Miracle-dz/UniFAR-FTUs huggingface dataset:
The Evolving Profile of the Signature Amino Acid Residues in HIV-1 Subtype C Tat.

Using several HIV-1 tat exon 1 amino acid sequences available from public databases and additional sequences derived from a southern Indian clinical cohort, we compared the profile of the signature amino acid residues (SAR) between two different time periods, 1986-2004 and 2005-2014. The analysis identified eight positions as signature residues in subtype C Tat and demonstrated a changing pattern at four of these positions between the two periods. At three locations (histidine 29, serine 57, and proline 60), there appears to be a nonuniform negative selection against the SAR. The negative selection appears to be severe, especially against histidine 29 (p < .0001) and moderate against proline 60 (p < .0001). The negative selection against serine 57 is statistically insignificant and appears to have begun recently. At position 63, the frequency of signature residue glutamic acid increased over the past decade, although the difference was not significant. Importantly, at the three locations where the negative selection is in progress, the substitute amino acids are the generic residues present in most of the other HIV-1 subtypes. Our data demonstrate that viral evolution can subject specific amino acid residues to subtle and progressive selection pressures without affecting the prevalence of other amino acid residues.
Phosphorylation of SPOROCYTELESS/NOZZLE by the MPK3/6 Kinase Is Required for Anther Development1

MPK3/6 is responsible for phosphorylation of SPOROCYTELESS/NOZZLE protein, which is required for its function in Arabidopsis anther development. Germ cells are indispensable carriers of genetic information from one generation to the next. In contrast to the well-understood process in animals, information on the mechanism of germ cell initiation in plants is very limited. SPOROCYTELESS/NOZZLE was previously identified as an essential regulator of diploid germ cell (archesporial cell) differentiation in the stamens and ovules of Arabidopsis (Arabidopsis thaliana). Although SPOROCYTELESS (SPL) transcription is activated by the floral organ identity regulator AGAMOUS and epigenetically regulated by SET DOMAIN GROUP2, little is known about the regulation of the SPL protein. Here, we report that the protein kinases MPK3 and MPK6 can both interact with SPL in vitro and in vivo and can phosphorylate the SPL protein in vitro. In addition, phosphorylation of the SPL protein by MPK3/6 is required for SPL function in the Arabidopsis anther, as measured by its effect on archesporial cell differentiation. We further demonstrate that phosphorylation enhances SPL protein stability. This work not only uncovers the importance of SPL phosphorylation for its regulatory role in Arabidopsis anther development, but also supports the hypothesis that the regulation of precise spatiotemporal patterning of germ cell initiation and that differentiation is achieved progressively through multiple levels of regulation, including transcriptional and posttranslational modification.
Inwardly rectifying K+ channels are major contributors to flow‐induced vasodilatation in resistance arteries

Endothelial inwardly rectifying K+ (Kir2.1) channels regulate flow‐induced vasodilatation via nitric oxide (NO) in mouse mesenteric resistance arteries. Deficiency of Kir2.1 channels results in elevated blood pressure and increased vascular resistance. Flow‐induced vasodilatation in human resistance arteries is also regulated by inwardly rectifying K+ channels. This study presents the first direct evidence that Kir channels play a critical role in physiological endothelial responses to flow.
Quantu mdo tbioconjugate sfo ri nvitro diagnostic s &i nviv oimaging

Semiconductor quantum dots are tiny light-emitting nanocrystals (2-10 nm) that have captivated researchers in the biomedical field in the last decade. Compared to organic dyes and fluorescent proteins, quantum dots (QDs) have unique optical properties such as tunable emission spectra, improved brightness, superior photostability, and simultaneous excitation of multiple fluorescence colors. Since the first successful reports on biological use of QDs a decade ago, QDs and their bioconjugates have been successfully applied in various imaging applications including fixed cell labeling, imaging of live cell dynamics, in situ tissue profiling, fluorescence detection, sensing and in vivo animal imaging. In this review, we will cover the optical properties of QDs, the biofunctionization strategies, their in vitro diagnostic applications and in vivo imaging applications. In addition, we will discuss the making of a new class of QDs - the self-illuminating QDs and their in vivo imaging and sensing applications. We will conclude with the issues and perspectives on QDs as in vivo imaging probes.
Opportunities and challenges in the wider adoption of liver and interconnected microphysiological systems

