bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-22 promotes immunosuppression via activating JAK/STAT3 signaling in cutaneous squamous cell carcinoma
Authors: Yuan Shukai , Zhu Tong , Wang Jianan , Jiang Ruoyu , Shu Aofeng , Zhang Zhenlei , Zhang Peitao , Feng Xuequan , Zhao Li 
Published: July 2023

Abstract
Immunotherapy is the only approved systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC), however, roughly 50% of patients do not respond to the therapy and resistance often occurs over time to those who initially respond. Immunosuppression could have a critical role in developing treatment resistance, thus, understanding the mechanisms of how immunosuppression is developed and regulated may be the key to improving clinical diagnosis and treatment strategies for cSCC. Here, through using a series of immunocompetent genetically engineered mouse models, we demonstrate that miR-22 promotes cSCC development by establishing regulatory T cells (Tregs)-mediated immunosuppressive tumor microenvironment (TME) in a tumor cell autonomous manner. Mechanism investigation revealed that miR-22 elicits the constitutive activation of JAK/STAT3 signaling by directly targeting its suppressor SOCS3, which augments cancer cell-derived chemokine secretion and Tregs recruitment. Epithelial-specific and global knockouts of miR-22 repress papilloma and cSCC development and progression, manifested with reduced Tregs infiltration and elevated CD8+ T cell activation. Transcriptomic analysis and functional rescue study confirmed CCL17, CCL20 and CCL22 as the main affected chemokines that mediate the chemotaxis between miR-22 highly expressing keratinocyte tumor cells and Tregs. Conversely, overexpression of SOCS3 reversed miR-22-induced Tregs recruitment toward tumor cells. Clinically, gradually increasing Tregs infiltration during cSCC progression was negatively correlated with SOCS3 abundance, supported by previously documented elevated miR-22 levels. Thus, our study uncovers a novel miR-22–SOCS3–JAK/STAT3–chemokines regulatory mechanism in defining the immunosuppressive TME and highlights the promising clinical application value of miR-22 as a common targeting molecule against JAK/STAT3 signaling and immune escape in cSCC.
Coexistence of apoptosis, pyroptosis, and necroptosis pathways in celiac disease
Authors: Ruera Carolina N , Perez Federico , Iribarren María Luz , Guzman Luciana , Menendez Lorena , Garbi Laura , Chirdo Fernando G 
Published: July 2023

Abstract
Usually, the massive elimination of cells under steady-state conditions occurs by apoptosis, which is also acknowledged to explain the loss of enterocytes in the small intestine of celiac disease (CD) patients. However, little is known about the role of proinflammatory cell death pathways in CD. Here, we have used confocal microscopy, western blot, and RT-qPCR analysis to assess the presence of regulated cell death pathways in the duodenum of CD patients. We found an increased number of dead (TUNEL+) cells in the lamina propria of small intestine of CD patients, most of them are plasma cells (CD138+). Many dying cells expressed FAS and were in close contact with CD3+ T cells. Caspase-8 and caspase-3 expression was increased in CD, confirming the activation of apoptosis. In parallel, caspase-1, IL-1β, and GSDMD were increased in CD samples indicating the presence of inflammasome-dependent pyroptosis. Necroptosis was also present, as shown by the increase of RIPK3 and phosphorylate MLKL. Analysis of published databases confirmed that CD has an increased expression of regulated cell death -related genes. Together, these results reveal that CD is characterized by cell death of different kinds. In particular, the presence of proinflammatory cell death pathways may contribute to mucosal damage.
Spatio-temporal evolution of human neural activity during visually cued hand movements
Authors: Li Guangye , Jiang Shize , Meng Jianjun , Wu Zehan , Jiang Haiteng , Fan Zhen , Hu Jie , Sheng Xinjun , Zhang Dingguo , Schalk Gerwin , Chen Liang , Zhu Xiangyang 
Published: July 2023

