Miracle-dz/UniFAR-FTUs huggingface dataset:
Nonequivalent release sites govern synaptic depression

Significance Activity-dependent depression is a common aspect of synaptic plasticity resulting from an inability to recover full-release competency during bouts of high-frequency stimulation. At the zebrafish neuromuscular synapse, frequencies between 1 and 10 Hz lead to 50% depression, but paradoxically, this synapse can still follow frequencies approaching the refractory period of the action potential without failure. Capitalizing on the advantages offered by this synapse, we report a new mechanism causal to nonlinear dependence of steady-state depression on frequency involving two types of release sites differing in vesicle reloading rates. The slow sites cannot sustain vesicle release at high frequencies, and therefore, it is the number of fast reloading sites that determines the steady-state level of transmission associated with depression. Synaptic depression is prominent among synapses, but the underlying mechanisms remain uncertain. Here, we use paired patch clamp recording to study neuromuscular transmission between the caudal primary motor neuron and target skeletal muscle in zebrafish. This synapse has an unusually low number of release sites, all with high probabilities of release in response to low-frequency stimulation. During high-frequency stimulation, the synapse undergoes short-term depression and reaches steady-state levels of transmission that sustain the swimming behavior. To determine the release parameters underlying this steady state, we applied variance analysis. Our analysis revealed two functionally distinct subclasses of release sites differing by over 60-fold in rates of vesicle reloading. A slow reloading class requires seconds to recover and contributes to depression onset but not the steady-state transmission. By contrast, a fast reloading class recovers within tens of milliseconds and is solely responsible for steady-state transmission. Thus, in contrast to most current models that assign levels of steady-state depression to vesicle availability, our findings instead assign this function to nonuniform release site kinetics. The duality of active-site properties accounts for the highly nonlinear dependence of steady-state depression levels on frequency.
NT-proBNP and the diagnosis of exercise-induced myocardial ischaemia

Summary Background Amino terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive marker of ventricular dysfunction. Exercise causes an increase in the secretion of NT-proBNP, and with myocardial ischaemia the increase is more pronounced. This increase has been found to improve the diagnostic sensitivity of the stress ECG in diagnosing myocardial ischaemia in subjects with normal ventricular function. Objective To assess whether the change in NT-proBNP can be used to diagnose effort-induced myocardial ischaemia in an unselected population. Methods We enrolled a total of 51 consecutive patients, referred for exercise stress 99mTc-sestamibi SPECT MPI (single-photon emission computed tomography myocardial perfusion imaging) to diagnose inducible myocardial ischaemia. NT-proBNP was determined at rest and 30 minutes after cessation of exercise. Results Of the 51 patients, 28 had normal perfusion scans, seven had scans with fixed perfusion defects (previous myocardial infarction with no inducible ischaemia) and 16 had reversible perfusion defects (inducible ischaemia). There was no correlation between ischaemia and resting NT-proBNP, post-stress NT-proBNP or the change in NTproBNP (delta-NT-proBNP). Conclusion In an unselected population the change in NT-proBNP cannot be used to diagnose effort-induced myocardial ischaemia.
The role of sevista in the management of dysfunctional uterine bleeding.

OBJECTIVE The complaints of excessive menstrual bleeding (menorrhagia) have a substantial impact on the gynaecological services and in most of the cases, no organic pathology is identified. Nonsteroidal anti-inflammatory drugs and tranexamic acid offer a simple therapy which has to be taken during menses, with reductions of 25-35% and 50% respectively in the Menstrual Blood Loss (MBL). Danazol and the gonadatrophin-releasing hormone analogues are highly effective, but their side-effects make them suitable only for a short-term use. In the present study, the role of ormeloxifene was studied in patients of DUB. MATERIALS & METHODS The subjects were diagnosed cases of DUB. After ruling out the possible causes of the abnormal uterine bleeding, a diagnosis of DUB was made and the treatment with ormiloxifene was started. The number of cases were 35 cases. The treatment with ormeloxifene was evaluated by measuring the Hb g/dl and the endometrial thickness before and after 3 months of treatment with sevista. Ormeloxifene was given in the dosage of a 60 mg tablet twice a week for 3 months, followed by once a week for another 3 months. OBSERVATION & RESULTS There was a statistically significant increase in the Hb g/dl (p < 0.001) and a statistically significant decrease in the endometrial thickness (p< 0.001) after the treatment with ormeloxifene. CONCLUSION Ormeloxifene can be used asa effective drug in the treatment of Dysfunctional uterine bleeding.
Genetic control of cell-mediated immunity in rats: involvement of RT1.B locus determinants in the proliferative response of T lymphocytes to Listeria antigens

