Miracle-dz/UniFAR-FTUs huggingface dataset:
Engineering of Glarea lozoyensis for Exclusive Production of the Pneumocandin B0 Precursor of the Antifungal Drug Caspofungin Acetate

ABSTRACT Pneumocandins produced by the fungus Glarea lozoyensis are acylated cyclic hexapeptides of the echinocandin family. Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate. In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization. The pneumocandin biosynthetic gene cluster was previously elucidated by a whole-genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to produce exclusively pneumocandin B0. Disruption of GLOXY4, encoding a nonheme, α-ketoglutarate-dependent oxygenase, confirmed its involvement in l-leucine cyclization to form 4S-methyl-l-proline. The absence of 4S-methyl-l-proline abolishes pneumocandin A0 production, and 3S-hydroxyl-l-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0. Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4. This one-step genetic manipulation can rationally engineer a high-yield production strain.
IL-7 Receptor Expression Levels Do Not Identify CD8+ Memory T Lymphocyte Precursors following Peptide Immunization1

Identification of the mechanisms underlying the survival of effector T cells and their differentiation into memory T lymphocytes are critically important to understanding memory development. Because cytokines regulate proliferation, differentiation, and survival of T lymphocytes, we hypothesized that cytokine signaling dictates the fate of effector T cells. To follow cytokine receptor expression during T cell responses, we transferred murine TCR transgenic T cells into naive recipients followed by immunization with peptide emulsified in adjuvant or pulsed on dendritic cells. Our findings did not correlate IL-7R α-chain and IL-2R β-chain expression on effector CD8+ cells with the generation of memory T lymphocytes. However, we could correlate the extent of IL-7Rα expression down-regulation on effector T cells with the level of inflammation generated by the immunization. Furthermore, our findings showed that the maintenance of a high level of IL-7R expression by effector T cells at the peak of the response does not preclude their death. This suggests that maintenance of IL-7R expression is not sufficient to prevent T cell contraction. Thus, our results indicate that expression of the IL-7R is not always a good marker for identifying precursors of memory T cells among effectors and that selective expression of the IL-7R by effector T cells should not be used to predict the success of vaccination.
Persistency in tourism expenditure in a small-open economy

Abstract This study aims to examine whether the shocks to the Turkish tourism have a permanent or a transitory effect on tourism expenditure for the period 1964–2012. We took the structural break periods from Lumsdaine and Papell (LP) unit-root test as a base and implemented the Augmented Dickey–Fuller unit-root test for the three different sub-periods of the series of tourism expenditure. In this study, we also estimated the measure of half-life for the effects of shocks on the series under consideration and the grid-bootstrap method to estimate confidence intervals. The results show, irrespective of the structural breaks, the effect of shocks on tourism expenditure is persistent; however, considering the structural breaks, the effect of shocks on tourism expenditure is transitory.
Protection of Neuronal Calcium Sensor 1 Protein in Cells Treated with Paclitaxel*

Paclitaxel (Taxol) is one of the most effective treatment options for patients suffering from a variety of cancers. A major side effect seen in a high percentage of patients treated with paclitaxel is irreversible peripheral neuropathy. We previously reported that prolonged treatment with paclitaxel activates a calcium-dependent enzyme, calpain, which degrades neuronal calcium sensor 1 (NCS-1) and subsequent loss of intracellular calcium signaling. Because it appears that activation of calpain is an early step in this destructive cascade, we proposed that inhibition of calpain will protect against the unwanted side effects of paclitaxel treatment. First, NCS-1 levels and intracellular calcium signaling were found to be protected by the presence of lactacystin, a protesome inhibitor. To reinforce the role of calpain in this process, we showed that increased concentrations of calpastatin, a naturally occurring calpain inhibitor, were protective. Next, we tested two mutated versions of NCS-1 developed with point mutations at the P2 position of the calpain cleavage site of NCS-1 to decrease the likelihood of NCS-1 degradation. One mutant was cleaved more favorably by calpain compared with NCS-1 WT, whereas the other mutant was less favorably cleaved. Expression of either mutated version of NCS-1 in neuroblastoma cells protected intracellular calcium signals from paclitaxel-induced changes. These results support our hypothesis that it is possible to protect cells from paclitaxel-induced degradation of NCS-1 by inhibiting calpain activity.
An assessment of the RIFLE criteria for acute renal failure in hospitalized patients*