Abstract
Making hand movements in response to visual cues is common in daily life. It has been well known that this process activates multiple areas in the brain, but how these neural activations progress across space and time remains largely unknown. Taking advantage of intracranial electroencephalographic (iEEG) recordings using depth and subdural electrodes from 36 human subjects using the same task, we applied single-trial and cross-trial analyses to high-frequency iEEG activity. The results show that the neural activation was widely distributed across the human brain both within and on the surface of the brain, and focused specifically on certain areas in the parietal, frontal, and occipital lobes, where parietal lobes present significant left lateralization on the activation. We also demonstrate temporal differences across these brain regions. Finally, we evaluated the degree to which the timing of activity within these regions was related to sensory or motor function. The findings of this study promote the understanding of task-related neural processing of the human brain, and may provide important insights for translational applications.
Impact of Molnupiravir Treatment on Patient-Reported COVID-19 Symptoms in the Phase 3 MOVe-OUT Trial: A Randomized, Placebo-Controlled Trial
Authors: Guan Yanfen , Puenpatom Amy , Johnson Matthew G , Zhang Ying , Zhao Yujie , Surber Joseph , Weinberg Aaron , Brotons Carlos , Kozlov Roman , Lopez Rudy , Coetzee Kathleen , Santiaguel Joel , Du Jiejun , Williams-Diaz Angela , Brown Michelle , Paschke Amanda , De Anda Carisa , Norquist Josephine M 
Published: July 2023

Abstract

Background
Molnupiravir is an orally administered antiviral authorized for COVID-19 treatment in adults at high risk of progression to severe disease. Here, we report secondary and post hoc analyses of participants’ self-reported symptoms in the MOVe-OUT trial, which evaluated molnupiravir initiated within 5 days of symptom onset in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19.

Methods
Eligible participants completed a 15-item symptom diary daily from day 1 (randomization) through day 29, rating symptom severity as “none,” “mild,” “moderate,” or “severe”; loss of smell and loss of taste were rated as “yes” or “no.” Time to sustained symptom resolution/improvement was defined as the number of days from randomization to the first of 3 consecutive days of reduced severity, without subsequent relapse. Time to symptom progression was defined as the number of days from randomization to the first of 2 consecutive days of worsening severity. The Kaplan-Meier method was used to estimate event rates at various time points. The Cox proportional hazards model was used to estimate the hazard ratio between molnupiravir and placebo.

Results
For most targeted COVID-19 symptoms, sustained resolution/improvement was more likely, and progression was less likely, in the molnupiravir versus placebo group through day 29. When evaluating 5 distinctive symptoms of COVID-19, molnupiravir participants had a shorter median time to first resolution (18 vs 20 d) and first alleviation (13 vs 15 d) of symptoms compared with placebo.

Conclusions
Molnupiravir treatment in at-risk, unvaccinated patients resulted in improved clinical outcomes for most participant-reported COVID-19 symptoms compared with placebo.
Clinical Trials Registration. ClinicalTrials.gov: NCT04575597.
Surviving trees are key elements in the fate of ectomycorrhizal community after severe bark-beetle forest disturbance
Authors: Choma Michal , Bače Radek , Čapek Petr , Kaňa Jiří , Kaštovská Eva , Tahovská Karolina , Kopáček Jiří 
Published: July 2023

Abstract
Bark beetle disturbances are a critical event in the life cycle of Norway spruce forests. However, our knowledge of their effects on ectomycorrhizal fungi (EMF), which play a key role in forest productivity and nutrient cycling, is still incomplete. Special attention has been paid to the dynamics and diversity of EMF communities in managed forests, but studies dealing with disturbed natural stands are underrepresented. We conducted a study in an unmanaged natural spruce forest in the Bohemian Forest (Czech Republic), which suffered severe forest dieback caused by bark beetle. Approximately a decade after the disturbance, the character of the forest structure in the study area (∼60 ha, 41 study plots) ranged from sites with open canopy and sparse tree cover to areas with dense spruce regeneration to patches of closed-canopy forest. We found that relative EMF abundance in soils was positively related to surviving tree and regeneration density. The number of surviving trees also positively affected species EMF richness and tended to support preservation of late-successional EMF species. Our results suggest that trees that survive bark beetle disturbance are key for the fate of the EMF community in natural forests.
Turning It Over to God: African American Assisted Living Residents’ End-of-Life Preferences and Advance Care Planning
Authors: Kemp Candace L , Skipper Antonius D , Bender Alexis A , Perkins Molly M 
Published: July 2023

