Miracle-dz/UniFAR-FTUs huggingface dataset:
Locked nucleic acid building blocks as versatile tools for advanced G-quadruplex design

Abstract A hybrid-type G-quadruplex is modified with LNA (locked nucleic acid) and 2′-F-riboguanosine in various combinations at the two syn positions of its third antiparallel G-tract. LNA substitution in the central tetrad causes a complete rearrangement to either a V-loop or antiparallel structure, depending on further modifications at the 5′-neighboring site. In the two distinct structural contexts, LNA-induced stabilization is most effective compared to modifications with other G surrogates, highlighting a potential use of LNA residues for designing not only parallel but various more complex G4 structures. For instance, the conventional V-loop is a structural element strongly favored by an LNA modification at the V-loop 3′-end in contrast with an alternative V-loop, clearly distinguishable by altered conformational properties and base-backbone interactions as shown in a detailed analysis of V-loop structures.
Defining Benchmark Outcomes for Pancreatoduodenectomy With Portomesenteric Venous Resection.

OBJECTIVE The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. SUMMARY BACKGROUND DATA PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. METHODS This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). RESULTS Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. CONCLUSION These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.
DNA-PKcs Inhibition Extends Allogeneic Skin Graft Survival.

BACKGROUND Organ transplantation is life-saving and continued investigations into immunological mechanisms that drive organ rejection are needed to improve immunosuppression therapies and prevent graft failure. DNA-dependent protein kinase catalytic subunit, DNA-PKcs, is a critical component of both the cellular and humoral immune responses. In this study, we investigate the contribution of DNA-PKcs to allogeneic skin graft rejection to potentially highlight a novel strategy for inhibiting transplant rejection. METHODS Fully MHC mismatched murine allogeneic skin graft studies were performed by transplanting skin from BalbC mice to C57bl6 mice and treating with either vehicle or the DNA-PKcs inhibitor NU7441. Graft rejection, cytokine production, immune cell infiltration, and donor-specific antibody (DSA) formation were analyzed. RESULTS DNA-PKcs inhibition significantly reduced necrosis and extended graft survival compared to controls (mean survival 14 days vs 9 days respectively). Inhibition reduced the production of the cytokines Interleukin (IL)2, IL4, IL6, IL10, TNFα, and IFNγ and the infiltration of CD3+ lymphocytes into grafts. Furthermore, DNA-PKcs inhibition reduced the number of CD19+ B cells and CD19+ CD138+ plasma cells coinciding with a significant reduction in DSAs. At a molecular level, we determined that the immunosuppressive effects of DNA-PKcs inhibition were mediated, in part, via inhibition of NFκB signaling through reduced expression of the p65 subunit. CONCLUSION Our data confirm that DNA-PKcs contributes to allogeneic graft rejection and highlight a novel immunological function for DNA-PKcs in the regulation of NFκB and concomitant cytokine production.
The burden of conflicting guidelines.

rn translating the clinical question into a generic question that can be answered by clinical research; 2. finding the studies that address this generic question; 3. appraising their quality and relevance; 4. critically synthesizing their results to answer the generic question; and 5. applying the generic answer to the clinical question with regards to the individual circumstances of the patient.
Cytomegalovirus Infection Downregulates Vitamin D Receptor in Patients Undergoing Hematopoietic Stem Cell Transplantation

Supplemental Digital Content is available in the text. Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with hematologic diseases but is associated with high mortality and morbidity. Cytomegalovirus (CMV) infection is common in HSCT patients and modulates vitamin D metabolism in vitro. We aimed at validating CMV-associated vitamin D metabolism in vivo in HSCT. Methods. Patients treated for significant CMV viremia after HSCT were evaluated for CMV load before, during, and after antiviral treatment. RNA was isolated from whole-blood samples to test for regulation of key components of the vitamin D receptor (VDR) pathway during different phases of CMV viremia. Results. CMV viremia developed a mean time of 102 (±34) d post-HSCT. Maximum levels of CMV-DNA reached a mean of 5668 (±7257) copies/mL. VDR expression was downregulated to a mean of 64.3% (±42.5%) relative to the VDR expression pre-CMV viremia (P = 0.035) and lagged in recovery following antiviral treatment. Toll-like receptor (TLR) 2 mRNA was upregulated to 225.4% during CMV viremia relative to the expression pre-CMV viremia (P = 0.012) but not TLR6/7/8 and the TLR-adaptor protein MyD88. Levels of 25-OH vitamin D were reduced in all viremic patients (48.0 ± 4.8 versus 25.1 ± 3.7 ng/mL) and were even lower after periods of CMV viremia compared with the control group (48.3 ± 3.5 versus 17.8 ± 1.8 ng/mL; P = 0.008). Conclusions. CMV viremia is associated with significant dysregulation of vitamin D metabolism in HSCT patients.
White Matter Hyperintensities Contribute to Language Deficits in Primary Progressive Aphasia

