Miracle-dz/UniFAR-FTUs huggingface dataset:
Human papillomaviruses: Knowns, mysteries, and unchartered territories

There has been an explosion in the number of papillomaviruses that have been identified and fully sequenced. Yet only a minute fraction of these has been studied in any detail. Most of our molecular research efforts have focused on the E6 and E7 proteins of “high‐risk,” cancer‐associated human papillomaviruses (HPVs). Interactions of the high‐risk HPV E6 and E7 proteins with their respective cellular targets, the p53 and the retinoblastoma tumor suppressors, have been investigated in minute detail. Some have thus questioned if research on papillomaviruses remains an exciting and worthwhile area of investigation. However, fundamentally new insights on the biological activities and cellular targets of the high‐risk HPV E6 and E7 proteins have been discovered and previously unstudied HPVs have been newly associated with human diseases. HPV infections continue to be an important cause of human morbidity and mortality and since there are no antivirals to combat HPV infections, research on HPVs should remain attractive to new investigators and biomedical funding agencies, alike.
Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy

Visual Abstract Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2–positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs’ subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.
Healthy sleep score changes and incident cardiovascular disease in European prospective community-based cohorts

Abstract Background and Aims Evidence on the link between sleep patterns and cardiovascular diseases (CVDs) in the community essentially relies on studies that investigated one single sleep pattern at one point in time. This study examined the joint effect of five sleep patterns at two time points with incident CVD events. Methods By combining the data from two prospective studies, the Paris Prospective Study III (Paris, France) and the CoLaus|PsyCoLaus study (Lausanne, Switzerland), a healthy sleep score (HSS, range 0–5) combining five sleep patterns (early chronotype, sleep duration of 7–8 h/day, never/rarely insomnia, no sleep apnoea, and no excessive daytime sleepiness) was calculated at baseline and follow-up. Results The study sample included 11 347 CVD-free participants aged 53–64 years (44.6% women). During a median follow-up of 8.9 years [interquartile range (IQR): 8.0–10.0], 499 first CVD events occurred (339 coronary heart disease (CHD) and 175 stroke). In multivariate Cox analysis, the risk of CVD decreased by 18% [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.76–0.89] per one-point increment in the HSS. After a median follow-up of 6.0 years (IQR: 4.0–8.0) after the second follow-up, 262 first CVD events occurred including 194 CHD and 72 stroke. After adjusting for baseline HSS and covariates, the risk of CVD decreased by 16% (HR 0.84, 95% CI 0.73–0.97) per unit higher in the follow-up HSS over 2–5 years. Conclusions Higher HSS and HSS improvement over time are associated with a lower risk of CHD and stroke in the community.
CRISPR-Cas9 base editing of pathogenic CaMKIIδ improves cardiac function in a humanized mouse model

Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was replaced with the human sequence. This enabled comparison and optimization of two different editing strategies for the human genome in mice. To edit CAMK2D in vivo, we packaged the optimized editing components into an engineered myotropic adeno-associated virus (MyoAAV 2A), which enabled efficient delivery at a very low AAV dose into the humanized mice at the time of IR injury. CAMK2D-edited mice recovered cardiac function, showed improved exercise performance, and were protected from myocardial fibrosis, which was otherwise observed in injured control mice after IR. Our findings identify a potentially effective strategy for cardioprotection in response to oxidative damage.
Optical Flow-Guided Cine MRI Segmentation With Learned Corrections

In cardiac cine magnetic resonance imaging (MRI), the heart is repeatedly imaged at numerous time points during the cardiac cycle. Frequently, the temporal evolution of a certain region of interest such as the ventricles or the atria is highly relevant for clinical diagnosis. In this paper, we devise a novel approach that allows for an automatized propagation of an arbitrary region of interest (ROI) along the cardiac cycle from respective annotated ROIs provided by medical experts at two different points in time, most frequently at the end-systolic (ES) and the end-diastolic (ED) cardiac phases. At its core, a 3D TV- $\boldsymbol {L^{1}}$ -based optical flow algorithm computes the apparent motion of consecutive MRI images in forward and backward directions. Subsequently, the given terminal annotated masks are propagated by this bidirectional optical flow in 3D, which results, however, in improper initial estimates of the segmentation masks due to numerical inaccuracies. These initially propagated segmentation masks are then refined by a 3D U-Net-based convolutional neural network (CNN), which was trained to enforce consistency with the forward and backward warped masks using a novel loss function. Moreover, a penalization term in the loss function controls large deviations from the initial segmentation masks. This method is benchmarked both on a new dataset with annotated single ventricles containing patients with severe heart diseases and on a publicly available dataset with different annotated ROIs. We emphasize that our novel loss function enables fine-tuning the CNN on a single patient, thereby yielding state-of-the-art results along the complete cardiac cycle.
Organic contaminant analytical methods of the National Status and Trends Program: update 2000-2006

