.01–1.16). In subjects aged 40–59, age (men, aOR = 1.03, CI = 1.01–1.06; women, aOR = 1.05, CI = 1.02–1.07) was the significant factor increasing the risk of prehypertension, whereas smoking (men, aOR = 0.55, CI = 0.38–0.80; women, aOR = 0.43, CI = 0.24–0.76) showed an inverse association with prehypertension. Alcohol intake showed a positive association with prehypertension in only men aged 40–59. Conclusion: Our findings suggest that different gender/age groups may have different patterns of risk factors associated with prehypertension. Thus, healthcare providers should consider both gender and age when designing community-based interventions for controlling BP and reducing prehypertension.
Real and Accrual-Based Earnings Management in the Pre- and Post-Sarbanes Oxley Periods

We document that accrual‐based earnings management increased steadily from 1987 until the passage of the Sarbanes‐Oxley Act (SOX) in 2002, followed by a significant decline after the passage of SOX. Conversely, the level of real earnings management activities declined prior to SOX and increased significantly after the passage of SOX, suggesting that firms switched from accrual‐based to real earnings management methods after the passage of SOX. We also document that the accrual‐based earnings management activities were particularly high in the period immediately preceding SOX. Consistent with these results, we find that firms that just achieved important earnings benchmarks used less accruals and more real earnings management after SOX when compared to similar firms before SOX. In addition, our analysis provides evidence that the increases in accrual‐based earnings management in the period preceding SOX were concurrent with increases in equity‐based compensation. Our results suggest that stock‐option compo.
Kernel Logistic Regression and the Import Vector Machine

The support vector machine (SVM) is known for its good performance in two-class classification, but its extension to multiclass classification is still an ongoing research issue. In this article, we propose a new approach for classification, called the import vector machine (IVM), which is built on kernel logistic regression (KLR). We show that the IVM not only performs as well as the SVM in two-class classification, but also can naturally be generalized to the multiclass case. Furthermore, the IVM provides an estimate of the underlying probability. Similar to the support points of the SVM, the IVM model uses only a fraction of the training data to index kernel basis functions, typically a much smaller fraction than the SVM. This gives the IVM a potential computational advantage over the SVM.
Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag–major histocompatibility complex (MHC) complexes to naive CD4+ T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag–MHC complexes presented by B cells were necessary to elicit the formation of a few T–B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag–MHC complexes per cell. Formation of T–DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T–DC adhesion precedes Ag recognition, whereas T–B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC–TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.