Objective:The Acute Dialysis Quality Initiative (ADQI) Group published a consensus definition (the RIFLE criteria) for acute renal failure. We sought to assess the ability of the RIFLE criteria to predict mortality in hospital patients. Design:Retrospective single-center study. Setting:University-affiliated hospital. Patients:All patients admitted to the study hospital between January 2000 and December 2002. Patients were excluded if they were younger than 15 yrs old, were on chronic dialysis, or had kidney transplant or if their length of hospital stay was <24 hrs. Interventions:None. Measurements and Main Results:We included 20,126 patients. Mean age was 64 yrs, 14.7% of patients required intensive care unit admission, and hospital mortality was 8.0%. According to the RIFLE criteria, 9.1% of all patients were in the Risk category for acute renal failure, 5.2% were in the Injury category, and 3.7% were in the Failure category. There was an almost linear increase in hospital mortality from Normal to Failure (Normal, 4.4%; Risk, 15.1%; Injury, 29.2%; and Failure, 41.1%). Multivariate logistic regression analysis showed that all RIFLE criteria were significantly predictive factors for hospital mortality, with an almost linear increase in odds ratios from Risk to Failure (odds ratios, Risk 2.5, Injury 5.4, Failure 10.1). Conclusions:The RIFLE criteria for acute renal failure classified close to 20% of our study patients as having some degrees of acute impairment in renal function and were useful in predicting their hospital mortality.
Glutamatergic and GABAergic Metabolism in Mouse Brain under Chronic Nicotine Exposure: Implications for Addiction

Background and Purpose The effects of nicotine on cerebral metabolism and its influence on smoking behavior is poorly understood. An understanding of the chronic effects of nicotine on excitatory and inhibitory metabolic demand, and corresponding neurotransmission may provide clues for designing strategies for the optimal smoking cessation intervention. The objective of the current study was to investigate neuronal and astroglial metabolism in mice exposed to nicotine (0.5 and 2.0 mg/kg, sc) three times in a day for 4 weeks. Experimental Approach/Principal Findings Metabolic measurements were carried out by co-infusing [U-13C6]glucose and [2-13C]acetate, and monitoring 13C labeling of amino acids in brain tissue extract using 1H-[13C] and 13C-[1H]-NMR spectroscopy. Concentration of 13C-labeled glutamate-C4 was increased significantly from glucose and acetate with chronic nicotine treatment indicating an increase in glucose oxidation by glutamatergic neurons in all brain regions and glutamate-glutamine neurotransmitter cycle in cortical and subcortical regions. However, chronic nicotine treatment led to increased labeling of GABA-C2 from glucose only in the cortical region. Further, increased labeling of glutamine-C4 from [2-13C]acetate is suggestive of increased astroglial activity in subcortical and cerebellum regions of brain with chronic nicotine treatment. Conclusions and Significance Chronic nicotine exposure enhanced excitatory activity in the majority of brain regions while inhibitory and astroglial functions were enhanced only in selected brain regions.
Macro Determinants Of Car In Indian Banking Sector