The cellular requirements for Listeria monocytogenes antigen-induced, specific [3H]thymidine incorporation into lymphoid cells were analysed. Nylon-nonadherent lymph node and peritoneal exudate cells from infected athymic rats and mice failed to respond by proliferation, whereas control cells of thymus-bearing animals gave significant responses. In mice, cells expressing Thy-1 at a high density were required for the initiation of the proliferative response, but cells with lower density also participated in proliferation. Immune T cells alone failed to respond to L. monocytogenes antigen, but the addition of accessory cells provided optimal responses. These were nylon wool adherent, absent from thoracic duct lymph, but present in thymus and lymph nodes and particularly abundant in spleens of nonimmune rats. Accessory cells had to be matched at the B region of RT1, the major histocompatibility complex, to provide a stimulatory signal for L. monocytogenes antigen-specific T cells. Thus, the genetic restriction criteria were the same as for the transfer of delayed-type hypersensitivity to L. monocytogenes antigen, but differed from those controlling the transfer of acquired cellular resistance. The interaction between T cells and accessory cells could be blocked by alloantisera directed against Ia-antigens expressed on the accessory cell population. The study suggests that killed L. monocytogenes bacteria are presented by Ia-positive adherent cells in a RT1.B-restricted fashion to provide a proliferative signal for sensitized T cells.
Hepatitis C virus increases the risk of kidney disease among HIV‐positive patients: Systematic review and meta‐analysis

Kidney disease has become an important co‐morbidity among human immunodeficiency virus‐infected patients as they live longer in the era of highly effective antiretroviral therapy. It remains unclear how co‐infection with hepatitis C virus impacts on the trajectory of kidney disease among HIV‐infected patients. To evaluate the effect of co‐infection with HCV on the risk of kidney disease in HIV‐infected populations. We conducted a systematic review of the published medical literature to determine if hepatitis C co‐infection is associated with increased likelihood of chronic kidney disease in HIV‐positive adults. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk for chronic kidney disease (defined by reduced glomerular filtration rate and/or detectable proteinuria) with hepatitis C virus across the published studies. Meta‐regression and stratified analysis were also conducted. We identified 19 studies (146,151 unique patients with HIV) and separate meta‐analyses were performed according to the outcome. Aggregation of longitudinal studies (n = 8, 105,462 unique patients) showed a relationship between HCV infection and increased risk of reduced glomerular filtration rate among HIV‐infected individuals, the summary estimate for adjusted hazard ratio was 1.64 (95%CI, 1.28; 2.0, P < 0.001) in HIV‐HCV co‐infected individuals compared with those having HIV mono‐infection. No between‐studies heterogeneity was noted (P‐value by Q test = 0.08). HCV positive serology was an independent risk factor for proteinuria; adjusted effect estimate, 1.23 (95% confidence interval, 1.18; 1.28, P = 0.001) (n = 6 studies; 26,835 unique patients). In meta‐regression, we noted the impact of ageing (P = 0.0001) upon the adjusted hazard ratio of incidence of reduced glomerular filtration rate among HCV‐HIV co‐infected patients; a negative association between frequency of males (P = 0.001) and the adjusted hazard ratio of prevalence of low glomerular filtration rate was found. Hepatitis C co‐infection is associated with a significant increase in the risk of reduced glomerular filtration rate and/or detectable proteinuria among HIV‐infected individuals. J. Med. Virol. 88:487–497, 2016. © 2015 Wiley Periodicals, Inc.
Virtual Balancing for Studying and Training Postural Control

