Miracle-dz/UniFAR-FTUs huggingface dataset:
Protein phosphorylation and its role in archaeal signal transduction

Reversible protein phosphorylation is the main mechanism of signal transduction that enables cells to rapidly respond to environmental changes by controlling the functional properties of proteins in response to external stimuli. However, whereas signal transduction is well studied in Eukaryotes and Bacteria, the knowledge in Archaea is still rather scarce. Archaea are special with regard to protein phosphorylation, due to the fact that the two best studied phyla, the Euryarchaeota and Crenarchaeaota, seem to exhibit fundamental differences in regulatory systems. Euryarchaeota (e.g. halophiles, methanogens, thermophiles), like Bacteria and Eukaryotes, rely on bacterial-type two-component signal transduction systems (phosphorylation on His and Asp), as well as on the protein phosphorylation on Ser, Thr and Tyr by Hanks-type protein kinases. Instead, Crenarchaeota (e.g. acidophiles and (hyper)thermophiles) only depend on Hanks-type protein phosphorylation. In this review, the current knowledge of reversible protein phosphorylation in Archaea is presented. It combines results from identified phosphoproteins, biochemical characterization of protein kinases and protein phosphatases as well as target enzymes and first insights into archaeal signal transduction by biochemical, genetic and polyomic studies.
Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics

Investigation of macromolecular structure and dynamics is fundamental to understanding how macromolecules carry out their functions in the cell. Significant advances have been made toward this end in silico, with a growing number of computational methods proposed yearly to study and simulate various aspects of macromolecular structure and dynamics. This review aims to provide an overview of recent advances, focusing primarily on methods proposed for exploring the structure space of macromolecules in isolation and in assemblies for the purpose of characterizing equilibrium structure and dynamics. In addition to surveying recent applications that showcase current capabilities of computational methods, this review highlights state-of-the-art algorithmic techniques proposed to overcome challenges posed in silico by the disparate spatial and time scales accessed by dynamic macromolecules. This review is not meant to be exhaustive, as such an endeavor is impossible, but rather aims to balance breadth and depth of strategies for modeling macromolecular structure and dynamics for a broad audience of novices and experts.
ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3–13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12–124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05). In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.
Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low‐dose cyclophosphamide: a randomized comparison

Autologous stem cell transplantation is a standard treatment in multiple myeloma (MM). Blood grafts are usually collected after mobilization with granulocyte–colony‐stimulating factor (G‐CSF) alone or in a combination with cyclophosphamide (CY). There is limited knowledge of the possible effects of different mobilization regimens on blood graft characteristics and posttransplant outcomes.
Maternal-fetal transmission of the zika virus: An intriguing interplay

ABSTRACT In this review, we give an overview of aspects related to the congenital transmission of the Zika virus (ZIKV). Although we acknowledge that important advances in research on ZIKV pathogenesis have come from studies using animal models, particularly non-human primates, this review emphasizes studies using ex-vivo human cells and tissues as well as natural infections in pregnant women. The possible routes used by ZIKV to cross or breach the placental barrier and infect the fetal central nervous system are presented. Understanding the viral infection biology and ZIKV pathogenesis during pregnancy may guide the design of affordable antiviral strategies to benefit pregnant women in areas at risk.
Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier’s principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.
Systemic Lupus Erythematosus (SLE) Responder Index response is associated with global benefit for patients with SLE

A post-hoc analysis of pooled data from two Phase IIb trials (sifalimumab; NCT01283139, anifrolumab; NCT01438489) assessed the clinical significance of a Systemic Lupus Erythematosus (SLE) Responder Index (SRI(4)) response (Week 52) for 736 patients with moderate to severe SLE disease activity (study entry). SRI(4) responders achieved significantly greater improvements in clinical outcome measures (including percentages of patients with a ≥ 7-point reduction in SLE Disease Activity Index (SLEDAI)–2000 (2K), British Isles Lupus Assessment Group “A” or “2B” flare rate, and oral corticosteroid reduction to ≤7.5 mg/day; change from baseline in Physician’s Global Assessment; and numbers of SLEDAI–2K organ domains with improvement), as well as in patient-reported outcomes (Patient’s Global Assessment, Functional Assessment of Chronic Illness Therapy−Fatigue; Short-Form 36 Health Survey Physical Component Summary, Mental Component Summary, Vitality domain scores) vs. nonresponders. Of patients with abnormal serologies, SRI(4) responders had numerically greater improvements (baseline to Week 52) in anti-double-stranded DNA concentrations vs. nonresponders (p = 0.051), but there were no differences in C3/C4 concentration changes between the two groups. These results confirm previous findings in a different cohort, indicating that an SRI(4) response is associated with global clinical benefit.
A Monoclonal Antibody-Based Enzyme-Linked Immunosorbent Assay for Determination of Homoharringtonine

