Miracle-dz/UniFAR-FTUs huggingface dataset:
Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 μg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (p < 0.01), and the significant increase in oxidative stress and inflammation evidenced by up-regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1β and tumour necrosis factor-α (p < 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (p < 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide dismutase activity (p < 0.01) compared with control and incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (p < 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down-regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn.
Ultrastructural and optogenetic dissection of V1 corticotectal terminal synaptic properties

The superior colliculus (SC) is a major site of sensorimotor integration in which sensory inputs are processed to initiate appropriate motor responses. Projections from the primary visual cortex (V1) to the SC have been shown to exert a substantial influence on visually induced behavior, including “freezing. ” However, it is unclear how V1 corticotectal terminals affect SC circuits to mediate these effects. To investigate this, we used anatomical and optogenetic techniques to examine the synaptic properties of V1 corticotectal terminals. Electron microscopy revealed that V1 corticotectal terminals labeled by anterograde transport primarily synapse (93%) on dendrites that do not contain gamma aminobutyric acid (GABA). This preference was confirmed using optogenetic techniques to photoactivate V1 corticotectal terminals in slices of the SC maintained in vitro. In a mouse line in which GABAergic SC interneurons express green fluorescent protein (GFP), few GFP‐labeled cells (11%) responded to activation of corticotectal terminals. In contrast, 67% of non‐GABAergic cells responded to activation of V1 corticotectal terminals. Biocytin‐labeling of recorded neurons revealed that wide‐field vertical (WFV) and non‐WFV cells were activated by V1 corticotectal inputs. However, WFV cells were activated in the most uniform manner; 85% of these cells responded with excitatory postsynaptic potentials (EPSPs) that maintained stable amplitudes when activated with light trains at 1–20 Hz. In contrast, in the majority of non‐WFV cells, the amplitude of evoked EPSPs varied across trials. Our results suggest that V1 corticotectal projections may initiate freezing behavior via uniform activation of the WFV cells, which project to the pulvinar nucleus.
Cell-Mediated Immune Responses and Immunopathogenesis of Human Tick-Borne Encephalitis Virus-Infection

Tick-borne encephalitis virus (TBEV) is a flavivirus that belongs to the Flaviviridae family. TBEV is transmitted to humans primarily from infected ticks. The virus causes tick-borne encephalitis (TBE), an acute viral disease that affects the central nervous system (CNS). Infection can lead to acute neurological symptoms of significant severity due to meningitis or meningo(myelo)encephalitis. TBE can cause long-term suffering and has been recognized as an increasing public health problem. TBEV-affected areas currently include large parts of central and northern Europe as well as northern Asia. Infection with TBEV triggers a humoral as well as a cell-mediated immune response. In contrast to the well-characterized humoral antibody-mediated response, the cell-mediated immune responses elicited to natural TBEV-infection have been poorly characterized until recently. Here, we review recent progress in our understanding of the cell-mediated immune response to human TBEV-infection. A particular emphasis is devoted to studies of the response mediated by natural killer (NK) cells and CD8 T cells. The studies described include results revealing the temporal dynamics of the T cell- as well as NK cell-responses in relation to disease state and functional characterization of these cells. Additionally, we discuss specific immunopathological aspects of TBEV-infection in the CNS.
Protective effect of extractive and biotechnological chondroitin in insulin amyloid and advanced glycation end product‐induced toxicity

Glycosaminoglycans are extracellular matrix components related to several biological functions and diseases. Chondroitin sulfate is a sulphated glycosaminoglycan synthesized as part of proteoglycan molecules. They are frequently associated with amyloid deposits and possess an active role in amyloid fibril formation. Recently, a neuroprotective effect of extracellular matrix components against amyloid toxicity and oxidative stress has been reported. Advanced glycation end products (AGEs), the end products of the glycation reaction, have been linked to amyloid‐based neurodegenerative disease as associated with oxidative stress and inflammation. In this study we have analyzed the effect of chondroitin sulfate isolated from different species, in comparison with a new biotechnological unsulfated chondroitin, in the amyloid aggregation process of insulin, as well as the ability to prevent the formation of AGEs and related toxicity. The results have showed a determining role of chondroitin sulfate groups in modulating insulin amyloid aggregation. In addition, both sulfated and unsulfated chondroitins have shown protective properties against amyloid and AGEs‐induced toxicity. These data are very relevant as a protective effect of these glycosaminoglycans in the AGE‐induced toxicity was never observed before. Moreover, considering the issues related to the purity and safety of chondroitin from natural sources, this study suggests a new potential application for the biotechnological chondroitin.
Lack of Bias Evaluation and Inadequate Study Selection May Produce Misleading Results.

