Miracle-dz/UniFAR-FTUs huggingface dataset:
Aquaporin-4-dependent glymphatic solute transport in the rodent brain

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.
Regulation of erythrocyte Na+/K+/2Cl− cotransport by an oxygen-switched kinase cascade

Many erythrocyte processes and pathways, including glycolysis, the pentose phosphate pathway (PPP), KCl cotransport, ATP release, Na+/K+-ATPase activity, ankyrin–band 3 interactions, and nitric oxide (NO) release, are regulated by changes in O2 pressure that occur as a red blood cell (RBC) transits between the lungs and tissues. The O2 dependence of glycolysis, PPP, and ankyrin–band 3 interactions (affecting RBC rheology) are controlled by O2-dependent competition between deoxyhemoglobin (deoxyHb), but not oxyhemoglobin (oxyHb), and other proteins for band 3. We undertook the present study to determine whether the O2 dependence of Na+/K+/2Cl− cotransport (catalyzed by Na+/K+/2Cl− cotransporter 1 [NKCC1]) might similarly originate from competition between deoxyHb and a protein involved in NKCC1 regulation for a common binding site on band 3. Using three transgenic mouse strains having mutated deoxyhemoglobin-binding sites on band 3, we found that docking of deoxyhemoglobin at the N terminus of band 3 displaces the protein with no lysine kinase 1 (WNK1) from its overlapping binding site on band 3. This displacement enabled WNK1 to phosphorylate oxidative stress-responsive kinase 1 (OSR1), which, in turn, phosphorylated and activated NKCC1. Under normal solution conditions, the NKCC1 activation increased RBC volume and thereby induced changes in RBC rheology. Because the deoxyhemoglobin-mediated WNK1 displacement from band 3 in this O2 regulation pathway may also occur in the regulation of other O2-regulated ion transporters, we hypothesize that the NKCC1-mediated regulatory mechanism may represent a general pattern of O2 modulation of ion transporters in erythrocytes.
Allantoin accumulation through overexpression of ureide permease1 improves rice growth under limited nitrogen conditions

Summary In legumes, nitrogen (N) can be stored as ureide allantoin and transported by ureide permease (UPS) from nodules to leaves where it is catabolized to release ammonium and assimilation to amino acids. In non‐leguminous plants especially rice, information on its roles in N metabolism is scarce. Here, we show that OsUPS1 is localized in plasma membranes and are highly expressed in vascular tissues of rice. We further evaluated an activation tagging rice overexpressing OsUPS1 (OsUPS1 OX) under several N regimes. Under normal field conditions, panicles from OsUPS1 OX plants (14 days after flowering (DAF)) showed significant allantoin accumulation. Under hydroponic system at the vegetative stage, plants were exposed to N‐starvation and measured the ammonium in roots after resupplying with ammonium sulphate. OsUPS1 OX plants displayed higher ammonium uptake in roots compared to wild type (WT). When grown under low‐N soil supplemented with different N‐concentrations, OsUPS1 OX exhibited better growth at 50% N showing higher chlorophyll, tiller number and at least 20% increase in shoot and root biomass relative to WT. To further confirm the effects of regulating the expression of OsUPS1, we evaluated whole‐body‐overexpressing plants driven by the GOS2 promoter (OsUPS1 GOS 2) as well as silencing plants (OsUPS1 RNA i). We found significant accumulation of allantoin in leaves, stems and roots of OsUPS1 GOS 2 while in OsUPS1 RNA i allantoin was significantly accumulated in roots. We propose that OsUPS1 is responsible for allantoin partitioning in rice and its overexpression can support plant growth through accumulation of allantoin in sink tissues which can be utilized when N is limiting.
Linbots: Soft Modular Robots Utilizing Voice Coils