This document describes the analytical methods used to quantify core organic chemicals in tissue and sediment collected as part of NOAA’s National Status and Trends Program (NST Lauenstein and Cantillo, 1998) for the years 1984-1992 and 1993-1996, respectively. These reports are available from our website (http://www.ccma.nos.gov) The methods detailed in this document were utilized by the Mussel Watch Project and Bioeffects Project, which are both part of the NST (1) levels of contaminants in sediments, (2) incidence and severity of toxicity, and (3) benthic macrofaunal conmmunities, the Bioeffects Project describes the spatial extent of sediment toxicity. Contaminant assessment is a core function of both projects. These methods, while discussed here in the context of sediment and bivalve tissue, were also used with other matricies including: fish fillet, fish liver, nepheloid layer, and suspended particulate matter. The methods described herein are for the core organic contaminants monitored in the NS&T Program and include polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), butyltins, and organochlorines that have been analyzed consistently over the past 15-20 years. Organic contaminants such as dioxins, perfluoro compounds and polybrominated biphenyl ethers (PBDEs) were analyzed periodically in special studies of the NS&T Program and will be described in another document. All of the analytical techniques described in this document were used by B&B Laboratories, Inc, an affiliate of TDI-Brook International, Inc. in College Station, Texas under contract to NOAA. The NS&T Program uses a performance-based system approach to obtain the best possible data quality and comparability, and requires laboratories to demonstrate precision, accuracy, and sensitivity to ensure results-based performance goals and measures. (PDF contains 75 pages)
Colorimetric Synchronization of Drosophila Larvae

The rapid succession of events during development poses an inherent challenge to achieve precise synchronization required for rigorous, quantitative phenotypic and genotypic analyses in multicellular model organisms. Drosophila melanogaster is an indispensable model for studying the development and function of higher order organisms due to extensive genome homology, tractability, and its relatively short lifespan. Presently, nine Nobel prizes serve as a testament to the utility of this elegant model system. Ongoing advancements in genetic and molecular tools allow for the underlying mechanisms of human disease to be investigated in Drosophila. However, the absence of a method to precisely age‐match tissues during larval development prevents further capitalization of this powerful model organism. Drosophila spends nearly half of its life cycle progressing through three morphologically distinct larval instar stages, during which the imaginal discs, precursors of mature adult external structures (e.g., eyes, legs, wings), grow and develop distinct cell fates. Other tissues, such as the central nervous system, undergo massive morphological changes during larval development. While these three larval stages and subsequent pupal stages have historically been identified based on the number of hours post egg‐laying under standard laboratory conditions, a reproducible, efficient, and inexpensive method is required to accurately age‐match larvae within the third instar. The third instar stage is of particular interest, as this developmental stage spans a 48‐hr window during which larval tissues switch from proliferative to differentiation programs. Moreover, some genetic manipulations can lead to developmental delays, further compounding the need for precise age‐matching between control and experimental samples. This article provides a protocol optimized for synchronous staging of Drosophila third instar larvae by colorimetric characterization and is useful for age‐matching a variety of tissues for numerous downstream applications. We also provide a brief discussion of the technical challenges associated with successful application of this protocol. © 2023 Wiley Periodicals LLC.
Antitumor Effects of PRMT5 Inhibition in Sarcomas