Abstract Homoharringtonine (HHT), also known as omacetaxine, is a natural compound found in the genus Cephalotaxus and is a promising pharmaceutical drug used for the treatment of chronic or accelerated phase chronic myeloid leukemia. As a tool for the quantitative determination of HHT, a specific monoclonal antibody against HHT (MAb 6A1) was generated by conjugates prepared via sodium periodate-mediated oxidation. The developed indirect competitive enzyme-linked immunosorbent assay (icELISA) using MAb 6A1 was found to be highly specific and sensitive with a limit of detection for HHT of 48.8 ng/mL. Validation assays to evaluate precision and accuracy of the method were conducted by the use of intra- and inter-assay analysis, recovery test, and comparison analysis between the amounts of HHT determined by ELISA and high-performance liquid chromatography. These results revealed that the established icELISA using MAb 6A1 is specific, sensitive, and reliable enough to be applied to the qualitative analysis for HHT. Furthermore, the results of this study support the usefulness of sodium periodate as a reagent for the conjugation between Cephalotaxus alkaloids and proteins for producing specific antibodies.
The effects of capillary transit time heterogeneity on the BOLD signal

Neurovascular coupling mechanisms give rise to vasodilation and functional hyperemia upon neural activation, thereby altering blood oxygenation. This blood oxygenation level dependent (BOLD) contrast allows studies of activation patterns in the working human brain by functional MRI (fMRI). The BOLD‐weighted fMRI signal shows characteristic transients in relation to functional activation, such as the so‐called initial dip, overshoot, and post‐stimulus undershoot. These transients are modulated by other physiological stimuli and in disease, but the underlying physiological mechanisms remain incompletely understood. Capillary transit time heterogeneity (CTH) has been shown to affect oxygen extraction, and hence blood oxygenation. Here, we examine how recently reported redistributions of capillary blood flow during functional activation would be expected to affect BOLD signal transients. We developed a three‐compartment (hemoglobin, plasma, and tissue) model to predict the BOLD signal, incorporating the effects of dynamic changes in CTH. Our model predicts that the BOLD signal represents the superposition of a positive component resulting from increases in cerebral blood flow (CBF), and a negative component, resulting from elevated tissue metabolism and homogenization of capillary flows (reduced CTH). The model reproduces salient features of BOLD signal dynamics under conditions such as hypercapnia, hyperoxia, and caffeine intake, where both brain physiology and BOLD characteristics are altered. Neuroglial signaling and metabolism could affect CBF and capillary flow patterns differently. Further studies of neurovascular and neuro‐capillary coupling mechanisms may help us relate BOLD signals to the firing of certain neuronal populations based on their respective BOLD “fingerprints. ”
A Dynamic Quota-Based Peer Selection Strategy in BitTorrent

BitTorrent employs a static quota-based peer selection strategy to fixedly allocate upload quotas for the tit-for-tat (TFT) choke algorithm and optimistic unchoke (OU) algorithm, which would incur a paradox of supply and demand between upload peers and request peers, where many request peers stay in the starvation state while many upload quotas stay in the idleness state. We propose a dynamic quota-based peer selection strategy, where request peers are classified by the principle of investment return and according to dynamic changed numbers of different request peers an upload peer adaptively allocates upload quotas for the TFT and OU algorithms. Simulation experiment shows that our dynamic quota allocation scheme can eliminate the paradox of supply and demand, increase the resource utility ratio of upload peers, and decrease the file download time, at the cost of uploading more a few file blocks for each upload peer.
Patient experience and quality of urologic cancer surgery in US hospitals

Care interactions as perceived by patients and families are increasingly viewed as both an indicator and lever for high‐value care. To promote patient‐centeredness and motivate quality improvement, payers have begun tying reimbursement with related measures of patient experience. Accordingly, the authors sought to determine whether such data correlate with outcomes among patients undergoing surgery for genitourinary cancer.
Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder.