Abstract Robots performing automated tasks in uncontrolled environments need to adapt to environmental changes. Through building large collectives of robots, this robust and adaptive behavior can emerge from simple individual rules. These collectives can also be reconfigured, allowing for adaption to new tasks. Larger collectives are more robust and more capable, but the size of existing collectives is limited by the cost of individual units. In this article, we present a soft, modular robot that we have explicitly designed for manufacturability: Linbots. Linbots use multifunctional voice coils to actuate linearly, to produce audio output, and to sense touch. When used in collectives, the Linbots can communicate with neighboring Linbots allowing for isolated behavior as well as the propagation of information throughout a collective. We demonstrate that these collectives of Linbots can perform complex tasks in a scalable distributed manner, and we show transport of objects by collective peristalsis and sorting of objects by a two-dimensional array of Linbots.
All in One: Cavity Detection, Druggability Estimate, Cavity-Based Pharmacophore Perception, and Virtual Screening

Discovering the very first ligands of pharmacologically important targets in a fast and cost-efficient manner is an important issue in drug discovery. In the absence of structural information on either endogenous or synthetic ligands, computational chemists classically identify the very first hits by docking compound libraries to a binding site of interest, with well-known biases arising from the usage of scoring functions. We herewith propose a novel computational method tailored to ligand-free protein structures and consisting in the generation of simple cavity-based pharmacophores to which potential ligands could be aligned by the use of a smooth Gaussian function. The method, embedded in the IChem toolkit, automatically detects ligand-binding cavities, then predicts their structural druggability, and last creates a structure-based pharmacophore for predicted druggable binding sites. A companion tool (Shaper2) was designed to align ligands to cavity-derived pharmacophoric features. The proposed method is as efficient as state-of-the-art virtual screening methods (ROCS, Surflex-Dock) in both posing and virtual screening challenges. Interestingly, IChem-Shaper2 is clearly orthogonal to these latter methods in retrieving unique chemotypes from high-throughput virtual screening data.
Semicircular canal biomechanics in health and disease

The semicircular canals are responsible for sensing angular head motion in three-dimensional space and for providing neural inputs to the central nervous system (CNS) essential for agile mobility, stable vision, and autonomic control of the cardiovascular and other gravity-sensitive systems. Sensation relies on fluid mechanics within the labyrinth to selectively convert angular head acceleration into sensory hair bundle displacements in each of three inner ear sensory organs. Canal afferent neurons encode the direction and time course of head movements over a broad range of movement frequencies and amplitudes. Disorders altering canal mechanics result in pathological inputs to the CNS, often leading to debilitating symptoms. Vestibular disorders and conditions with mechanical substrates include benign paroxysmal positional nystagmus, direction-changing positional nystagmus, alcohol positional nystagmus, caloric nystagmus, Tullio phenomena, and others. Here, the mechanics of angular motion transduction and how it contributes to neural encoding by the semicircular canals is reviewed in both health and disease.
The Prosody of Rhetorical and Information-Seeking Questions in German

This paper reports on the prosody of rhetorical questions (RQs) and information-seeking questions (ISQs) in German for two question types—polar questions and constituent questions (henceforth “wh-questions”). The results are as follows: Phonologically, polar RQs were mainly realized with H-% (high plateau), while polar ISQs mostly ended in H-^H% (high-rise). Wh-RQs almost exclusively terminated in a low edge tone, whereas wh-ISQs allowed for more tonal variation (L-%, L-H%, H-^H%). Irrespective of question type, RQs were mainly produced with L*+H accents. Phonetically, RQs were more often realized with breathy voice quality than ISQs, in particular in the beginning of the interrogative. Furthermore, they were produced with longer constituent durations than ISQs, in particular at the end of the interrogative. While the difference between RQs and ISQs is reflected in the intonational terminus of the utterance, this does not happen in the way suggested in the semantic literature, and in addition, accent type and phonetic parameters also play a role. Crucially, a simple distinction between rising and falling intonation is insufficient to capture the realization of the different illocution types (RQs, ISQs), against frequent claims in the semantic and pragmatic literature. We suggest alternative ways to interpret the findings.
Nonparametric Maximum Likelihood Estimators of Time-Dependent Accuracy Measures for Survival Outcome Under Two-Stage Sampling Designs