Supplemental Digital Content is available in the text. Objective: To determine the contribution of white matter hyperintensities (WMH) to language deficits while accounting for cortical atrophy in individuals with primary progressive aphasia (PPA). Method: Forty-three individuals with PPA completed neuropsychological assessments of nonverbal semantics, naming, and sentence repetition plus T2-weighted and fluid-attenuated inversion recovery scans. Using three visual scales, we rated WMH and cerebral ventricle size for both scan types. We used Spearman correlations to evaluate associations between the scales and scans. To test whether visual ratings—particularly of WMH—are associated with language, we compared a base model (including gray matter component scores obtained via principal component analysis, age, and days between assessment and MRI as independent variables) with full models (ie, the base model plus visual ratings) for each language variable. Results: Visual ratings were significantly associated within and between scans and were significantly correlated with age but not with other vascular risk factors. Only the T2 scan ratings were associated with language abilities. Specifically, controlling for other variables, poorer naming was significantly related to larger ventricles (P = 0.033) and greater global (P = 0.033) and periventricular (P = 0.049) WMH. High global WMH (P = 0.034) were also correlated with worse sentence repetition skills. Conclusion: Visual ratings of global brain health were associated with language deficits in PPA independent of cortical atrophy and age. While WMH are not unique to PPA, measuring WMH in conjunction with cortical atrophy may elucidate more accurate brain structure–behavior relationships in PPA than cortical atrophy measures alone.
Visit-to-visit blood pressure variability and renal outcomes: results from ONTARGET and TRANSCEND trials.

AIMS There is conflicting evidence on whether in treated hypertensive patients the risk of renal outcomes is associated with visit-to-visit SBP variability. Furthermore, limited evidence is available on how important is SBP variability for prediction of renal outcomes compared with on-treatment mean SBP. We addressed these issues in 28 790 participants of the Ongoing Treatment Alone and in combination with Ramipril Global End point Trial and Telmisartan Randomized Assessment Study in ace iNtolerant Subjects with Cardiovascular Disease trials. METHODS AND RESULTS SBP variability was expressed as the coefficient of variation of the mean with which it showed no relationship. SBP variability and mean values were obtained from five visits during the first 2 years of treatment after the end of the titration phase. Incidence of several renal outcomes (end-stage renal disease, doubling of serum creatinine, new microalbuminuria, new macroalbuminuria and their composite) was calculated from the third year of treatment onward. Patients were divided in quintiles of SBP-coefficient of variation (SBP-CV) or mean SBP, which exhibited superimposable mean blood pressure and SBP-CV values, respectively. A progressive increase of SBP-CV was not accompanied by a parallel increase in a widely adjusted (baseline and on-treatment confounders) risk of most renal outcomes (end-stage renal disease, new macroalbuminuria, new microalbuminuria and their composite) in the subsequent on-treatment years. In contrast, the adjusted risk of most renal outcomes increased progressively from the lowest to the highest quintile of on-treatment mean SBP. Progression from lowest to highest mean on-treatment SBP, but not SBP-CV, was also associated with a less frequent return to normoalbuminuria in patients with initial micro or macroalbuminuria. Renal outcome prediction was slightly improved by the combined use of SBP-CV and mean SBP quintiles. CONCLUSION Visit-to-visit SBP variability had no major predictive value for the risk of renal outcomes, which, in contrast, was sensitively predicted by mean on-treatment SBP. A further slight increase in prediction of renal outcomes was seen by combining on-treatment mean SBP and variability.
Endoscopic diagnosis and management of gastric subepithelial lesions

Purpose of review The purpose of this manuscript is to provide an in-depth review of gastric subepithelial lesions (SELs) and describe the current approach to endoscopic diagnosis and management of these lesions. Recent findings Gastric SELs are a relatively frequent finding on routine endoscopy (incidence 0.2–3%). A systematic approach to diagnosis and management is key because many SELs are of little consequence, while others carry a high risk of malignant transformation. Because esophagogastroduodenoscopy (EGD) cannot delineate depth of invasion or subepithelial appearance, endoscopic ultrasound (EUS) should be considered a first-line modality. Recent data suggest EUS-guided fine needle biopsy (FNB) may be superior to traditional fine needle aspiration (FNA) for the diagnosis of gastric SELs due to its ability to obtain histologic specimens for immunohistochemical staining. Alternative techniques for tissue sampling (combined with simultaneous resection) include submucosal resection, endoscopic submucosal dissection (ESD), submucosal tunnelling with endoscopic resection (STER) or endoscopic full-thickness resection (EFTR). Summary This review details the endoscopic diagnosis and management of gastric SELs. Although EUS-guided sampling remains a first-line strategy (preferably with FNB), recent techniques including ESD, STER and EFTR have the potential to provide additional diagnostic and therapeutic options.
Schlieren-Bound Magmatic Structures Record Crystal Flow-Sorting in Dynamic Upper-Crustal Magma-Mush Chambers