AbstractObjectivesAssisted living (AL), a popular long-term care setting for older Americans, increasingly is a site for end-of-life care. Although most residents prefer AL to be their final home, relatively little is known about end-of-life preferences and advance care planning, especially among African American residents. Our research addresses this knowledge gap.MethodsInformed by grounded theory, we present an analysis of qualitative data collected over 2 years in a 100-bed AL community catering to African American residents. Data consisted of field notes from participant observation conducted during 310 site visits and 818 observation hours, in-depth interviews with 25 residents, and a review of their AL records.ResultsResidents varied in their end-of-life preferences and advance care planning, but united in the belief that God was in control. We identified “Turning it over to God” as an explanatory framework for understanding how this group negotiated end-of-life preferences and advance care planning. Individual-level resident factors (e.g., age, pain, and function) and factors reflecting broader cultural and societal influences, including health literacy and care experiences, were influential.DiscussionContradictions arose from turning it over to God, including those between care preferences, planning, and anticipated or actual end-of-life outcomes.
A Single-Dose Intranasal Combination Panebolavirus Vaccine
Authors: Malherbe Delphine C , Kimble J Brian , Atyeo Caroline , Fischinger Stephanie , Meyer Michelle , Cody S Gabrielle , Hyde Matthew , Alter Galit , Bukreyev Alexander 
Published: July 2023

Abstract

Background
Ebolaviruses Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) cause severe human disease, which may be accompanied by hemorrhagic syndrome, with high case fatality rates. Monovalent vaccines do not offer cross-protection against these viruses whose endemic areas overlap. Therefore, development of a panebolavirus vaccine is a priority. As a vaccine vector, human parainfluenza virus type 3 (HPIV3) has the advantages of needle-free administration and induction of both systemic and local mucosal antibody responses in the respiratory tract.

Methods
To minimize the antivector immunity, genes encoding the HPIV3 envelope proteins F and HN were removed from the vaccine constructs, resulting in expression of only the ebolavirus envelope protein—glycoprotein. These second-generation vaccine constructs were used to develop a combination vaccine against EBOV, SUDV, and BDBV.

Results
A single intranasal vaccination of guinea pigs or ferrets with the trivalent combination vaccine elicited humoral responses to each of the targeted ebolaviruses, including binding and neutralizing antibodies, as well as Fc-mediated effector functions. This vaccine protected animals from death and disease caused by lethal challenges with EBOV, SUDV, or BDBV.

Conclusions
The combination vaccine elicited protection that was comparable to that induced by the monovalent vaccines, thus demonstrating the value of this combination trivalent vaccine.
Limited Benefit of Postexposure Prophylaxis With VSV-EBOV in Ebola Virus–Infected Rhesus Macaques
Authors: Bushmaker Trenton , Feldmann Friederike , Lovaglio Jamie , Saturday Greg , Griffin Amanda J , O’Donnell Kyle L , Strong James E , Sprecher Armand , Kobinger Gary , Geisbert Thomas W , Marzi Andrea , Feldmann Heinz 
Published: July 2023

Abstract
Vesicular stomatitis virus–Ebola virus (VSV-EBOV) vaccine has been successfully used in ring vaccination approaches during EBOV disease outbreaks demonstrating its general benefit in short-term prophylactic vaccination, but actual proof of its benefit in true postexposure prophylaxis (PEP) for humans is missing. Animal studies have indicated PEP efficacy when VSV-EBOV was used within hours of lethal EBOV challenge. Here, we used a lower EBOV challenge dose and a combined intravenous and intramuscular VSV-EBOV administration to improve PEP efficacy in the rhesus macaque model. VSV-EBOV treatment 1 hour after EBOV challenge resulted in delayed disease progression but little benefit in outcome. Thus, we could not confirm previous results indicating questionable benefit of VSV-EBOV for EBOV PEP in a nonhuman primate model.
Cefepime pharmacokinetics in critically ill children and young adults undergoing continuous kidney replacement therapy
Authors: Pavia Kathryn , Hambrick H Rhodes , Paice Kelli , Tang Peter , Punt Nieko , Kaplan Jennifer , Goldstein Stuart L , Vinks Alexander A , Mizuno Tomoyuki , Tang Girdwood Sonya 
Published: July 2023