Banks as a channel of monetary policy transmission play a very important role in facilitating the process of credit creation in an economy. It is crucial for financial stability that banks stay financially healthy. Capital Adequacy Ratio (CAR) is an important indicator of banks financial health. By nature the banking-operations and performance are subject to business cycles and fluctuations in economic activity. The global financial crisis saw the failure of financial sector giants like Lehman Brothers and banks in the U.S.A and other countries. The spread of global financial crisis worldwide attracted the interest of academicians and policy makers in banking sector and its soundness. Thus, after the financial crisis of 2008 the research on banking sector particularly CAR has gained lot of attention worldwide. Our review of extant literature highlights scanty evidence of papers examining the influence of macro-economic indicators in influencing changes in CAR of banks. We believe macro-economic variables may have a significant impact on CAR of banks as financial soundness in banks also to a large extent depends on the external factors and the state of macro-economy. Hence, this paper attempts to investigate and evaluate the impact of macroeconomic indicators on CAR for Indian banks. The study uses dynamic panel data analysis on 65 Indian commercial banks from 2007 to 2013. The findings of the study based on Generalized Method of Moments reveals that Real GDP Growth, Inflation rate, Interest rate and Exchange rate have strong impact on CAR of Indian Banks. The findings of the study suggest that the policy prescriptions that focus on the bank-specific determinants of CAR should also appropriately account for the influence of macro-economic indicators. Policy makers and regulators like Reserve Bank of India should take into consideration the effect of macroeconomic variables on CAR while framing policies on CAR and monitoring banks.
Inferring the geographic origin of a range expansion: Latitudinal and longitudinal coordinates inferred from genomic data in an ABC framework with the program x‐origin

Climatic or environmental change is not only driving distributional shifts in species today, but it has also caused distributions to expand and contract in the past. Inferences about the geographic locations of past populations especially regions that served as refugia (i.e., source populations) and migratory routes are a challenging endeavour. Refugial areas may be evidenced from fossil records or regions of temporal stability inferred from ecological niche models. Genomic data offer an alternative and broadly applicable source of information about the locality of refugial areas, especially relative to fossil data, which are either unavailable or incomplete for most species. Here, we present a pipeline we developed (called x‐origin) for statistically inferring the geographic origin of range expansion using a spatially explicit coalescent model and an approximate Bayesian computation testing framework. In addition to assessing the probability of specific latitudinal and longitudinal coordinates of refugial or source populations, such inferences can also be made accounting for the effects of temporal and spatial environmental heterogeneity, which may impact migration routes. We demonstrate x‐origin with an analysis of genomic data collected in the Collared pika that underwent postglacial expansion across Alaska, as well as present an assessment of its accuracy under a known model of expansion to validate the approach.
Free light chain: a novel predictor of adverse outcome in chronic lymphocytic leukemia

Objectives: Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. This retrospective study is planned to assess the prognostic value of serum free light chain (sFLC) levels and FLC ratio (FLCR) in CLL. Methods: Quantitative levels of sFLC were measured nephelometrically in sera collected at diagnosis. The expressions of ZAP70 and CD38 were quantified by flow cytometry. Chromosomal abnormalities were determined by interphase fluorescence in situ hybridization (FISH). Results: In a cohort of 101 patients with a median follow‐up of 29 (1–234) months, sFLC levels were found to be high in 55 patients (54.5%). An abnormal FLCR was found in 30 patients (29.7%). FISH‐based genetic risk groups did not differ significantly with respect to sFLC and FLCR (P > 0.05). Median time to first treatment was shorter in patients with high sFLC levels (P = 0.02). Median overall survival (OS) was shorter in patients with high sFLC levels (P = 0.01) and abnormal FLCR (P = 0.05). In patients with early stage disease, median OS was shorter in high sFLC (P = 0.03) and abnormal FLCR groups (P = 0.048). A relationship was observed between abnormal sFLC levels and CD38 positivity on logistic regression analysis (P = 0.003; OR: 4.44; 95% CI: 1.66–11.8). Conclusions: This study highlighted the adverse prognostic impact of high sFLC levels and abnormal FLCR with regard to survival in CLL, even in early stage patients. Prospective studies are warranted to validate the adverse impact of sFLC and FLCR on clinical outcome.
Chronic psychosocial stress regulates the expression of both GR and MR mRNA in the hippocampal formation of tree shrews

