Miracle-dz/UniFAR-FTUs huggingface dataset:
Polymyxin B‐Triggered Assembly of Peptide Hydrogels for Localized and Sustained Release of Combined Antimicrobial Therapy

Repurposing old antibiotics into more effective and safer formulations is an emergent approach to tackle the growing threat of antimicrobial resistance. Herein, a peptide hydrogel is reported for the localized and sustained release of polymyxin B (PMB), a decade‐old antibiotic with increasing clinical utility for treating multidrug‐resistant Gram‐negative bacterial infections. The hydrogel is assembled by additing PMB solution into a rationally designed peptide amphiphile (PA) solution and its mechanical properties can be adjusted through the addition of counterions, envisioning its application in diverse infection scenarios. Sustained release of PMB from the hydrogel over a 5‐day period and prolonged antimicrobial activities against Gram‐negative bacteria are observed. The localized release of active PMB from the hydrogel is shown to be effective in vivo for treating Pseudomonas aeruginosa infection in the Galleria mellonella burn wound infection model, dramatically reducing the mortality from 93% to 13%. Complementary antimicrobial activity against Gram‐positive Staphylococcus aureus and enhanced antimicrobial effect against the Gram‐negative Acinetobacter baumannii are observed when an additional antibiotic fusidic acid is incorporated into the hydrogen network. These results demonstrate the potential of the PMB‐triggered PA hydrogel as a versatile platform for the localized and sustained delivery of combined antimicrobial therapies.
Aufbau und Synthese neuartiger Polymere zur Absorption von Kohlenstoffdioxid

Im Rahmen dieser Doktorarbeit wurden neuartige aminhaltige Polymere auf Basis von verzweigtem Polyethylenimin und Polyvinylphosphonaten synthetisiert und entwickelt. Aufgrund der thermo- und pH-responsiven Eigenschaften dieser Polymere konnte die Regernation dieser wassrigen Polymerlosungen nach der Absorption von Kohlenstoffdioxid entscheidend verbessert werden. Das LCST-Verhalten dieser Polymere kann als „gruner“ Ansatz gesehen werden, dem hohen Wirkungsgradverlust des Standardabtrennungsverfahrens von CO2 entgegen zu wirken.
Skin Lesions, Skin Care, and Characteristics of Pruritus in Patients Undergoing Haemodialysis

Introduction: Pruritus has been shown to be a common and burdensome complaint in the general population. In some diseases, there is an even higher rate and intensity of pruritus such as in chronic kidney diseases. In particular, patients requiring dialysis commonly suffer from pruritus with proportions between 22.0 and 90.0%. Few data on the characteristics and burden of such pruritus have been published. Therefore, the aim of this study was to investigate the extent and profiles of pruritus in such patients related to skin lesions and care. Methods: A non-interventional cross-sectional study in 14 centres for haemodialysis across Germany was conducted. The survey explored the prevalence, severity, and resulting burden of pruritus and skin lesions. Results: In total, 302 patients with uraemia (56.5% male, mean age 66.0 ± 14.4 years, mean duration of dialysis 3.9 ± 4.8 years) were included. Skin lesions appeared since start of dialysis in 50.0% of patients, with xerosis (94.7%) and desquamation (25.8%) being the most frequent and disturbing findings. Pruritus was reported by 60.9% of patients undergoing dialysis with a current mean numerical rating scale of 5.1 ± 2.4 occurring most frequently in the back, legs, and arms. About 89.0% of patients with xerosis and 69.0% with desquamation reported self-medication. However, only 40.0% and 28.0% sought medical help, respectively, indicating a remarkable lack of healthcare. Discussion: The current data suggest a more intensive focus on the skin symptoms and signs related to uraemia in the patients with dialysis and thus underline claims from a previous German large-scale study. Recommendations for early treatment and prevention of skin lesions in dialysis patients should be developed. Further research should be conducted focusing on recognizing subgroups of patients of particular vulnerability to pruritus and skin lesions, which may facilitate identifying patients at risk in an early moment. Moreover, a more specific tool for screening of skin lesions as well as pruritus may be useful since the existing instruments lack such specificity.
Myocardial injury after noncardiac surgery: facts, fallacies and how to approach clinically