The size, longevity, and mobility of upper-crustal magma mushes, and thus their ability to mix and interact with newly arriving magma batches, are key factors determining the evolution of magma reservoirs. Magmatic structures in plutons represent local sites of structural and compositional diversity and provide an opportunity to test the extent of physical and chemical processes that operated through time. Regional compilation of compositionally defined magmatic structures, specifically those involving schlieren, in the Tuolumne Intrusive Complex (TIC), yields a synthesis of ∼1500 schlieren-bound structure measurements. Field observations, petrography, and whole-rock geochemistry were integrated to test schlieren formation mechanisms. At a local scale (1 mm–1 m), we find that schlieren-bound structures formed from the surrounding host magma during dynamic magmatic processes such as crystal flow-sorting, magmatic faulting, and folding. Fluidization of the magma mush, interpreted from 1 m to 1 km wide domains of clustered schlieren-bound structures, appears to have operated within a hydrogranular medium, or “crystal slurry” (Bergantz et al., 2017). At the regional scale (10’s km), outward younging patterns of troughs, migrating tubes, and plumes indicate that the mush convected, driven by intrusion of new pulses. Troughs and planar schlieren are weakly oriented parallel to nearby major unit contacts, which could be related to internal mush convection or effects of high thermochemical gradients at internal unit boundaries. We hypothesize that these younging patterns and orientations have the potential to constrain the size of mobile magma mixing regions, that in the TIC extended to a minimum of 150 km2 (∼1500 km3) and were long-lived (>1 m.y). These require the generation of extensive melt-present reservoirs that could flow magmatically, formed from the amalgamation of intruding magma pulses, and precludes dike, sill, or laccolith emplacement models. We conclude that schlieren-bound structures are faithful recorders of the multi-scale, hypersolidus evolution of upper-crustal magma bodies, and represent useful tools for studying plutonic systems.
Low Dimensional Material based Electro-Optic Phase Modulation Performance Analysis

Electro-optic modulators are utilized ubiquitously ranging from applications in data communication to photonic neural networks. While tremendous progress has been made over the years, efficient phase-shifting modulators are challenged with fundamental tradeoffs, such as voltage-length, index change-losses or energy-bandwidth, and no single solution available checks all boxes. While voltage-driven phase modulators, such as based on lithium niobate, offer low loss and high speed operation, their footprint of 10's of cm-scale is prohibitively large, especially for density-critical applications, for example in photonic neural networks. Ignoring modulators for quantum applications, where loss is critical, here we distinguish between current versus voltage-driven modulators. We focus on the former, since current-based schemes of emerging thin electro-optical materials have shown unity-strong index modulation suitable for heterogeneous integration into foundry waveguides. Here, we provide an in-depth ab-initio analysis of obtainable modulator performance based on heterogeneously integrating low-dimensional materials, i.e. graphene, thin films of indium tin oxide, and transition metal dichalcogenide monolayers into a plurality of optical waveguide designs atop silicon photonics. Using the fundamental modulator tradeoff of energy-bandwidth-product as a design-quality quantifier, we show that a small modal cross section, such as given by plasmonic modes, enables high-performance operation, physically realized by arguments on charge-distribution and low electrical resistance. An in-depth design understanding of phase-modulator performance, beyond doped-junctions in silicon, offers opportunities for micrometer-compact yet energy-bandwidth-ratio constrained modulators with timely opportunities to hardware-accelerate applications beyond data communication towards photonic machine intelligence.
Lack of evidence for association of UQCRC1 with Parkinson's disease in Europeans

Recently, a novel variant p.Y314S in UQCRC1 has been implicated as pathogenic in Parkinson' s disease (PD). In the current study, we aimed to examine the association of UQCRC1 with PD in large cohorts of European origin. We examined common and rare genetic variation in UQCRC1 using genome-wide association study data from the International Parkinson Disease Genomics Consortium (IPDGC), including 14,671 cases and 17,667 controls, and whole-genome sequencing data from the Accelerating Medicines Partnership - Parkinson' s disease initiative (AMP-PD), including 1,647 PD patients and 1,050 controls. No common variants were consistently associated with PD, and a variety of burden analyses did not reveal an association between rare variants in UQCRC1 and PD. Therefore, our results do not support a major role for UQCRC1 in PD in the European population, and additional studies in other populations are warranted.
COVID-19 Preprints and Their Publishing Rate: An Improved Method