A persistent hyperactivity of the hypothalamic‐pituitary‐adrenal axis and thus elevated glucocorticoid levels are main neuroendocrine features of depressive symptomatology in humans. The broad range of effects that are set off by glucocorticoids is mediated by glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs), which themselves are subject to autoregulation. In order to investigate the impact of long‐lasting psychological stress on corticosteroid receptor mRNA expression in the hippocampal formation, we employed the psychosocial stress paradigm in male tree shrews (Tupaia belangeri). By in situ hybridization studies and semiquantitative evaluation of stress‐induced changes of GR and MR mRNA expression at the single‐cell level, brain tissue from subordinate animals which were exposed to 27 days (1 h/day) of social confrontation was compared to that of nonstressed animals. Four weeks of stress exposure resulted in a downregulation of GR mRNA in the dentate gyrus and hippocampal subfields CA1 and CA3 of subordinate male tree shrews compared to controls. The MR mRNA content in these subfields of the anterior hippocampus was also clearly reduced. On the contrary, in a more posterior location on the longitudinal axis of the tree shrew hippocampus, the MR message was increased in subfields CA1 and CA3 and in the dentate gyrus. These results suggest a relevance of the stress‐induced regulation of both corticosteroid receptor subtype mRNAs in a naturalistic challenging situation. Moreover, the differential regulation of MR mRNA along the rostrocaudal axis of the hippocampus adds another feature to the heterogenous composition of this structure. Hippocampus 2001;11:329–336. © 2001 Wiley‐Liss, Inc.
Reasons for Journal Impact Factor Changes: Influence of Changing Source Items

Both the concept and the application of the impact factor (IF) have been subject to widespread critique, including concerns over its potential manipulation. This study provides a systematic analysis of significant journal Impact Factor changes, based on the relative contribution of either one or both variables of the IF equation (i.e. citations / articles as the numerator / denominator of the quotient). A cohort of JCR-listed journals which faced the most dramatic absolute IF changes between 2013 and 2014 (ΔIF ≥ 3.0, n = 49) was analyzed for the causes resulting in IF changes that theses journals have experienced in the last five years. Along with the variation by number of articles and citations, this analysis includes the relative change of both variables compared to each other and offers a classification of `valid`and `invalid`scenarios of IF variation in terms of the intended goal of the IF to measure journal quality. The sample cohort features a considerable incidence of IF increases (18%) which are qualified as `invalid`according to this classification because the IF increase is merely based on a favorably changing number of articles (denominator). The results of this analysis point out the potentially delusive effect of IF increases gained through effective shrinkage of publication output. Therefore, careful consideration of the details of the IF equation and possible implementation of control mechanisms versus the volatile factor of number of articles may help to improve the expressiveness of this metric.
A compact electric potential sensor array for the acquisition and reconstruction of the 7-lead electrocardiogram without electrical charge contact with the skin

Conventional electrocardiogram (ECG) systems make use of separate electrical connections to the arms and legs. These use a ‘long baseline’ for the voltage reference potential which in the case of precordial ECG leads is provided using a Wilson central terminal (WCT) wiring configuration. The aims of this project were (a) to construct compact, non-invasive surface ECG sensor arrays which would operate without the need for a WCT reference, (b) to obtain high quality precordial ECGs showing fine differences in ECG detail between small adjacent areas of the chest and (c) to reconstruct, from a compact array of four sensors, ECGs which closely match to the conventional 7-lead ECG system, but without the need for multiple wires and long baselines. In this paper, we describe two sensor array configurations which have been constructed using electric potential sensors (EPSs). We show high quality precordial ECGs obtained from small areas of the surface of the chest and show the different angular vectors (leads) in the frontal cardiac plane constructed using signals from the array elements. We suggest that these ECG arrays, which are simple to apply, should prove to be a valuable tool in providing useful information about the state of the heart.
Roles of Cbln1 in Non-Motor Functions of Mice