ABSTRACT Large prospective cohort studies of rare chronic diseases require thoughtful planning of study designs, especially for biomarker studies when measurements are based on stored tissue or blood specimens. Two-phase designs, including nested case–control and case-cohort sampling designs, provide cost-effective strategies for conducting biomarker evaluation studies.Existing literature for biomarker assessment under two-phase designs largely focuses on simple inverse probability weighting (IPW) estimators. Drawing on recent theoretical development on the maximum likelihood estimators for relative risk parameters in two-phase studies, we propose nonparametric maximum likelihood-based estimators to evaluate the accuracy and predictiveness of a risk prediction biomarker under both types of two-phase designs. In addition, hybrid estimators that combine IPW estimators and maximum likelihood estimation procedure are proposed to improve efficiency and alleviate computational burden. We derive large sample properties of proposed estimators and evaluate their finite sample performance using numerical studies. We illustrate new procedures using a two-phase biomarker study aiming to evaluate the accuracy of a novel biomarker, des-γ-carboxy prothrombin, for early detection of hepatocellular carcinoma. Supplementary materials for this article are available online.
Targeting the lysosome by an aminomethylated Riccardin D triggers DNA damage through cathepsin B‐mediated degradation of BRCA1

RD‐N, an aminomethylated derivative of riccardin D, is a lysosomotropic agent that can trigger lysosomal membrane permeabilization followed by cathepsin B (CTSB)‐dependent apoptosis in prostate cancer (PCa) cells, but the underlying mechanisms remain unknown. Here we show that RD‐N treatment drives CTSB translocation from the lysosomes to the nucleus where it promotes DNA damage by suppression of the breast cancer 1 protein (BRCA1). Inhibition of CTSB activity with its specific inhibitors, or by CTSB‐targeting siRNA or CTSB with enzyme‐negative domain attenuated activation of BRCA1 and DNA damage induced by RD‐N. Conversely, CTSB overexpression resulted in inhibition of BRCA1 and sensitized PCa cells to RD‐N‐induced cell death. Furthermore, RD‐N‐induced cell death was exacerbated in BRCA1‐deficient cancer cells. We also demonstrated that CTSB/BRCA1‐dependent DNA damage was critical for RD‐N, but not for etoposide, reinforcing the importance of CTSB/BRCA1 in RD‐N‐mediated cell death. In addition, RD‐N synergistically increased cell sensitivity to cisplatin, and this effect was more evidenced in BRCA1‐deficient cancer cells. This study reveals a novel molecular mechanism that RD‐N promotes CTSB‐dependent DNA damage by the suppression of BRCA1 in PCa cells, leading to the identification of a potential compound that target lysosomes for cancer treatment.
Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease

The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive. ABSTRACT The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive. From these efforts, the triphenylethylene class of selective estrogen receptor modulators related to tamoxifen has shown activity against a wide range of medically important human pathogens, including bacteria, fungi, parasites, and viruses. Because it has activity against many pathogens affecting people in resource-limited areas of the world, TAM and related drugs may be particularly useful. Here, we review the in vitro, in vivo, and mechanistic studies of the anti-infective activity of tamoxifen, toremifene, clomiphene, and their analogs. We also discuss the pharmacologic properties of this privileged scaffold and its potential utility in treating infectious diseases.
All three IP3 receptor isoforms generate Ca2+ puffs that display similar characteristics