is not routine to alter succinylcholine doses in patients simply because they are receiving oral contraceptives. If we accept that succinylcholine dosing should be driven by pseudocholinesterase activity changes alone, then we must alter our succinylcholine dose for exhaustive subsets of patients, such as women when they enter menopause given the equally important impact of menopause on pseudocholinesterase levels.3 Similarly, we acknowledge that sugammadex may have drug interactions with hormonal contraceptives that potentially affect the efficacy of these drugs.4 It is important to note that patients receiving several forms of antihistamines, antibiotics, anticonvulsants, and antiemetics are at similar risk, and management recommendations are tendentious.5,6 Because of the short half-life of sugammadex and the continuous use of estrogens to promote feminization over the course of years in transgender women, this interaction will not significantly alter the course of feminizing hormone therapy for a transgender woman. The authors would like to emphasize that the optimal care of transgender patients necessitates a multidisciplinary approach with open channels of communication between patient and all providers. As stated in our article, the decision to withhold hormone therapy—or its corollary—assumes the risk of a missed dose of estrogen in the perioperative period is made by the endocrinologist and surgeon. It is imperative that information on hormone regimens of transgender patients is effectively conveyed to the anesthesiologist to ensure that the appropriate clinical decisions are made during the perioperative period. In conclusion, we commend Tsai et al1 for the thoughtprovoking dialogue. To avoid doing harm to an already vulnerable population, Tsai et al1 are absolutely correct: we must all remain vigilant.
Association Between Cerebral Hypoperfusion and Cognitive Impairment in Patients With Chronic Vertebra-Basilar Stenosis

Objective: This study aimed to investigate the association between cognitive impairment and cerebral haemodynamic changes in patients with chronic vertebra-basilar (VB) stenosis. Methods: Patients with severe posterior circulation VB stenosis and infarction or a history of infarction for more than 2 weeks from January 2014 to January 2015 were enrolled (n = 96). They were divided into three groups, namely, the computed tomography perfusion (CTP) normal group, the CTP compensated group, and the CTP decompensated group. Cognitive function was assessed using a validated Chinese version of the Mini-Mental State Examination (MMSE), the Frontal Assessment Battery (FAB), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Regression models were used to identify independent risk factors for cognitive impairment. Results: The MMSE and FAB scores of patients in the CTP decompensated group were significantly lower than those of patients in the CTP normal and CTP compensated groups (all p < 0.05). The RBANS total and its domain scores, including immediate memory, visual acuity, and delayed memory, in the CTP compensated and CTP decompensated groups were significantly lower than those in the CTP normal group (all p < 0.05). Multiple regression analyses showed that CTP compensation, CTP decompensation, severe VB tandem stenosis, and multiple infarctions were independent risk factors for cognitive impairment. Conclusions: Low perfusion caused by severe VB stenosis can lead to extensive cognitive impairments in areas such as immediate memory, visual span, and delayed memory.
Taking a Closer Look at Domain Shift: Category-Level Adversaries for Semantics Consistent Domain Adaptation

We consider the problem of unsupervised domain adaptation in semantic segmentation. The key in this campaign consists in reducing the domain shift, i.e., enforcing the data distributions of the two domains to be similar. A popular strategy is to align the marginal distribution in the feature space through adversarial learning. However, this global alignment strategy does not consider the local category-level feature distribution. A possible consequence of the global movement is that some categories which are originally well aligned between the source and target may be incorrectly mapped. To address this problem, this paper introduces a category-level adversarial network, aiming to enforce local semantic consistency during the trend of global alignment. Our idea is to take a close look at the category-level data distribution and align each class with an adaptive adversarial loss. Specifically, we reduce the weight of the adversarial loss for category-level aligned features while increasing the adversarial force for those poorly aligned. In this process, we decide how well a feature is category-level aligned between source and target by a co-training approach. In two domain adaptation tasks, i.e., GTA5 -> Cityscapes and SYNTHIA -> Cityscapes, we validate that the proposed method matches the state of the art in segmentation accuracy.
Evidence of Zip1 Promoting Sister Kinetochore Mono-orientation During Meiosis in Budding Yeast