The cerebellum is thought to be involved in cognitive functions in addition to its well established role in motor coordination and motor learning in humans. Cerebellin 1 (Cbln1) is predominantly expressed in cerebellar granule cells and plays a crucial role in the formation and function of parallel fiber–Purkinje cell synapses. Although genes encoding Cbln1 and its postsynaptic receptor, the delta2 glutamate receptor (GluD2), are suggested to be associated with autistic-like traits and many psychiatric disorders, whether such cognitive impairments are caused by cerebellar dysfunction remains unclear. In the present study, we investigated whether and how Cbln1 signaling is involved in non-motor functions in adult mice. We show that acquisition and retention/retrieval of cued and contextual fear memory were impaired in Cbln1-null mice. In situ hybridization and immunohistochemical analyses revealed that Cbln1 is expressed in various extracerebellar regions, including the retrosplenial granular cortex and the hippocampus. In the hippocampus, Cbln1 immunoreactivity was present at the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare without overt mRNA expression, suggesting that Cbln1 is provided by perforant path fibers. Retention/retrieval, but not acquisition, of cued and contextual fear memory was impaired in forebrain-predominant Cbln1-null mice. Spatial learning in the radial arm water maze was also abrogated. In contrast, acquisition of fear memory was affected in cerebellum-predominant Cbln1-null mice. These results indicate that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially and that Cbln1 signaling likely regulates motor and non-motor functions in multiple brain regions. SIGNIFICANCE STATEMENT Despites its well known role in motor coordination and motor learning, whether and how the cerebellum is involved in cognitive functions remains less clear. Cerebellin 1 (Cbln1) is highly expressed in the cerebellum and serves as an essential synaptic organizer. Although genes encoding Cbln1 and its receptor are associated with many psychiatric disorders, it remains unknown whether such cognitive impairments are caused by cerebellar dysfunction. Here, we show that Cbln1 is also expressed in the forebrain, including the hippocampus and retrosplenial granular cortex. Using forebrain- and cerebellum-predominant conditional Cbln1-null mice, we show that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially, indicating that Cbln1 signaling regulates both motor and non-motor functions in multiple brain regions.
Effects of amino acid changes in the extracellular domain of the human immunodeficiency virus type 1 gp41 envelope glycoprotein

Changes were introduced into conserved amino acids within the ectodomain of the human immunodeficiency virus type 1 (HIV-1) gp41 transmembrane envelope glycoprotein. The effect of these changes on the structure and function of the HIV-1 envelope glycoproteins was examined. The gp41 glycoprotein contains an amino-terminal fusion peptide (residues 512 to 527) and a disulfide loop near the middle of the extracellular domain (residues 598 to 604). Mutations affecting the hydrophobic sequences between these two regions resulted in two phenotypes. Some changes in amino acids 528 to 562 resulted in a loss of the noncovalent association between gp41 and the gp120 exterior glycoprotein. Amino acid changes in other parts of the gp41 glycoprotein (residues 608 and 628) also resulted in subunit dissociation. Some changes affecting amino acids 568 to 596 resulted in envelope glycoproteins partially or completely defective in mediating membrane fusion. Syncytium formation was more sensitive than virus entry to these changes. Changes in several amino acids from 647 to 675 resulted in higher-than-wild-type syncytium-forming ability. One of these amino acid changes affecting tryptophan 666 resulted in escape from neutralization by an anti-gp41 human monoclonal antibody, 2F5. These results contribute to an understanding of the functional regions of the HIV-1 gp41 ectodomain.
Adaptive fuzzy nonsingular fast terminal sliding mode control for spacecraft formation flying

This paper deals with the design of a robust adaptive fuzzy nonsingular fast terminal sliding mode control strategy for the relative motion control of spacecraft in formation. A nonsingular terminal sliding surface, along with a fast reaching law, has been considered for fast and finite time convergence. Adaptive tuning algorithms are derived based on Lyapunov stability theory for updating the controller gains involved in the fast reaching law. In order to reduce the chattering, the discontinuous term in the reaching law has been replaced by a fuzzy inference mechanism. Lyapunov based adaptive tuning laws are derived for updating the fuzzy parameters involved. Numerical simulations based on nonlinear dynamics defined in leader centered Hill's frame, have been presented to prove the robustness of the proposed approach.