Context: As the COVID-19 pandemic persists around the world, the scientific community continues to produce and circulate knowledge on the deadly disease at an unprecedented rate. During the early stage of the pandemic, preprints represented nearly 40% of all English-language COVID-19 scientific corpus (6, 000+ preprints | 16, 000+ articles). As of mid-August 2020, that proportion dropped to around 28% (13, 000+ preprints | 49, 000+ articles). Nevertheless, preprint servers remain a key engine in the efficient dissemination of scientific work on this infectious disease. But, giving the uncertified nature of the scientific manuscripts curated on preprint repositories, their integration to the global ecosystem of scientific communication is not without creating serious tensions. This is especially the case for biomedical knowledge since the dissemination of bad science can have widespread societal consequences. Scope: In this paper, I propose a robust method that will allow the repeated monitoring and measuring of COVID-19 preprint's publication rate. I also introduce a new API called Upload-or-Perish. It is a micro-API service that enables a client to query a specific preprint manuscript's publication status and associated meta-data using a unique ID. This tool is in active development. Data: I use Covid-19 Open Research Dataset (CORD-19) to calculate COVID-19 preprint corpus' conversion rate to peer-reviewed articles. CORD-19 dataset includes preprints from arXiv, bioRxiv, and medRxiv. Methods: I utilize conditional fuzzy logic on article titles to determine if a preprint has a published counterpart version in the database. My approach is an important departure from previous studies that rely exclusively on bioRxiv API to ascertain preprints' publication status. This is problematic since the level of false positives in bioRxiv metadata could be as high as 37%. Findings: My analysis reveals that around 15% of COVID-19 preprint manuscripts in CORD-19 dataset that were uploaded on from arXiv, bioRxiv, and medRxiv between January and early August 2020 were published in a peer-reviewed venue. When compared to the most recent measure available, this represents a two-fold increase in a period of two months. My discussion review and theorize on the potential explanations for COVID-19 preprints' low conversion rate.
Is climate a curse or a bless in the Covid-19 virus fighting?

Faced with the global pandemic of Covid-19, we need to better understand the links between meteorological factors and the virus and investigate the existence of potential seasonal patterns. In the vein of a recent empirical literature, we reassess the impact of weather factors on Covid-19 daily cases in a panel of advanced and emerging countries between January the first and 28th May 2020. We consider 5 different meteorological factors and go further previous studies. In addition, we give a short-run and medium/long-run time perspective of the dramatic outcomes of the pandemic by both considering infected people (short-run) and fatalities (long-run). Our results reveal that the choice of delays and time perspective of the effects of climatic factors on the virus are crucial as well as Covid-19 outcomes can explain the discrepancies in the previous literature. For the first time, we use a dynamic panel model and consider two different kinds of channels between climate and Covid-19 virus: 1) direct/physical factors related to the survivals and durability dynamics of the virus in surfaces and outdoors and 2) an indirect factor through human behaviors and individual mobility - walking or driving outdoors - to capture the impact of climate on social distancing and thus on Covid-19 outcomes. Our model is estimated emph{per se} two different estimators and persistence, delays in patterns, nonlinearities and numerous specifications changes are taken into account with many robustness checks. Our work reveal that temperatures and, more interestingly, solar radiation - that has been clearly undervalued in previous studies - are significant climatic drivers on Covid-19 outbreak. Indirect effects through human behaviors ie interrelationships between climatic variables and people mobility are significantly positive and should be considered to correctly assess the effects of climatic factors. Since climate is per se purely exogenous, climate tend to strengthen the effect of mobility on virus spread. The net effect from climate on Covid-19 outbreak will thus result from the direct negative effect of climatic variables and from the indirect effect due to the interaction between mobility and them. Direct negative effects from climatic factors on Covid-19 outcomes - when they are significant - are partly compensated by positive indirect effects through human mobility. Suitable control policies should be implemented to control the mobility and social distancing. \
The karyotype of amphioxus Branchiostoma belcheri tsingtauense (Cephalochordata)

The chromosome number and karyotype of amphioxus Branchiostoma belcheri tsingtauense were studied using embryonic cells. The diploid chromosome number (2n) of B. belcheri tsingtauense is 36, and its karyotype 2n=36, 2st+34t, FN=36. This is the first report on the karyotype of the cephalochordate. Evidence suggesting the possible presence of a pair of sex-chromosomes in the amphioxus has been provided.