CONTEXT Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Even when the best available treatments are applied, approximately 10% of patients remain severely afflicted and run a long-term deteriorating course of OCD. OBJECTIVE To determine whether bilateral deep brain stimulation of the nucleus accumbens is an effective and safe treatment for treatment-refractory OCD. DESIGN The study consisted of an open 8-month treatment phase, followed by a double-blind crossover phase with randomly assigned 2-week periods of active or sham stimulation, ending with an open 12-month maintenance phase. SETTING Academic research. Patients Sixteen patients (age range, 18-65 years) with OCD according to DSM-IV criteria meeting stringent criteria for refractoriness to treatment were included in the study. INTERVENTIONS Treatment with bilateral deep brain stimulation of the nucleus accumbens. MAIN OUTCOME MEASURES Primary efficacy was assessed by score change from baseline on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Responders were defined by a score decrease of at least 35% on the Y-BOCS. RESULTS In the open phase, the mean (SD) Y-BOCS score decreased by 46%, from 33.7 (3.6) at baseline to 18.0 (11.4) after 8 months (P < .001). Nine of 16 patients were responders, with a mean (SD) Y-BOCS score decrease of 23.7 (7.0), or 72%. In the double-blind, sham-controlled phase (n = 14), the mean (SD) Y-BOCS score difference between active and sham stimulation was 8.3 (2.3), or 25% (P = .004). Depression and anxiety decreased significantly. Except for mild forgetfulness and word-finding problems, no permanent adverse events were reported. CONCLUSION Bilateral deep brain stimulation of the nucleus accumbens may be an effective and safe treatment for treatment-refractory OCD. CLINICAL TRIAL REGISTRATION isrctn.org Identifier: ISRCTN23255677.
Blood lead levels and risk factors for lead exposure among pregnant women in western French Guiana: the role of manioc consumption

ABSTRACT Concerns regarding lead (Pb) poisoning in French Guiana first arose in 2011 following the discovery of excessively high levels of the metal amongst children in a small neighborhood without any apparent source of Pb. Since 2012, blood lead level (BLL) measurement has been proposed for all pregnant women in western French Guiana. The aim of this study was to determine BLL in pregnant women in this region and identify factors associated with elevated BLL. An observational study of a consecutive sample of women who delivered in the maternity ward of the hospital was conducted. Risk factors were investigated using a questionnaire administered postdelivery by midwives (N = 531). Approximately 25 and 5% of women displayed BLL of ≥50 μg/L and ≥100 µg/L, respectively. The geometric mean was 32.6 μg/L. Factors that were significantly associated with an elevated BLL after modeling (multivariate linear regression) included place of residence along the Maroni river, low level of education, daily consumption of manioc derivatives, weekly and daily consumption or personal preparation of manioc flour during pregnancy, and weekly consumption of wild game. This study provides insight into the regional and social disparities in BLL in French Guiana and potential sources of exposure. Evidence indicates that foods that are primarily produced and consumed in the Guiana Shield significantly affect BLL levels. Taken together with existing data, our results demonstrate that specific actions in terms of prevention, screening, and care are required to be adapted and put into place in order to reduce exposure.
The &agr;2C-adrenoceptor antagonist, ORM-10921, exerts antidepressant-like effects in the Flinders Sensitive Line rat