Liver disease represents a growing global health burden. The development of in vitro liver models which allow the study of disease and the prediction of metabolism and drug-induced liver injury in humans remains a challenge. The maintenance of functional primary hepatocytes cultures, the parenchymal cell of the liver, has historically been difficult with dedifferentiation and the consequent loss of hepatic function limiting utility. The desire for longer term functional liver cultures sparked the development of numerous systems, including collagen sandwiches, spheroids, micropatterned co-cultures and liver microphysiological systems. This review will focus on liver microphysiological systems, often referred to as liver-on-a-chip, and broaden to include platforms with interconnected microphysiological systems or multi-organ-chips. The interconnection of microphysiological systems presents the opportunity to explore system level effects, investigate organ cross talk, and address questions which were previously the preserve of animal experimentation. As a field, microphysiological systems have reached a level of maturity suitable for commercialization and consequent evaluation by a wider community of users, in academia and the pharmaceutical industry. Here scientific, operational, and organizational considerations relevant to the wider adoption of microphysiological systems will be discussed. Applications in which microphysiological systems might offer unique scientific insights or enable studies currently feasible only with animal models are described, and challenges which might be addressed to enable wider adoption of the technologies are highlighted. A path forward which envisions the development of microphysiological systems in partnerships between academia, vendors and industry, is proposed. Impact statement Microphysiological systems are in vitro models of human tissues and organs. These systems have advanced rapidly in recent years and are now being commercialized. To achieve wide adoption in the biological and pharmaceutical research communities, microphysiological systems must provide unique insights which translate to humans. This will be achieved by identifying key applications and making microphysiological systems intuitive to use.
ABO Mistyping of cis-AB Blood Group by the Automated Microplate Technique

Background: The cis-AB phenotype, although rare, is the relatively most frequent of ABO subgroups in Koreans. To prevent ABO mistyping of cis-AB samples, our hospital has applied a combination of the manual tile method with automated devices. Herein, we report cases of ABO mistyping detected by the combination testing system. Methods: Cases that showed discrepant results by automated devices and the manual tile method were evaluated. These samples were also tested by the standard tube method. The automated devices used in this study were a QWALYS-3 and Galileo NEO. Exons 6 and 7 of the ABO gene were sequenced. Results: 13 cases that had the cis-AB allele showed results suggestive of the cis-AB subgroup by manual methods, but were interpreted as AB by either automated device. This happened in 87.5% of these cases by QWALYS-3 and 70.0% by Galileo NEO. Genotyping results showed that 12 cases were ABO*cis-AB01/ABO*O01 or ABO*cis-AB01/ABO*O02, and one case was ABO*cis-AB01/ ABO*A102. Conclusion: Cis-AB samples were mistyped as AB by the automated microplate technique in some cases. We suggest that the manual tile method can be a simple supplemental test for the detection of the cis-AB phenotype, especially in countries with relatively high cis-AB prevalence.
Time-resolved Phosphoproteome Analysis of Paradoxical RAF Activation Reveals Novel Targets of ERK *

Small molecules targeting aberrant RAF activity, like vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream “paradoxical” ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to vemurafenib. Comprehensive data mining and filtering identified a total of 37,910 phosphorylation sites, 660 of which were dynamically modulated upon treatment with vemurafenib. We established that 83% of these dynamic phosphorylation sites were modulated in accordance with the phospho-ERK profile of the two cell lines. Accordingly, kinase substrate prediction algorithms linked most of these dynamic sites to direct ERK1/2-mediated phosphorylation, supporting a low off-target rate for vemurafenib. Functional classification of target proteins indicated the enrichment of known (nuclear pore, transcription factors, and RAS-RTK signaling) and novel (Rho GTPases signaling and actin cytoskeleton) ERK-controlled functions. Our phosphoproteomic data combined with experimental validation established novel dynamic connections between ERK signaling and the transcriptional regulators TEAD3 (Hippo pathway), MKL1, and MKL2 (Rho serum-response elements pathway). We also confirm that an ERK-docking site found in MKL1 is directly antagonized by overlapping actin binding, defining a novel mechanism of actin-modulated phosphorylation. Altogether, time-resolved phosphoproteomics further documented vemurafenib selectivity and identified novel ERK downstream substrates.
Neonatal abstinence syndrome: an update