Postural control during free stance has been frequently interpreted in terms of balancing an inverted pendulum. This even holds, if subjects do not balance their own, but an external body weight. We introduce here a virtual balancing apparatus, which produces torque in the ankle joint as a function of ankle angle resembling the gravity and inertial effects of free standing. As a first aim of this study, we systematically modified gravity, damping, and inertia to examine its effect on postural control beyond the physical constraints given in the real world. As a second aim, we compared virtual balancing to free stance to test its suitability for balance training in patients who are not able to balance their full body weight due to certain medical conditions. In a feasibility study, we analyzed postural control during free stance and virtual balancing in 15 healthy subjects. Postural control was characterized by spontaneous sway measures and measures of perturbed stance. During free stance, perturbations were induced by pseudorandom anterior-posterior tilts of the body support surface. In the virtual balancing task, we systematically varied the anterior-posterior position of the foot plate where the balancing forces are zero following a similar pseudorandom stimulus profile. We found that subjects' behavior during virtual balancing resembles free stance on a tilting platform. This specifically holds for the profile of body excursions as a function of stimulus frequencies. Moreover, non-linearity between stimulus and response amplitude is similar in free and virtual balancing. The overall larger stimulus induced body excursions together with an altered phase behavior between stimulus and response could be in part explained by the limited use of vestibular and visual feedback in our experimental setting. Varying gravity or damping significantly affected postural behavior. Inertia as an isolated factor had a mild effect on the response functions. We conclude that virtual balancing may be well suited to simulate conditions which could otherwise only be realized in space experiments or during parabolic flights. Further studies are needed to examine patients' potential benefit of virtual balance training.
Near‐infrared spectroscopy provides an index of blood flow and vasoconstriction in calf skeletal muscle during lower body negative pressure

Aim: Near‐infrared spectroscopy (NIRS) has been used previously for forearm blood flow estimation at rest and during exercise. In this study we applied NIRS to selectively monitor deep calf oxygenated haemoglobin (Hb) responses in order to estimate blood flow changes in the calf muscle during lower body negative pressure (LBNP). The purpose of this study was to test the hypothesis that changes in calf skeletal muscle oxygenated‐Hb, after the removal of superficial tissue responses, were related to blood flow changes during orthostatic stress, and to determine the efficacy of using NIRS measurements as an index of vasoconstriction.
Neutrophil chemoattractant receptors and the membrane skeleton

Signal transduction via receptors for N‐formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process which involves participation of cytoskeletal elements. Evidence exists suggesting that the cytoskeleton and/or the membrane skeleton controls the distribution of FPR in the plane of the plasma membrane, thus controlling the accessibility of FPR to different proteins in functionally distinct domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and fodrin. Thus, the G protein signal transduction partners of FPR become inaccessible to the agonist‐occupied receptor, preventing cell activation. The mechanism of interaction of FPR with the membrane skeleton is poorly understood but evidence is accumulating that suggests a direct binding of FPR (and other receptors) to cytoskeletal proteins such as actin.
Protein Phosphatase 2C Acts Independently of Stress-activated Kinase Cascade to Regulate the Stress Response in Fission Yeast*