Halving of the genome during meiosis I is achieved as the homologous chromosomes move to the opposite spindle poles whereas the sister chromatids stay together and move to the same pole. This requires that the sister kinetochores should take a side-by-side orientation in order to connect to the microtubules emanating from the same pole. Factors that constrain sister kinetochores to adopt such orientation are therefore crucial to achieve reductional chromosome segregation in meiosis I. In budding yeast, a protein complex, known as monopolin, is involved in conjoining of the sister kinetochores and thus facilitates their binding to the microtubules from the same pole. In this study, we report Zip1, a synaptonemal complex component, as another factor that might help the sister kinetochores to take the side-by-side orientation and promote their mono-orientation on the meiosis I spindle. From our results, we propose that the localization of Zip1 at the centromere may provide an additional constraining factor that promotes monopolin to cross-link the sister kinetochores enabling them to mono-orient.
Kinetic mechanism of coupled binding in sodium-aspartate symporter GltPh

Many secondary active membrane transporters pump substrates against concentration gradients by coupling their uptake to symport of sodium ions. Symport requires the substrate and ions to be always transported together. Cooperative binding of the solutes is a key mechanism contributing to coupled transport in the sodium and aspartate symporter from Pyrococcus horikoshii GltPh. Here, we describe the kinetic mechanism of coupled binding for GltPh in the inward facing state. The first of the three coupled sodium ions, binds weakly and slowly, enabling the protein to accept the rest of the ions and the substrate. The last ion binds tightly, but is in rapid equilibrium with solution. Its release is required for the complex disassembly. Thus, the first ion serves to ‘open the door’ for the substrate, the last ion ‘locks the door’ once the substrate is in, and one ion contributes to both events.
BlockPKI: An Automated, Resilient, and Transparent Public-Key Infrastructure

This paper describes BlockPKI, a blockchain-based public-key infrastructure that enables an automated, resilient, and transparent issuance of digital certificates. Our goal is to address several shortcomings of the current TLS infrastructure and its proposed extensions. In particular, we aim at reducing the power of individual certification authorities and make their actions publicly visible and accountable, without introducing yet another trusted third party. To demonstrate the benefits and practicality of our system, we present evaluation results and describe our prototype implementation.
Divalent ions tune the kinetics of a bacterial GTPase center rRNA folding transition from secondary to tertiary structure

Folding of an RNA from secondary to tertiary structure often depends on divalent ions for efficient electrostatic charge screening (nonspecific association) or binding (specific association). To measure how different divalent cations modify folding kinetics of the 60 nucleotide E. coli rRNA GTPase center, we combined stopped-flow fluorescence in the presence of Mg2+, Ca2+, or Sr2+ together with time-resolved small angle X-ray scattering (SAXS) in the presence of Mg2+ to observe the folding process. Immediately upon addition of each divalent ion, the RNA undergoes a transition from an extended state with secondary structure to a more compact structure. Subsequently, specific divalent ions modulate populations of intermediates in conformational ensembles along the folding pathway with transition times longer than 10 msec. Rate constants for the five folding transitions act on timescales from submillisecond to tens of seconds. The sensitivity of RNA tertiary structure to divalent cation identity affects all but the fastest events in RNA folding, and allowed us to identify those states that prefer Mg2+. The GTPase center RNA appears to have optimized its folding trajectory to specifically utilize this most abundant intracellular divalent ion.
Evaluating stochastic seeding strategies in networks

When trying to maximize the adoption of a behavior in a population connected by a social network, it is common to strategize about where in the network to seed the behavior, often with an element of randomness. Selecting seeds uniformly at random is a basic but compelling strategy in that it distributes seeds broadly throughout the network. A more sophisticated stochastic strategy, one-hop targeting, is to select random network neighbors of random individuals; this exploits a version of the friendship paradox, whereby the friend of a random individual is expected to have more friends than a random individual, with the hope that seeding a behavior at more connected individuals leads to more adoption. Many seeding strategies have been proposed, but empirical evaluations have demanded large field experiments designed specifically for this purpose and have yielded relatively imprecise comparisons of strategies. Here we show how stochastic seeding strategies can be evaluated more efficiently in such experiments, how they can be evaluated “off-policy” using existing data arising from experiments designed for other purposes, and how to design more efficient experiments. In particular, we consider contrasts between stochastic seeding strategies and analyze nonparametric estimators adapted from policy evaluation and importance sampling. We use simulations on real networks to show that the proposed estimators and designs can substantially increase precision while yielding valid inference. We then apply our proposed estimators to two field experiments, one that assigned households to an intensive marketing intervention and one that assigned students to an antibullying intervention. This paper was accepted by Gui Liberali, Special Issue on Data-Driven Prescriptive Analytics.
Association of IL‐1β, IL‐1RN, and ESR1 genes polymorphism with risk of infection and response to sofosbuvir plus daclatasvir combination therapy in hepatitis C virus genotype‐4 patients