Abstract Patients with advanced soft-tissue sarcomas (STS) have few therapeutic options. Protein arginine methyltransferase 5 (PRMT5), an anticancer target, has been extensively investigated in recent years in epithelial tumors. To date, no data related to the biological role of PRMT5 inhibition and its potential effect as a treatment in STS have been reported. To investigate the therapeutic potential of PRMT5 targeting in STS, we first evaluated the prognostic value of PRMT5 expression in two different cohorts of patients with STS. We then used the potent and selective GSK3326595 (GSK595) compound to investigate the antitumor effect of the pharmacologic inhibition of PRMT5 in vitro via MTT, apoptosis, cell cycle, clonogenicity, and proliferation assays. In vivo studies were performed with two animal models to evaluate the effects of GSK595 on tumor growth. The mechanisms of action were investigated by RNA sequencing, metabolic pathway analysis, Western blotting, and glucose uptake/lactate production assays. High PRMT5 gene expression levels were significantly associated with worsened metastasis-free survival of patients with STS. GSK595 decreased the global symmetric dimethylarginine level, the proliferation rate and clonogenicity of STS cell lines in vitro and tumor growth in vivo. Moreover, PRMT5 inhibition regulated aerobic glycolysis through downregulation of key enzymes of glycolysis as well as glucose uptake and lactate production. The current study demonstrated that PRMT5 regulates STS cell metabolism and thus represents a potential therapeutic target for STS. Additional studies in diverse sarcoma subtypes will be essential to confirm and expand upon these findings. Significance: STSs have limited therapeutic options. We show here the poor prognostic value of high PRMT5 expression in STS. Moreover, we demonstrate that the pharmacologic inhibition of PRMT5 has significant antitumor activity through the downregulation of glycolysis. Our findings support the clinical investigation of PRMT5 inhibition in STSs.
Joint status, pain and quality of life in elderly people with haemophilia: A case‐control study

Elderly people with haemophilia (PwH) develop haemophilic arthropathy, pain, and reduced health‐related quality of life (HR‐QoL). The condition of elderly mild haemophilia patients have rarely been evaluated. This study aimed to compare joint status, pain, and HR‐QoL between elderly with mild, moderate/severe haemophilia and healthy elderlies.
Acute care for burn patients: fluids, surgery, and what else?

Purpose of review Recently published initiatives spanning the burn care spectrum have substantially changed the standard of care in burn care. The purpose of this article is to describe new impactful concepts in burn first aid, triage, resuscitation, and treatment as well as their impact on future research. Recent findings First aid after burn injury traditionally consists of extinguishing the burn and applying dressings. Recent evidence suggests that applying 20 min of cool tap water to the burn wound in the first 3 h postburn mitigates burn injury extent. National burn center transfer criteria have been updated, impacting patient initial transfer and management. The adverse effects of hydroxocobalamin, a commonly used antidote for cyanide toxicity, have been delineated. Initial burn resuscitation recommendations for both volume and potentially fluid type are being reexamined. The emergence of innovative skin substitutes may improve burn survival by providing a physiologically stabilizing intermediate dressing. Finally, formal clinical practice guidelines for early mobility in the ICU after burn injury have been defined. Summary These changes in burn care, triage, resuscitation, and treatment have challenged traditional burn care standards, created new standards, and are the basis for future prospective randomized trials.
Tephrochronological Study of Higashiyama Volcano at Hachijojima, Izu Islands

Hachijojima, one of the Izu Islands, is located on the Volcanic front of the Izu-Ogasawara (Bonin) Arc which lies south to north along the boundary of the Pacific plate and the Philippine Sea Plate. Hachijojima consists of two stratovolcanoes : Higashiyama and Nishiyama. There is a sharp contrast between Higahshiyama, which is a well-dissected mountain, and Nishiyama, which is cone-shaped. It is topographically clear that Higashiyama was formed earlier than Nishiyama. The following is a summary of the results of this study.1) The eruptive history of Higashiyama can be divided into six ages : Sokodo I (40-50 ka), Sokodo II (ca. 25-33 ka), Sueyoshi (ca. 17-25 ka), Nakanogo I (ca. 11-17 ka), Nakanogo II (ca. 5.8-11) and Mitsune (ca. 5.8 ka and later). 2) At Higashiyama, a large amount of dacitic magma erupted in the Sokodo I Age and the Sueyoshi Age, and formed a caldera. In the Sokodo I age, the early stratovolcanoes were subjected to landslides and collapsed, and the Higashiyama caldera emarged. In the Sueyoshi Age, the summit of Higashiyama stratovolcanoes were subject to landslides and collapsed to form the Nishihakuunzan caldera.3) the Higashiyama stratovolcano (young stratovolcano I) was formed in the Sokodo II Age and Mihara stratovolcano (young stratovolcano II a, b) in the Nakanogo I Age by eruptions of basalt and andesite magma.4) Higashiyama formed a central cone at the end of Nakanogo I Age and eruptions from the summit ended around ca. II ka. Thereafter, it transformed into a flank eruption which issued andesite magma in the Nakanogo II age. In the Mitsune age, volcanic activities of Higashiyama receded.5) In the Nishiyama region, eruptions became active from the Nakanogo I Age and issued mainly basaltic tephra and pyroclastic surges. However, dacitic tephra was also issued. Occasional finding of pumice fall deposit suggest the generation of daciticmagma.6) On Higashiyama, deposits Aira-Tn ash (ca. 24.5 ka) and Kikai-Akahoya ash (ca. 6.3 ka) were transported by westerlies from the Kyusyu area. They prove to be important marker tephras clarifing the tephra stratigraphy and eruptive history in this region.
Culicoides-borne Orbivirus epidemiology in a changing climate