Purpose of review Acute myocardial injury occurs commonly during perioperative care. There is still considerable confusion regarding its diagnosis and definition, and a lack of consensus on who and how to screen, exacerbated by a lack of studies addressing how to manage patients with detected myocardial injury. Recent findings Far from a benign biochemical anomaly, myocardial injury occurring perioperatively is largely a silent disease and is not necessarily because of ischaemia. Preoperative, postoperative, and perioperative changes in cardiac troponins (cTns) are independently associated with increased mortality and adverse cardiovascular outcomes. Routine screening with cTns is required for reliable detection of myocardial injury. Measurement of changes (from preoperative to postoperative) will detect acute events as well as identify patients with chronic troponin increases. Summary This review aims to bring together current literature regarding myocardial injury that is detected perioperatively, identifies knowledge gaps for future research and provides suggestions for management.
The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II

Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing–derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.
COVID-19 in Pregnancy and Early Childhood (COPE): study protocol for a prospective, multicentre biobank, survey and database cohort study

Introduction There is limited knowledge on how the SARS-CoV-2 affects pregnancy outcomes. Studies investigating the impact of COVID-19 in early pregnancy are scarce and information on long-term follow-up is lacking. The purpose of this project is to study the impact of COVID-19 on pregnancy outcomes and long-term maternal and child health by: (1) establishing a database and biobank from pregnant women with COVID-19 and presumably non-infected women and their infants and (2) examining how women and their partners experience pregnancy, childbirth and early parenthood in the COVID-19 pandemic. Methods and analysis This is a national, multicentre, prospective cohort study involving 27 Swedish maternity units accounting for over 86 000 deliveries/year. Pregnant women are included when they: (1) test positive for SARS-CoV-2 (COVID-19 group) or (2) are non-infected and seek healthcare at one of their routine antenatal visits (screening group). Blood, as well as other biological samples, are collected at different time points during and after pregnancy. Child health up to 4 years of age and parent experience of pregnancy, delivery, early parenthood, healthcare and society in general will be examined using web-based questionnaires based on validated instruments. Short- and long-term health outcomes will be collected from Swedish health registers and the parents’ experiences will be studied by performing qualitative interviews. Ethics and dissemination Confidentiality aspects such as data encryption and storage comply with the General Data Protection Regulation and with ethical committee requirements. This study has been granted national ethical approval by the Swedish Ethical Review Authority (dnr 2020-02189 and amendments 2020-02848, 2020-05016, 2020-06696 and 2021-00870) and national biobank approval by the Biobank Väst (dnr B2000526:970). Results from the project will be published in peer-reviewed journals. Trial registration number NCT04433364.
The Viral ORF3 Protein Is Required for Hepatitis E Virus Apical Release and Efficient Growth in Polarized Hepatocytes and Humanized Mice