Purpose of review The current review provides an update focused on the evolving epidemiology of neonatal abstinence syndrome (NAS), factors influencing disease expression, advances in clinical assessment of withdrawal, novel approaches to NAS treatment, and the emerging role of quality improvement in assessment and management of NAS. Recent findings The rise in the incidence of NAS disproportionately occurred in rural and suburban areas. Polysubstance exposure and genetic polymorphisms have been shown to modify NAS expression and severity. New bedside assessments using a limited number of factors to identify infants with NAS result in fewer infants receiving pharmacotherapy. In addition, buprenorphine may be a promising therapeutic alternative to morphine to treat NAS. Lastly, local, state, and national quality improvement initiatives have emerged as an effective mechanism to advance the care of infants with NAS. Summary NAS remains a critical public health issue associated with significant medical, economic, and personal burdens. Emerging data on associated risk factors, assessment of and treatment for NAS provide clinicians and hospitals with new knowledge and an urgency to promote standardization of care for infants with NAS.
Targeted delivery of mannosylated-PLGA nanoparticles of antiretroviral drug to brain

Mannosylated polymeric nanoparticles (NPs) enable improvement of brain bioavailability and reduction of dosing due to efficient drug delivery at the target site. Mannose receptors are present on the surface of macrophages, and therefore, in this study, it is expected that mannosylated NPs of anti-human immunodeficiency virus drug may target the macrophages, which may improve the therapeutic outcome and reduce the toxicity of antiretroviral bioactives. Poly(lactic-co-glycolic acid) (PLGA) and mannosylated-PLGA NPs (Mn-PLGA NPs) were prepared and administered by intravenous route in a dose of 10 mg/kg. After predetermined time period, the pharmacokinetics and biodistribution of NPs were analyzed using high-performance liquid chromatography and confocal microscopy, respectively. Results of this study indicated that Mn-PLGA NPs would be a promising therapeutic system for efficient delivery of the drug into brain macrophages.
Lumacaftor/Ivacaftor in Patients Aged 6‐11 Years with Cystic Fibrosis and Homozygous for F508del‐CFTR

Rationale: Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del‐CFTR, but it has not been assessed in younger patients. Objectives: In this open‐label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6‐11 years with cystic fibrosis who were homozygous for F508del‐CFTR. Methods: Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications. Measurements and Main Results: Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug‐related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], −0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (−24.8 mmol/L; 95% CI, −29.1 to −20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire‐Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (−0.88; 95% CI, −1.40 to −0.37; P = 0.0018). Conclusions: Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health‐related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials. gov (NCT01897233).
e-ASPECTS Correlates with and Is Predictive of Outcome after Mechanical Thrombectomy

BACKGROUND AND PURPOSE: The e-ASPECTS software is a tool for the automated use of ASPECTS. Our aim was to analyze whether baseline e-ASPECT scores correlate with outcome after mechanical thrombectomy. MATERIALS AND METHODS: Patients with ischemic strokes in the anterior circulation who were admitted between 2010 and 2015, diagnosed by CT, and received mechanical thrombectomy were included. The ASPECTS on baseline CT was scored by e-ASPECTS and 3 expert raters, and interclass correlation coefficients were calculated. The e-ASPECTS was correlated with functional outcome (modified Rankin Scale) at 3 months by using the Spearman rank correlation coefficient. Unfavorable outcome was defined as mRS 4–6 at 3 months, and a poor scan was defined as e-ASPECTS 0–5. RESULTS: Two hundred twenty patients were included, and 147 (67%) were treated with bridging protocols. The median e-ASPECTS was 9 (interquartile range, 8–10). Intraclass correlation coefficients between e-ASPECTS and raters were 0.72, 0.74, and 0.76 (all, P < .001). e-ASPECTS (Spearman rank correlation coefficient = −0.15, P = .027) correlated with mRS at 3 months. Patients with unfavorable outcome had lower e-ASPECTS (median, 8; interquartile range, 7–10 versus median, 9; interquartile range, 8–10; P = .014). Sixteen patients (7.4%) had a poor scan, which was associated with unfavorable outcome (OR, 13.6; 95% CI, 1.8–104). Independent predictors of unfavorable outcome were e-ASPECTS (OR, 0.79; 95% CI, 0.63–0.99), blood sugar (OR, 1.01; 95% CI, 1.004–1.02), atrial fibrillation (OR, 2.64; 95% CI, 1.22–5.69), premorbid mRS (OR, 1.77; 95% CI, 1.21–2.58), NIHSS (OR, 1.11; 95% CI, 1.04–1.19), general anesthesia (OR, 0.24; 95% CI, 0.07–0.84), failed recanalization (OR, 8.47; 95% CI, 3.5–20.2), and symptomatic intracerebral hemorrhage (OR, 25.8; 95% CI, 2.5–268). CONCLUSIONS: The e-ASPECTS correlated with mRS at 3 months and was predictive of unfavorable outcome after mechanical thrombectomy, but further studies in patients with poor scan are needed.
Web-based graphical querying of databases through an ontology: the Wonder system