Orbiviruses are of significant importance to the health of wildlife and domestic animals worldwide; the major orbiviruses transmitted by multiple biting midge (Culicoides) species include bluetongue virus, epizootic hemorrhagic disease virus, and African horse sickness virus. The viruses, insect vectors, and hosts are anticipated to be impacted by global climate change, altering established Orbivirus epidemiology. Changes in global climate have the potential to alter the vector competence and extrinsic incubation period of certain biting midge species, affect local and long-distance dispersal dynamics, lead to range expansion in the geographic distribution of vector species, and increase transmission period duration (earlier spring onset and later fall transmission). If transmission intensity is associated with weather anomalies such as droughts and wind speeds, there may be changes in the number of outbreaks and periods between outbreaks for some regions. Warmer temperatures and changing climates may impact the viral genome by facilitating reassortment and through the emergence of novel viral mutations. As the climate changes, Orbivirus epidemiology will be inextricably altered as has been seen with recent outbreaks of bluetongue, epizootic hemorrhagic disease, and African horse sickness outside of endemic areas, and requires interdisciplinary teams and approaches to assess and mitigate future outbreak threats. Graphical Abstract
Radium 228 as a tracer of basin wide processes in the abyssal ocean

A simple model of isopycnal mixing in a circular basin is developed in order to examine the utility of the 5.75-year half-life tracer radium 228 for studying basin wide processes in the deep ocean. The model shows that it is possible to resolve diffusivities of ≤8×107 cm2 s−1 in a basin of ∼3000-km diameter with profiles measured near the center and edge of the basin. A least squares fit of the model to four abyssal profiles measured during GEOSECS in the North American Basin gives an isopycnal diffusivity of 6×107 cm2 s−1.
Flood‐plain responses to contemporary climate change in small High‐Arctic basins (Svalbard, Norway)

Changes in the supply of water and sediment to high‐latitude rivers related to contemporary climate change and glacier fluctuations largely determine the activity of fluvial processes. This study reconstructs fluvial dynamics since the end of the Little Ice Age (LIA) in two small, partially glaciated basins in the southern part of Spitsbergen, Svalbard Archipelago. We use a combination of aerial photograph interpretation, field mapping and dendrochronological analysis. Sequences of abandoned channels and glacifluvial terraces are distinctly visible in middle and lower parts of the Brattegg and Arie basins in this area. The advance of glaciers during the LIA in the upper part of the basins led to the development of a braiding pattern and to channel aggradation corresponding to the highest glacifluvial levels. The decreasing activity of these braidplains occurred at the turn of the 19th and 20th centuries, immediately prior to a significant incision period. A second generation of braided channels developed during the first half of the 20th century. Ice‐marginal lake development, less input of fine‐grained sediment to the river channel, and fast incision began from the second half of the 20th century onward. During the last two decades, the main fluvial response to the climatic warming has been contraction of flow within a narrower channel and the abandonment of braidplains. The increased lateral erosion and rate of downcutting and the formation of the most downstream reaches of the modern valley bottom occurred in the 1980s and 1990s. This process was intensified under flood conditions generated by extreme rainfall events. These micro‐scale (small partially glaciated basins) observations concerning the changes of the activity of fluvial processes since the end of LIA may be helpful for the reconstruction of past fluvial changes over longer time scales.