Stress-activated signal transduction pathways, which are largely conserved among a broad spectrum of eukaryotic species, have a crucial role in the survival of many forms of stress. It is therefore important to discover how these pathways are both positively and negatively regulated. Recent genetic studies have implicated protein phosphatase 2C (PP2C) as a novel negative regulator of stress response pathways in both budding and fission yeasts. Moreover, it was hypothesized that PP2C dephosphorylates one or more components of protein kinase cascades that are at the core of stress-activated signal transduction pathways. Herein we present genetic and biochemical studies of the fission yeastSchizosaccharomyces pombe that disprove this hypothesis and indicate that PP2C instead negatively regulates a downstream element of the pathway. First, high expression of PP2C produces phenotypes that are inconsistent with negative regulation of the Wik1-Wis1-Spc1 stress-activated kinase cascade. Second, high expression of PP2C leads to sustained activating tyrosine phosphorylation of Spc1. Third, Spc1-dependent phosphorylation of Atf1, a transcription factor substrate of Spc1, is unaffected by high expression of PP2C. Fourth, high expression of PP2C suppresses Atf1-dependent transcription of a stress-response gene. These studies strongly suggest that PP2C acts downstream of Spc1 kinase in the stress-activated signal transduction pathway.
Identification of an N-domain Histidine Essential for Chaperone Function in Calreticulin*

Calreticulin is an endoplasmic reticulum (ER) luminal Ca2+-binding chaperone involved in folding of newly synthesized glycoproteins via the “calreticulin-calnexin cycle. ” We reconstituted ER of calreticulin-deficient cells with N-terminal histidine (His25, His82, His128, and His153) calreticulin mutants and carried out a functional analysis. In crt-/- cells bradykinin-dependent Ca2+ release is altered, and the reestablishment of bradykinin-dependent Ca2+ release was used as a marker for calreticulin function. Bradykinin-dependent Ca2+ release from the ER was rescued by wild type calreticulin and by the His25, His82, or His128 mutant but not by the His153 mutant. Wild type calreticulin and the His25, His82, and His128 mutants all prevented in vitro thermal aggregation of malate dehydrogenase and IgY, whereas the His153 mutant did not, indicating that His153 chaperone function was impaired. Biophysical analysis of His153 mutant revealed that conformation changes in calreticulin mutant may be responsible for the loss of its chaperone activity. We conclude that mutation of a single amino acid residue in calreticulin has devastating consequences for its chaperone function, indicating that mutations in chaperones may play a significant role in protein folding disorders.
Data driven modeling for energy consumption prediction in smart buildings

Energy efficiency is in the interest of everyone, from individuals to governments, since it yields economical savings, reduces greenhouse gas emissions and alleviates energy poverty. Buildings are one of the largest consumers of primary energy and attaining their efficiency is, therefore, an important goal. The Internet of Things currently provides vast amounts of data that can be used to extract knowledge of all kinds, including that regarding energy prediction. This has motivated us to test wether the prior information on the physics of building heat transfer, that is currently available is now redundant owing to the completeness of the data from the system. We propose a machine learning approach and a grey-box model approach with which to test this hypothesis. The former is blind to the physiscs of the problem, while the latter is greatly influenced by it. The energy consumption prediction models were created with both approaches and then used to estimate energy consumption in a normal operation state and compare it with energy consumption when an energy efficiency campaign is run. Our black-box method, which is based on a combination of statistical and machine learning models and on a time series structurization of the data, shows better prediction accuracy than the so-called grey-box methods that include basic physical equations. This shows that also a data driven approach outperforms more informed methods in this, like other fields.
Restriction of lentivirus in monkeys

Retroviruses are able to cross species barriers and have done so many times throughout evolution. Perhaps as a consequence, dominant mechanisms have arisen to block infection by murine retroviruses in mice (restriction factor Fv1) and humans (restriction factor Ref1), as well as in other mammals. Here we describe a block to HIV and simian immunodeficiency virus in monkeys. Like previously described restrictions the block is saturable and gives rise to multiple-hit infection kinetics. Furthermore, like restriction of murine leukemia virus in humans, the block is before reverse transcription. Intriguingly, African green monkey cells are able to block both HIV and simian immunodeficiency virus, and each virus is able to saturate and abrogate the restriction of the other, suggesting that a common factor is responsible.
Improved Breast Cancer Care Quality Metrics After Implementation of a Standardized Tumor Board Documentation Template.