HEV infections are associated with significant morbidity and mortality. HEV gt3 additionally can cause persistent infection, which can rapidly progress to liver cirrhosis. ABSTRACT Hepatitis E virus (HEV), an enterically transmitted RNA virus, is a major cause of acute hepatitis worldwide. Additionally, HEV genotype 3 (gt3) can frequently persist in immunocompromised individuals with an increased risk for developing severe liver disease. Currently, no HEV-specific treatment is available. The viral open reading frame 3 (ORF3) protein facilitates HEV egress in vitro and is essential for establishing productive infection in macaques. Thus, ORF3, which is unique to HEV, has the potential to be explored as a target for antiviral therapy. However, significant gaps exist in our understanding of the critical functions of ORF3 in HEV infection in vivo. Here, we utilized a polarized hepatocyte culture model and a human liver chimeric mouse model to dissect the roles of ORF3 in gt3 HEV release and persistent infection. We show that ORF3’s absence substantially decreased HEV replication and virion release from the apical surface but not the basolateral surface of polarized hepatocytes. While wild-type HEV established a persistent infection in humanized mice, mutant HEV lacking ORF3 (ORF3null) failed to sustain the infection despite transient replication in the liver and was ultimately cleared. Strikingly, mice inoculated with the ORF3null virus displayed no fecal shedding throughout the 6-week experiment. Overall, our results demonstrate that ORF3 is required for HEV fecal shedding and persistent infection, providing a rationale for targeting ORF3 as a treatment strategy for HEV infection. IMPORTANCE HEV infections are associated with significant morbidity and mortality. HEV gt3 additionally can cause persistent infection, which can rapidly progress to liver cirrhosis. Currently, no HEV-specific treatments are available. The poorly understood HEV life cycle hampers the development of antivirals for HEV. Here, we investigated the role of the viral ORF3 protein in HEV infection in polarized hepatocyte cultures and human liver chimeric mice. We found that two major aspects of the HEV life cycle require ORF3: fecal virus shedding and persistent infection. These results provide a rationale for targeting ORF3 to treat HEV infection.
Low-volume regimen without additional liquids or adjunctive agents versus standard bowel preparation in non-constipated patients: a propensity score matching analysis

Abstract Aims Split-dose, 4-L polyethylene glycol (PEG, HSD) is currently the first-line choice for unselected or difficult colon preparations. Almost all low-volume bowel preparations (BPs) include a large volume of additional liquid and adjunctive agents to improve cleansing efficiency. However, neither HSD nor additional liquids or adjunctive agents of low-volume regimens may be necessary for low-risk patients. The aim of this study was to compare the cleansing efficiency between split-dose, low-volume (2-L) PEG without additional liquids or adjunctive agents (LSD) and HSD in non-constipated patients. Methods A retrospective study was performed from January 2013 to December 2015. Consecutive non-constipated patients who received LSD or HSD BPs were enrolled into LSD and HSD groups. Propensity score matching (PSM) was used to reduce selection bias and potential confounders. The primary outcome was bowel cleansing quality, as evaluated by the Boston Bowel Preparation Scale (BBPS). The adenoma detection rate (ADR), the most important secondary outcome, was also recorded. Follow-up was conducted in 2016. Results After excluding those participants who meet exclusion criteria or lost follow-up, 1656 non-constipated patients underwent LSD (n = 999) or HSD (n = 657) BP. Most patients had a BBPS score ≥6 (LSD vs. HSD, 93.6 vs. 92.9%, p = .166). The segmental BBPS scores were ≥2 in 92 and 91.9% in the LSD and HSD groups, respectively. The overall ADR was 16.7% in the LSD group and 17.5% in the HSD group (p = .334). Conclusion For non-constipated patients, LSD is not inferior to HSD in cleansing efficiency, while more willing to repeat the same BP.
Proteogenomic Analysis Provides Novel Insight into Genome Annotation and Nitrogen Metabolism in Nostoc sp. PCC 7120