Depression involves deficits in monoaminergic neurotransmission. Differential roles for &agr;2A, B and C subtypes of the &agr;2-adrenoceptor (AR) are evident, with selective &agr;2C-AR antagonists purported to have antidepressant and procognitive properties. However, this has not been demonstrated in a genetic animal model of depression. The role of the &agr;2C-AR in modulating two key depression-related behaviours in the Flinders Sensitive Line (FSL) rat was studied using a dose–response analysis following subcutaneous administration with the selective &agr;2C-AR antagonist ORM-10921 (0.03; 0.3 mg/kg), the nonselective &agr;2-AR antagonist idazoxan (3 mg/kg), or vehicle once daily for 14 days. Behaviour in the novel object recognition test, forced swim test (FST) and locomotor activity test was assessed. To ratify the validity of the FSL model, the reference tricyclic antidepressant imipramine (15 mg/kg, intraperitoneally) was used as a comparator drug in the FST. FSL rats demonstrated significantly increased immobility and recognition memory deficits versus Flinders Resistant Line controls, with imipramine significantly reversing said immobility. Similarly, ORM-10921 at both doses but not idazoxan significantly reversed immobility in the FST as well as attenuated cognitive deficits in FSL animals. We conclude that selective &agr;2C-AR antagonism has potential as a novel therapeutic strategy in the treatment of depression and cognitive dysfunction.
Physiological stress and welfare of broiler chickens in transit: solutions not problems!

The rearing of large numbers of broiler chickens at geographically dispersed sites means that they have to be transported by road, over various distances, to centralized processing plants for slaughter. The birds may be exposed to a variety of stressors during transit, including the thermal demands of the transport microenvironment. The thermal environments experienced by broiler chickens during routine transport in the U.K. on a large number of commercial vehicles under a wide range of external climatic conditions have been characterized using three-dimensional thermal mapping (temperature and water vapor density). Inadequate ventilation results in heterogeneous distributions of temperature and humidity and, thus, thermal loads within the vehicle, and, therefore, the existence of a "thermal core" in which the risk of heat stress is increased. Relationships between specific physiological indices of stress and quantified thermal loads have been determined in accurate transport simulations in the laboratory. The findings have been employed to establish a predictive model of the induction of heat stress during commercial transportation, as well as to define the acceptable ranges and limits for temperature and humidity within the transport containers. These principles have been utilized in developing a monitoring system to warn of impending heat stress and in improving vehicle design to facilitate the prevention of heat stress during broiler transportation.
Influence of hiatal hernia and male sex on the relationship between alcohol intake and occurrence of Barrett’s esophagus

Background The association of alcohol intake with the incidence of Barrett’s esophagus (BE) has been inconsistent. Although hiatal hernia and male sex are well-known risk factors of BE, its effect on the association of alcohol intake with the incidence of BE remains unknown. Aim To investigate whether the influence of alcohol intake on the occurrence of BE might differ depending on male sex and presence of hiatal hernia. Methods We utilized a database of 8031 patients that underwent upper endoscopy for health screening in a prospective, multicenter, cohort study (the Upper Gastro Intestinal Disease study). The incidence of endoscopic columnar-lined esophagus (eCLE; endoscopically diagnosed BE) was the outcome variable. Multivariable logistic regression analysis was conducted to assess the association between alcohol intake and eCLE stratified by male sex and hiatal hernia, adjusting for clinical features and other potential confounders. Results Alcohol intake (≥20 g/day) showed a marginally significant association with the incidence of eCLE in participants without hiatal hernia (0 vs. ≥20 g/day; odds ratio [OR], 1.62; 95% confidence interval [CI], 0.92–2.85, P = 0.09) but not in participants with hiatal hernia (0 vs. ≥20/day; OR, 0.99; 95% CI, 0.59–1.65; P = 0.95). Furthermore, alcohol intake (≥20 g/day) was significantly associated with the incidence of eCLE in male participants without hiatal hernia (0 vs. ≥20 g/day; OR, 1.98; 95% CI, 1.04–4.03; P = 0.04) but not in female participants without hiatal hernia (0 vs. ≥20 g/day; OR, 0.47; 95% CI, 0.03–2.37; P = 0.42). Conclusions The effect of alcohol intake on the incidence of eCLE might be associated with hiatal hernia status and male sex.
Occupational Hazards and Social Disability Insurance Working

Using retrospective data, we introduce evidence that occupational exposure significantly affects disability risk. Incorporating this into a general equilibrium model, social disability insurance (SDI) affects welfare through (i) the classic, risk-sharing channel and (ii) a new channel of occupational reallocation. Both channels can increase welfare, but at the optimal SDI they are at odds. Welfare gains from additional risk-sharing are reduced by overly incentivizing workers to choose risky occupations. In a calibration, optimal SDI increases welfare by 2.3% relative to actuarially fair insurance, mostly due to risk sharing. JEL CODES: E62, I13