Biological scientists have made large amounts of data available on the Web, which can be accessed by canned or precomputed queries presented via web forms. To satisfy further information needs, users currently have to have a good understanding of SQL and how the data is stored in the database. While accessing information at the ontological layer seems more appropriate, this poses two challenges: (1) to query data in databases and triple stores through an ontology with little performance overhead, and (2) to provide an intuitive web-based access to users that are not IT experts. To address these issues, we draw upon the theory and technology developed for Ontology-Based Data Access for DL-Lite. With an OWL ontology and the DIG-QuOnto reasoner as building blocks, we have developed an application that allows for graphical ontology browsing, query formulation, and answer retrieval via a Web browser. We have evaluated our system for Web-ONtology baseD Extraction of Relational data (Wonder) with an existing large genomics database about horizontal gene transfer and found that it meets both the scalability and the usability requirements.
Retinal Vessel Diameters and Physical Activity in Patients With Mild to Moderate Rheumatic Disease Without Cardiovascular Comorbidities

Objectives: Low-grade systemic inflammation is responsible for atherosclerotic lesions in patients with rheumatic diseases. Vascular dysfunction is a precursor of atherosclerosis and can be improved by physical activity (PA). Our aim was to asses micro- and macrovascular function as well as PA and cardiorespiratory fitness (CRF) in patients with rheumatic diseases in the absence of cardiovascular (CV) comorbidities compared to controls. Methods: Fifty-one patients without CV comorbidities were compared to 35 controls. Retinal microvascular diameters were assessed using a Retinal Vessel Analyzer. Arterial stiffness (AST) was measured by applanation tonometry. CRF was assessed as peak oxygen consumption and PA was assessed with a questionnaire. Results: Retinal venular diameters were significantly wider in patients [median 221 μm (interquartile range (IQR) 211, 231)] compared to controls [median 215 μm (IQR 196, 223); p = 0.01]. One hour increase of PA per week led to a venular constriction of −0.56 μm (95%CI −1.09, −0.03; p = 0.04). In our patients with low disease activity (median DAS28 1.9; median BASDAI 2.8), no differences in AST were evident compared to controls. The association of PA and CRF with AST was not independent of blood pressure. Conclusions: Patients with rheumatic disease and mild-to-moderate disease activity show an impairment of the retinal microvasculature but not of large artery stiffness. Retinal vessel analysis seems to be a sensitive biomarker to unmask vascular impairments even in the absence of classic CV risk factors. PA may have the potential to counteract the development of small artery disease at early stages of rheumatic disease.
Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication

ABSTRACT Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication. IMPORTANCE HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification of infection. The recruitment of specific cellular protein complexes to these factories aids efficient and controlled viral replication. We have identified a novel HPV-host interaction that functions in the cellular response to DNA damage and cell cycle control. We show that the HPV E2 protein targets Rad50-interacting protein 1 (Rint1) to facilitate virus genome replication. These findings add to our understanding of how HPV replicates and the host cell pathways that are targeted by HPV to support virus replication. Understanding these pathways will allow further research into novel inhibitors of HPV genome replication.
Rank-One Projections With Adaptive Margins for Face Recognition

In supervised dimensionality reduction, tensor representations of images have recently been employed to enhance classification of high dimensional data with small training sets. Previous approaches for handling tensor data have been formulated with tight restrictions on projection directions that, along with convergence issues and the assumption of Gaussian-distributed class data, limit its face-recognition performance. To overcome these problems, we propose a method of rank-one projections with adaptive margins (RPAM) that gives a provably convergent solution for tensor data over a more general class of projections, while accounting for margins between samples of different classes. In contrast to previous margin-based works which determine margin sample pairs within the original high dimensional feature space, RPAM aims instead to maximize the margins defined in the expected lower dimensional feature subspace by progressive margin refinement after each rank-one projection. In addition to handling tensor data, vector-based variants of RPAM are presented for linear mappings and for nonlinear mappings using kernel tricks. Comprehensive experimental results demonstrate that RPAM brings significant improvement in face recognition over previous subspace learning techniques.