Cyanobacteria are a large group of prokaryotes capable of oxygenic photosynthesis and play a vital role in nitrogen and carbon cycles on Earth. Nostoc 7120 is a commonly used model cyanobacterium for studying cell differentiation and nitrogen metabolism. In this study, we presented the first comprehensive draft map of the Nostoc 7120 proteome and a wide range of posttranslational modifications. ABSTRACT Cyanobacteria, capable of oxygenic photosynthesis, play a vital role in nitrogen and carbon cycles. Nostoc sp. PCC 7120 (Nostoc 7120) is a model cyanobacterium commonly used to study cell differentiation and nitrogen metabolism. Although its genome was released in 2002, a high-quality genome annotation remains unavailable for this model cyanobacterium. Therefore, in this study, we performed an in-depth proteogenomic analysis based on high-resolution mass spectrometry (MS) data to refine the genome annotation of Nostoc 7120. We unambiguously identified 5,519 predicted protein-coding genes and revealed 26 novel genes, 75 revised genes, and 27 different kinds of posttranslational modifications in Nostoc 7120. A subset of these novel proteins were further validated at both the mRNA and peptide levels. Functional analysis suggested that many newly annotated proteins may participate in nitrogen or cadmium/mercury metabolism in Nostoc 7120. Moreover, we constructed an updated Nostoc 7120 database based on our proteogenomic results and presented examples of how the updated database could be used to improve the annotation of proteomic data. Our study provides the most comprehensive annotation of the Nostoc 7120 genome thus far and will serve as a valuable resource for the study of nitrogen metabolism in Nostoc 7120. IMPORTANCE Cyanobacteria are a large group of prokaryotes capable of oxygenic photosynthesis and play a vital role in nitrogen and carbon cycles on Earth. Nostoc 7120 is a commonly used model cyanobacterium for studying cell differentiation and nitrogen metabolism. In this study, we presented the first comprehensive draft map of the Nostoc 7120 proteome and a wide range of posttranslational modifications. In addition, we constructed an updated database of Nostoc 7120 based on our proteogenomic results and presented examples of how the updated database could be used for system-level studies of Nostoc 7120. Our study provides the most comprehensive annotation of Nostoc 7120 genome and a valuable resource for the study of nitrogen metabolism in this model cyanobacterium.
How Selection Over Time Contributes to the Inconsistency of the Association between Sex/Gender and Cognitive Decline across Cognitive Aging Cohorts.

The sex/gender and aging-related cognitive decline association remains poorly understood due to inconsistencies in findings. Such heterogeneity could be attributable to the cognitive functions studied and study population characteristics, but also to a differential selection by drop-out and death between men and women. This work aims to evaluate the impact of selection by drop-out and death on the association between sex/gender and cognitive decline. We first compared the most frequently used statistical methods for longitudinal data, targeting either population estimands (marginal models estimated by Generalized Estimating Equations) or subject-specific estimands (mixed/joint models estimated by likelihood maximization) on eight aging studies: six population-based (ACTIVE(1996-2009), Paquid(1988-2014), REGARDS(2003-2016), 3-City(1999-2016), WHICAP(1992-2017), Whitehall II(2007-2016)) and two clinic-based (ADNI(2004-2017), MEMENTO(2011-2016)) studies. We illustrated the differences in the estimands of the sex/gender association with cognitive decline in selected examples and highlighted the critical role of differential selection by drop-out and death. By using the same estimand, we then contrasted the sex/gender association across cohorts and cognitive measures suggesting residual differential sex/gender association depending on the targeted cognitive measure (memory or animal fluency) and the initial cohort selection. We recommend focusing on subject-specific estimands in the alive population for assessing sex/gender differences while handling differential selection over time.
Intranasal delivery of mesenchymal stem cells‐derived extracellular vesicles for the treatment of neurological diseases

Neurological disorders are diseases of the central nervous system (CNS), characterized by a progressive degeneration of cells and deficiencies in neural functions. Mesenchymal stem cells (MSCs) are a promising therapy for diseases and disorders of the CNS. Increasing evidence suggests that their beneficial abilities can be attributed to their paracrine secretion of extracellular vesicles (EVs). Administration of EVs that contain a mixture of proteins, lipids, and nucleic acids, resembling the secretome of MSCs, has been shown to mimic most of the effects of the parental cells. Moreover, the small size and safety profile of EVs provide a number of advantages over cell transplantation. Intranasal (IN) administration of EVs has been established as an effective and reliable way to bypass the blood‐brain barrier and deliver drugs to the CNS. In addition to pharmacological drugs, EVs can be loaded with a diverse range of cargo designed to modulate gene expression and protein functions in recipient cells, and lead to immunomodulation, neurogenesis, neuroprotection, and degradation of protein aggregates. In this review, we will explore the proposed physiological pathways by which EVs migrate through the nasal route to the CNS where they can actively target a region of injury or inflammation and exert their therapeutic effects. We will summarize the functional outcomes observed in animal models of neurological diseases following IN treatment with MSC‐derived EVs. We will also examine key mechanisms that have been suggested to mediate the beneficial effects of EV‐based therapy.
The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region