The three IP3R isoforms produce Ca2+ puffs with largely indistinguishable features. Different isoforms, similar Ca2+ puffs Cells express three different isoforms of the inositol trisphosphate receptor (IP3R), which underlie Ca2+ signals ranging from local puffs to global waves. Lock et al. used CRISPR-Cas9 gene editing to create HEK-293 cell lines that expressed individual IP3R isoforms. Despite their reported divergent functional properties, each isoform produced Ca2+ puffs with similar characteristics. Future work is required to determine how these conserved Ca2+ puffs give rise to different global Ca2+ signals. Inositol 1,4,5-trisphosphate (IP3) evokes Ca2+ release through IP3 receptors (IP3Rs) to generate both local Ca2+ puffs arising from concerted openings of clustered IP3Rs and cell-wide Ca2+ waves. Imaging Ca2+ puffs with single-channel resolution yields information on the localization and properties of native IP3Rs in intact cells, but interpretation has been complicated because cells express varying proportions of three structurally and functionally distinct isoforms of IP3Rs. Here, we used TIRF and light-sheet microscopy to image Ca2+ puffs in HEK-293 cell lines generated by CRISPR-Cas9 technology to express exclusively IP3R type 1, 2, or 3. Photorelease of the IP3 analog i-IP3 in all three cell lines evoked puffs with largely similar mean amplitudes, temporal characteristics, and spatial extents. Moreover, the single-channel Ca2+ flux was similar among isoforms, indicating that clusters of different IP3R isoforms contain comparable numbers of active channels. Our results show that all three IP3R isoforms cluster to generate local Ca2+ puffs and, contrary to findings of divergent properties from in vitro electrophysiological studies, display similar conductances and gating kinetics in intact cells.
Randomised controlled trials as part of clinical care: A seven‐step routinisation framework proposal

Evidence translation in wound care relies on the need for evidence generation. Clinical practice may generate evidence only if evidence‐generating research projects, such as randomised controlled trials (RCTs), became routinised in clinical settings. The aim of this study was to identify optimal trial‐related practices to routinise trial‐related activities in Melbourne‐located wound clinics as reported by clinicians and researchers. We conducted a secondary analysis of the available data on how to routinise RCTs in clinical care, with a focus on enablers and suggestions provided by the participants during face‐to‐face and telephone interviews. Data were obtained from a qualitative observational study nested within a randomised, double‐blinded, placebo‐controlled trial on clinical effectiveness of aspirin as an adjunct to compression therapy in healing chronic venous leg ulcers (ASPiVLU). We developed a seven‐step Routinisation of Trials in Clinical Care Framework. These steps include: (1) pre‐trial clinical site assessment, (2) optimising pre‐recruitment arrangements, (3) developing and updating trial‐related skills, (4) embedding RCT recruitment as part of routine clinical care, (5) promoting teamwork and trial‐related collaboration, (6) addressing trial‐related financial issues, and (7) communicating trial results to clinicians.
The Bazaar: Markets and Merchants of the Islamic World

In the empire of the senses the endless caravan shrine and market place - how the bazaar works craftsmen and shopkeepers - their work and goods the heart of the city - portraits of the best bazaars - Cairo, Damascus, Aleppo, Istanbul, Sanaa, Dubai, Kairouan, Tunis, Marrakesh, Fez, Shiraz, Isfahan, Samarkand, Bukhara, Khiva.
Roco Proteins and the Parkinson’s Disease-Associated LRRK2

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.
Morfologia e biologia floral de cinco especies de Passiflora L. (Passifloraceae)