Sofosbuvir (SOF) and daclatasvir combination with or without ribavirin proved to be effective and safe in the treatment of hepatitis C virus infection. The study aimed to assess the efficacy of (SOF plus daclatasvir) combination + ribavirin in the treatment of treatment‐experienced HCV genotype 4 Egyptian patients and to investigate the impact of IL‐1β _31, IL‐1β _511, and IL‐1RN and T29C of ESR1 genes polymorphisms on treatment outcome. The study also aimed to assess the effect of the treatment on liver fibrosis. The sustained virologic response was assessed at 0, 4, 12, and 24 weeks from the beginning of treatment by RT‐PCR. IL‐1β _31, IL‐1β _511, IL‐1RN, and T29C genes polymorphisms were examined by PCR‐based techniques in two groups of patients (responders and non‐responders) and a control group of healthy subjects. A significant association between IL‐1β_511 gene polymorphism and SOF/DAV‐induced response was observed, where the “CC” genotype was the most frequent in responders while the “CT” genotype was the most frequent among non‐responders (P = 0.0001, OR = 39; 95% CI = 4.7–316). IL‐1RN gene polymorphism also showed significant associations with response to treatment, genotypes that include allele “1” were the most frequent in responders, particularly the homozygous genotype “1/1” (P = 0.0001, OR = 2.3; 95% CI = 1.57–3.2). However, the genotypes “4/4” and “2/4” were the most frequent in non‐responders; (P = 0.0001). At least 71% of the responders carry allele “1” while 54% of non‐responders were allele “4” carriers (P value = 0.0001. OR = 2.8; 95% CI = 6.4–134.2). Liver fibrosis is significantly improved regardless of the response. © 2018 IUBMB Life, 70(11):1156–1163, 2018
Single-molecule analysis of endogenous β-actin mRNA trafficking reveals a mechanism for compartmentalized mRNA localization in axons

Significance De novo protein synthesis in neuronal axons plays important roles in neural circuit formation, maintenance, and disease. Key to the selectivity of axonal protein synthesis is whether an mRNA is present at the right place to be translated, but the mechanisms behind axonal mRNA localization remain poorly understood. In this work, we quantitatively analyze the link between axonal β-actin mRNA trafficking and its localization patterns. By developing a single-molecule approach to live-image β-actin mRNAs in axons, we explore the biophysical drivers behind β-actin mRNA motion and uncover a mechanism for generating increased density at the axon tip by differences in motor protein-driven transport speeds. These results provide mechanistic insight into the control of local translation through mRNA trafficking. During embryonic nervous system assembly, mRNA localization is precisely regulated in growing axons, affording subcellular autonomy by allowing controlled protein expression in space and time. Different sets of mRNAs exhibit different localization patterns across the axon. However, little is known about how mRNAs move in axons or how these patterns are generated. Here, we couple molecular beacon technology with highly inclined and laminated optical sheet microscopy to image single molecules of identified endogenous mRNA in growing axons. By combining quantitative single-molecule imaging with biophysical motion models, we show that β-actin mRNA travels mainly as single copies and exhibits different motion-type frequencies in different axonal subcompartments. We find that β-actin mRNA density is fourfold enriched in the growth cone central domain compared with the axon shaft and that a modicum of directed transport is vital for delivery of mRNA to the axon tip. Through mathematical modeling we further demonstrate that directional differences in motor-driven mRNA transport speeds are sufficient to generate β-actin mRNA enrichment at the growth cone. Our results provide insight into how mRNAs are trafficked in axons and a mechanism for generating different mRNA densities across axonal subcompartments.
High tacrolimus clearance – a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single‐center cohort study

Patients with high tacrolimus clearance are more likely to experience transient under‐immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1‐year post‐transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1‐year post‐transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11–2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18–3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.