Although imputation of missing SNP results has been widely used in genetic studies, claims about the quality and usefulness of imputation have outnumbered the few studies that have questioned its limitations. But it is becoming clear that these limitations are real—for example, disease association signals can be missed in regions of LD breakdown. Here, as a case study, using the chromosomal region of the well‐known lactase gene, LCT, we address the issue of imputation in the context of variants that have become frequent in a limited number of modern population groups only recently, due to selection. We study SNPs in a 500 bp region covering the enhancer of LCT, and compare imputed genotypes with directly genotyped data. We examine the haplotype pairs of all individuals with discrepant and missing genotypes. We highlight the nonrandom nature of the allelic errors and show that most incorrect imputations and missing data result from long haplotypes that are evolutionarily closely related to those carrying the derived alleles, while some relate to rare and recombinant haplotypes. We conclude that bias of incorrectly imputed and missing genotypes can decrease the accuracy of imputed results substantially.
Salicylic acid induces tolerance of Vitisriparia×V.labrusca to chilling stress by altered photosynthetic, antioxidant mechanisms and expression of cold stress responsive genes

ABSTRACT The yield and quality of wine grapes are severely persecuted by low-temperaturestresses. Salicylic acid (SA) assists plants in coping with abiotic stresses such as drought, heavy metal toxicity, and osmotic stress. The objective of this study was to evaluate the effect of foliar spraying of different concentrations of SA on the mitigation of cold damage in grapes, which is useful for the cultivation of wine grapes.Vitisriparia×V.labruscaseedlings were treated with foliar-sprayedSA at concentrations of 0–2 mM and then subjected to chilling stress at 4°C for 2 or 4 days, while the expression of relevant physiological indicators and cold response genes (CBF1, CBF2, CBF3) were measured. The findings indicated that low temperature stresses markedly reduced chlorophyll content, and increased proline as well as soluble sugar content, enhanced superoxide dismutase (SOD) and peroxidase (POD) activities, decreased catalase (CAT) activity and inducedCBFgene expression in leaves. Physiologically, foliar spraying of different concentrations of SA greatly increased antioxidant enzyme activity (P < .05), soluble sugars, proline, and chlorophyll content of grapes leave under low temperature stress. With regard to gene expression, SA has significantly regulated the cold response genesCBF1, CBF2, andCBF3. Therefore, SA could reduce cold damage in grapevines under low-temperaturestress, and the effect of SA was most pronounced in the 1 and 2 mM concentrates.
Deductive Reinforcement Learning for Visual Autonomous Urban Driving Navigation

Existing deep reinforcement learning (RL) are devoted to research applications on video games, e.g., The Open Racing Car Simulator (TORCS) and Atari games. However, it remains under-explored for vision-based autonomous urban driving navigation (VB-AUDN). VB-AUDN requires a sophisticated agent working safely in structured, changing, and unpredictable environments; otherwise, inappropriate operations may lead to irreversible or catastrophic damages. In this work, we propose a deductive RL (DeRL) to address this challenge. A deduction reasoner (DR) is introduced to endow the agent with ability to foresee the future and to promote policy learning. Specifically, DR first predicts future transitions through a parameterized environment model. Then, DR conducts self-assessment at the predicted trajectory to perceive the consequences of current policy resulting in a more reliable decision-making process. Additionally, a semantic encoder module (SEM) is designed to extract compact driving representation from the raw images, which is robust to the changes of the environment. Extensive experimental results demonstrate that DeRL outperforms the state-of-the-art model-free RL approaches on the public CAR Learning to Act (CARLA) benchmark and presents a superior performance on success rate and driving safety for goal-directed navigation.