Abstract

Objectives
Cefepime is an antibiotic commonly used to treat sepsis and is cleared by renal excretion. Cefepime dosing requires adjustment in patients with decreased kidney function and in those receiving continuous kidney replacement therapy (CKRT). We aimed to characterize cefepime PK in a diverse cohort of critically ill paediatric patients on CKRT.

Methods
Patients were identified from an ongoing pharmacokinetic/pharmacodynamic (PK/PD) study of beta-lactam antibiotics, and were included if they had received at least two cefepime doses in the ICU and were on CKRT for at least 24 h. PK parameters were estimated using MwPharm++ with Bayesian estimation and a paediatric population PK model. Target attainment was assessed as time of free cefepime concentrations above minimum inhibitory concentration (fT &gt; 1× or 4 × MIC).

Results
Seven patients were included in the study (ages 2 to 20 years). CKRT indications included liver failure (n = 1), renal failure (n = 4) and fluid overload (n = 2). Total effluent flow rates ranged from 1833 to 3115 (mean 2603) mL/1.73 m2/h, while clearance was 2.11–3.70 (mean 3.0) L/h/70 kg. Effluent flows were lower, but clearance and fT &gt; MIC were similar to paediatric data published previously. Using Pseudomonas aeruginosa MIC breakpoints, all patients had 100% of dosing interval above MIC, but only one had 100% of dosing interval above 4× MIC.

Conclusions
Since most patients failed to attain stringent targets of 100% fT &gt; 4×  MIC, model-informed precision dosing may benefit such patients.
The clinical application of beta-lactam antibiotic therapeutic drug monitoring in the critical care setting
Authors: Pai Mangalore Rekha , Peel Trisha N , Udy Andrew A , Peleg Anton Y 
Published: July 2023

AbstractCritically ill patients have increased variability in beta-lactam antibiotic (beta-lactam) exposure due to alterations in their volume of distribution and elimination. Therapeutic drug monitoring (TDM) of beta-lactams, as a dose optimization and individualization tool, has been recommended to overcome this variability in exposure. Despite its potential benefit, only a few centres worldwide perform beta-lactam TDM. An important reason for the low uptake is that the evidence for clinical benefits of beta-lactam TDM is not well established. TDM also requires the availability of specific infrastructure, knowledge and expertise. Observational studies and systematic reviews have demonstrated that TDM leads to an improvement in achieving target concentrations, a reduction in potentially toxic concentrations and improvement of clinical and microbiological outcomes. However, a small number of randomized controlled trials have not shown a mortality benefit. Opportunities for improved study design are apparent, as existing studies are limited by their inclusion of heterogeneous patient populations, including patients that may not even have infection, small sample size, variability in the types of beta-lactams included, infections caused by highly susceptible bacteria, and varied sampling, analytical and dosing algorithm methods. Here we review the fundamentals of beta-lactam TDM in critically ill patients, the existing clinical evidence and the practical aspects involved in beta-lactam TDM implementation.
Recent advances in cellular degradation and nuclear control of leaf senescence
Authors: Lei Pei , Yu Fei , Liu Xiayan 
Published: July 2023

Abstract
Senescence is the final stage of plant growth and development, and is a highly regulated process at the molecular, cellular, and organismal levels. When triggered by age, hormonal, or environmental cues, plants actively adjust their metabolism and gene expression to execute the progression of senescence. Regulation of senescence is vital for the reallocation of nutrients to sink organs, to ensure reproductive success and adaptations to stresses. Identification and characterization of hallmarks of leaf senescence are of great importance for understanding the molecular regulatory mechanisms of plant senescence, and breeding future crops with more desirable senescence traits. Tremendous progress has been made in elucidating the genetic network underpinning the metabolic and cellular changes in leaf senescence. In this review, we focus on three hallmarks of leaf senescence – chlorophyll and chloroplast degradation, loss of proteostasis, and activation of senescence-associated genes (SAGs), and discuss recent findings of the molecular players and the crosstalk of senescence pathways.
The wheat VQ motif-containing protein TaVQ4-D positively regulates drought tolerance in transgenic plants
Authors: Zhang Lili , Zheng Yan , Xiong Xinxin , Li Hui , Zhang Xin , Song Yulong , Zhang Xiaohong , Min Donghong 
Published: July 2023