PURPOSE Cancer treatment requires a coordinated multidisciplinary treatment approach, which led to the development of the Rapid Quality Reporting System by the Commission on Cancer. However, the lack of immediate availability of documented treatment plans and the inefficiency of global medical record reviews represent significant barriers to adherence reporting and the timely implementation of quality improvement measures. METHODS Adherence to national guidelines in the areas of radiation treatment, chemotherapy, and hormone therapy was assessed after breast conservation surgery (BCS). Adherence rates within 1 year of BCS were analyzed 10 weeks before and after the implementation of a standardized documentation template at weekly multidisciplinary breast cancer conferences. RESULTS Documented adherence rates increased postimplementation in patients undergoing consideration for both radiation treatment and hormone therapy within 1 year of BCS (89% v 65%; P = .045% and 85% v 62%; P = .002, respectively). No change was observed in patients undergoing evaluation for cytotoxic chemotherapy (80% v 85%; P = 1.00). CONCLUSION The addition of a documentation template to multidisciplinary breast cancer conferences resulted in increased recorded adherence rates to national guidelines. This template provided a means of both accurate and efficient documentation of evidence-based practice, which represents a concept with broad application in quality improvement. Although evaluation of the project was not continued beyond the pilot stage, current quality measure scores remain within the same range.
Success in elite cycling: A prospective and retrospective analysis of race results

Abstract The development of peak performances is a main research focus in sports science. It is unclear how many former top junior athletes achieve success in the elite class later. The aim of the present study was to examine the careers of athletes who participated in major junior or adult/elite cycling events using prospective and retrospective analysis of competition results. The official results of major junior (age ≤ 18 years) and elite (age > 18 years) cycling races from 1980 to 2004 were analysed. Age-related aspects, career lengths, and success were compared between riders who presented results in both junior and elite races (JUNIOR ELITE) and riders who had no junior race results (ELITE ONLY). Altogether, 27,454 results of 8004 athletes from 108 countries were collected. We found that 29.4% of the elite athletes had participated in junior World Championships, and that 34% of the participants in junior World Championships later participated in major elite competitions. JUNIOR ELITE athletes are significantly more successful in several cycling disciplines and have their first and last elite result at a younger age than ELITE ONLY athletes. No difference was found in career lengths. The data presented here emphasize the importance of long-term training programmes in the development of peak performance in cycling.
Behavioral state modulates the ON visual motion pathway of Drosophila

Significance Animal visual systems are typically thought of by analogy to cameras—sensory systems providing continuous information streams that are processed through fixed algorithms. However, studies in flies and mice have shown that visual neurons are dynamically and adaptively retuned by the behavioral state of the animal. In Drosophila, prominent higher-order neurons in the visual system respond more strongly to fast-moving stimuli once the animal starts walking or flying. In this study, we systematically investigated the neurobiological mechanism governing the behavioral-state modulation of directionally selective neurons in Drosophila. We show that behavioral activity modifies the physiological properties of critical neurons in this visual motion circuit and that neuromodulation by central feedback neurons recapitulates these effects. The behavioral state of an animal can dynamically modulate visual processing. In flies, the behavioral state is known to alter the temporal tuning of neurons that carry visual motion information into the central brain. However, where this modulation occurs and how it tunes the properties of this neural circuit are not well understood. Here, we show that the behavioral state alters the baseline activity levels and the temporal tuning of the first directionally selective neuron in the ON motion pathway (T4) as well as its primary input neurons (Mi1, Tm3, Mi4, Mi9). These effects are especially prominent in the inhibitory neuron Mi4, and we show that central octopaminergic neurons provide input to Mi4 and increase its excitability. We further show that octopamine neurons are required for sustained behavioral responses to fast-moving, but not slow-moving, visual stimuli in walking flies. These results indicate that behavioral-state modulation acts directly on the inputs to the directionally selective neurons and supports efficient neural coding of motion stimuli.