Foi realizado o estudo comparativo sobre a morfologia e a biologia floral de cinco especies de Passiflora (P. alata, P. amethystina, P. capsularis, P. miersii e P.suberosa), ocorrentes na Reserva Municipal de Santa Genebra. Passiflora alata, P. amethystina e P. miersii possuem flores com corona filamentosa de cor purpura ao violeta, operculo membranaceo que encobre a câmara nectarifera de formato campanulado. Florescem basicamente na estacao chuvosa. Suas flores abrem no inicio da manha e duram um dia, sao perfumadas, a corona e um guia de nectar visual e olfativo, a concentracao de acucares do nectar mede de 31 a 41%, sao autoincompativeis e sua polinizacao e feita por abelhas de grande porte. As morfologias florais de P. amethystina e P. miersii sao semelhantes, diferindo de P. alata por apresentarem no operculo filamentos livres em sua parte superior. Em P. alata o operculo e horizontal e denticulado. Estas caracteristicas do operculo exigem das abelhas um comportamento distinto durante as visitas. Passiflora suberosa possui flores inconspicuas, verdeamareladas, com corona de duas series de filamentos, operculo plicado e câmara nectarifera de formato anular. Floresce durante o ano todo. As flores abrem as 06:00h e duram apenas um dia. sao inodoras, a concentracao de acucares do nectar e de 25%, sao autocompativeis e polinizadas por vespas. Passiflora capsularis possui flores brancas, com corona de uma serie de filamentos, operculo plicado e câmara nectarifera de formato anular. Floresce de outubro a maio. As flores abrem as OO:30h e duram ca. 13 horas, sao perfumadas, a concentracao de acucares do nectar e de 27%, sao autocompativeis e possivelmente polinizadas por mariposas. o operculo plicado destas especies permite que os visitantes tenham facil acesso ao nectar. Baseando-se neste estudo, sugerimos que as especies de Passiflora polinizadas por abelhas provavelmente representem o grupo ancestral do qual derivaram as especies polinizadas por outros agentes polinizadores (lepidoteros, beija-flores, morcegos) Abstract
Electrophysiological properties of the South Asian heart

Objective The South Asian population has a lower burden of arrhythmia compared with Caucasians despite a higher prevalence of traditional cardiovascular risk factors. We aimed to determine whether this was due to differences in the electrophysiological properties of the South Asian heart. Methods We performed a retrospective cohort study of South Asian and Caucasian patients who underwent an electrophysiology study for supraventricular tachycardia between 2005 and 2017. Surface ECG, intracardiac ECG and intracardiac conduction intervals were measured and a comparison between the two ethnic cohorts was performed. Results A total of 5908 patients underwent an electrophysiology study at the Yorkshire Heart Centre, UK, during the study period. Of these 262 were South Asian and 113 met the eligibility criteria. South Asians had a significantly higher resting heart rate (p=0.024), shorter QRS duration (p=0.012) and a shorter atrioventricular (AV; p=0.001)) and ventriculoatrial (VA; p=0.013) effective refractory period (ERP). There was no difference in atrial or ventricular ERP. On linear regression analysis, South Asian ethnicity was independently predictive of a higher resting heart rate, narrower QRS and shorter AV-ERP and VA-ERP. Conclusions South Asians have significant differences in their resting heart rate, QRS duration and AV nodal function compared with Caucasians. These differences may reflect variations in autonomic function and may also be influenced by genetic factors. Electrophysiological differences such as these may help to explain why South Asians have a lower burden of arrhythmia.
[Effects of ERK and STAT3 on cell signal transduction in alveolar epithelium A549 cells stimulated by mechanical force].

OBJECTIVE To observe the effect of mechanical force on the expression of p-ERK and p-STAT3 when pulmonary epithelium A549 cells were subjected to tensile stress. METHODS By the self-made four-point bending system, the A549 cells were subjected to cyclic tensile stress of 3000 microstrain for 30 min, 1 h, 2 h or 4 h respectively, then the total protein of each time point was collected and the expression of p-ERK and p-STAT3 were detected by Western blot analysis. RESULTS (1) The expression of p-ERK was activated at 1 h and remained at a high level until 4 h. (2) The expression of p-STAT3 (Ser) was activated at 30 min and remained at a high level until 4 h. CONCLUSION Tensile stress can activate the expression of p-ERK and p-STAT3 (Ser) in alveolar epithelium A549 cells. ERK and STAT3 may participate in the cell mechanotransduction in A549 cells.