Abstract
VQ motif-containing proteins play important roles in plant abiotic and biotic stresses. In this study, we cloned the VQ protein gene TaVQ4-D that is induced by drought stress. Arabidopsis and wheat plants overexpressing TaVQ4-D showed increased tolerance to drought stress. In contrast, wheat lines in which TaVQ4-D expression had been silenced showed decreased drought tolerance. Under drought stress conditions, the contents of superoxide dismutase and proline increased and the content of malondialdehyde decreased in transgenic wheat plants overexpressing TaVQ4-D compared with the wild type. At the same time, the expression of reactive oxygen species-scavenging-related genes and stress-related genes was up-regulated. However, plants of TaVQ4-D-silenced wheat lines showed decreased activities of antioxidant enzymes and reduced expression of some stress-related and antioxidant-related genes. In addition, the TaVQ4-D protein physically interacts with two mitogen-activated protein kinases (MPK3 and MPK6) and plays a role in plant drought stress as the phosphorylated substrates of MPK3 and MPK6. In summary, the results of our study suggest that TaVQ4-D can positively regulate drought stress tolerance in wheat.
Multiwavelength study of TeV blazar 1ES 1218+304 using gamma-ray, X-ray and optical observations
Authors: Diwan Rishank , Prince Raj , Agarwal Aditi , Bose Debanjan , Majumdar Pratik , Özdönmez Aykut , Chandra Sunil , Khatoon Rukaiya , Ege Ergün 
Published: July 2023

ABSTRACT
We report on a multiwavelength study of the high-synchrotron-peaked BL Lac 1ES 1218+304 using near-simultaneous data obtained during the period from 2018 January 1 to 2021 May 31 (MJD 58119–59365) from various instruments, including Fermi–LAT, Swift–XRT, AstroSat, and optical data from Swift-UVOT and the TUBITAK observatory in Turkey. The source was reported to be flaring in the TeV γ-ray band during 2019, but no significant variation was observed with Fermi–LAT. A sub-hour variability is seen in the SXT light curve, suggesting a compact emission region for the variability. However, hour-scale variability is observed in the γ-ray light curve. A ‘softer-when-brighter’ trend is observed in the γ-ray, and an opposite trend is seen in the X-ray, suggesting that the two emissions are produced through two different processes, as expected from a high-frequency-peaked BL Lac source. We have chosen the two epochs in 2019 January to study and compare their physical parameters. A joint fit of SXT and LAXPC provides a constraint on the synchrotron peak, estimated to be ∼1.6 keV. A clear shift in the synchrotron peak is observed from ∼1 keV to above 10 keV, revealing its extreme nature or behaviour like an extreme blazar-type source. The optical observation provides a colour-index variation as ‘blue-when-brighter’. The broad-band spectral energy distribution is fitted with a single-zone synchrotron-self Compton model, and their parameters are discussed in the context of a TeV blazar and the possible mechanism behind the broad-band emission.
The impact of Chat Generative Pre-trained Transformer (ChatGPT) on medical education
Authors: Heng Jonathan J Y , Teo Desmond B , Tan L F 
Published: July 2023

Abstract
Artificial intelligence (AI) in medicine is developing rapidly. The advent of Chat Generative Pre-trained Transformer (ChatGPT) has taken the world by storm with its potential uses and efficiencies. However, technology leaders, researchers, educators, and policy makers have also sounded the alarm on its potential harms and unintended consequences. AI will increasingly find its way into medicine and is a force of both disruption and innovation. We discuss the potential benefits and limitations of this new league of technology and how medical educators have to develop skills and curricula to best harness this innovative power.