bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on the (2+1)-dimensional extension of Hietarinta equation: soliton solutions and Bäcklund transformation
Authors: Gao Di , Lü Xing , Peng Ming-Shu
Published: July 2023

The (1+1)-dimensional bilinear Hietarinta equation was firstly proposed when searching for integrable nonlinear evolution equations by the three-soliton method. In this paper, we focus on the (2+1)-dimensional extension of Hietarinta equation, which enjoys potential application in environmental engineering. Based on the bilinear form, one-soliotn and two-soliton solutions are derived. Bilinear Bäcklund transformation and Bell-polynomial-typed Bäcklund transformation are derived through the Hirota bilinear method and Bell polynomials, respectively. The three-dimensional plots of soliton solutions have been given by selecting appropriate parameters.
Impacts of recycling impurity on the background ELM behavior during repetitive radiative divertor experiments in EAST
Authors: Yang Q.Q. , Lin X. , Xu G.S. , Zhang L. , Zhang W.M. , Ye Y. , Li K.D. , Wu D.G. , Zang Q. , Chen Y.J. , Zhong X.M. , Wang Y.F. , Meng L.Y. , Wang Y.M. , Li Y.Y. , Duan Y.M.
Published: July 2023

A significant change in the background ELM behavior prior to neon (Ne) seeding has been observed in a series of repetitive radiative divertor experiments in EAST. With similar operational parameters, the ELM behavior before Ne seeding changes from large to mixed ELMs, and finally evolves to pure small ELMs. Meanwhile, a significant increase in both Ne and high-Z impurity (W and Mo) emissions has been observed in the bulk plasma, suggesting the retention and recycling of Ne impurity from the wall surface. Experimental results show that the variation in background ELM behavior is highly correlated with the occurrence of high-Z impurity accumulation. The increased accumulation of high-Z impurities leads to a lower electron temperature both in the plasma core and edge, accompanied by a higher and more peaked electron density in the plasma core. Pedestal linear stability analysis reveals that the decreased pedestal electron temperature and thus the lower pressure gradient and lower edge current density are the primary reason for the change of background ELM behavior. The concentration of recycling Ne in the bulk plasma is estimated to be ∼1% in the discharges with pure small ELMs.
Analysis of Load and Deflection Curves on Reinforced Styro-Con Beams
Authors: Sariman Syahrul , Yuniarto Eka , Yusuf Andi Rumpang , Pertiwi Nurlita
Published: July 2023

Lightweight concrete technology develops along with construction needs. Styrofoam is an alternative ingredient that can be used in a mixture of concrete to produce lightweight concrete. Experimental research to see the performance of lightweight concrete with the addition of styrofoam. This study uses two types of samples, namely concrete cylinders and beams. The compressive strength and deflection tests were carried out on four types of concrete with various styrofoam mixtures. The results showed that the styro-con performed equivalent to regular concrete based on deflection and strength.
Mechanical Properties of Brick Using Rice Husk Ash
Authors: Panennungi T. , Rauf Bakhrani A. , Adam Asmah , Ahmad Irma Aswani , Sampebua Onesimus
Published: July 2023

Rice husk waste is very much produced because Indonesia is an agricultural country. This waste is freely burned around the factory and produces ash. This study used rice husk ash as an additive in bricks. This research aims to describe: (1) the compressive strength of brick with various percentages of RHA (0% - 15%), (2) the water absorption of brick with various percentages of RHA (0% - 15%), and (3) quality level of compressive strength and water absorption based on Indonesian Standard SNI 15-2094-2000. The methods are: (1) preparation of clay and rice husk ash, (2) produce brick with different percentages of RHA, (3) Drying with direct sunlight and furnacing with rice husk on an industrial site, (4) examining compressive strength and water absorption, and(5) analyzing data to find out compressive strength and water absorption, and quality of brick. The results showed that the use of RHA added to bricks caused a decrease in compressive strength. Meanwhile, the water absorption value of the bricks increases significantly. The RHA brick did not meet the requirements based on the compressive strength. However, according to water absorption, 5% RHA and 10% RHA meet the requirements.
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

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

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

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

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

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

Objectives

Assisted 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.

Methods

Informed 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.

Results

Residents 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.

Discussion

Contradictions 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

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

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

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 > 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 > 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 > 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

Critically 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

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

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

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

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.
The impact of psoriasis on wellbeing and clinical outcomes in juvenile psoriatic arthritis
Authors: Low Jie Man , Hyrich Kimme L , Ciurtin Coziana , McErlane Flora , Wedderburn Lucy R , Geifman Nophar , Shoop-Worrall Stephanie J W ,   CAPS Principal Investigators, Cleary G , Baildam E , Wedderburn L , Davidson J , Chieng A , McErlane F , Foster H , Ciurtin C , Ioannou Y , Thomson W , Hyrich K
Published: July 2023

Objectives

Juvenile PsA (JPsA) has varied clinical features that are distinctive from other JIA categories. This study investigates whether such features impact patient-reported and clinical outcomes.

Methods

Children and young people (CYP) were selected if recruited to the Childhood Arthritis Prospective Study, a UK multicentre JIA inception cohort, between January 2001 and March 2018. At diagnosis, patient/parent-reported outcomes (as age-appropriate) included the parental global assessment (10 cm visual analogue scale), functional ability (Childhood Health Assessment Questionnaire (CHAQ)), pain (10 cm visual analogue scale), health-related quality of life (Child Health Questionnaire PF50 psychosocial score), mood/depressive symptoms (Moods and Feelings Questionnaire) and parent psychosocial health (General Health Questionnaire 30). Three-year outcome trajectories have previously been defined using active joint counts, physician and parent global assessments (PGA and PaGA, respectively). Patient-reported outcomes and outcome trajectories were compared in (i) CYP with JPsA vs other JIA categories and (ii) CYP within JPsA, with and without psoriasis via multivariable linear regression.

Results

There were no significant differences in patient-reported outcomes at diagnosis between CYP with JPsA and non-JPsA. Within JPsA, those with psoriasis had more depressive symptoms (coefficient = 9.8; 95% CI: 0.5, 19.0) than those without psoriasis at diagnosis. CYP with JPsA had 2.3 times the odds of persistent high PaGA than other ILAR categories, despite improving joint counts and PGA (95% CI: 1.2, 4.6).

Conclusion

CYP with psoriasis at JPsA diagnosis report worse mood, supporting a greater disease impact in those with both skin and joint involvement. Multidisciplinary care with added focus to support wellbeing in children with JPsA plus psoriasis may help improve these outcomes.
Virulence of NovelRalstonia pseudosolanacearum(Phylotype I) Strains from Rose, Blueberry, and Mandevilla on Seed Potato
Authors: Overeem Remco , Pel Chiel , Tjou-Tam-Sin Napoleon , van de Bilt Jeroen , Gorkink-Smits Peggy , Landman Marco , Bocsanczy Ana Maria B. , Norman David , Bergsma-Vlami Maria
Published: July 2023

Potato (Solanum tuberosum L.) ranks fourth among the most important staple food in the world. Ralstonia solanacearum (phylotype [phy] IIB, sequevar [seq] 1 and 2), also known as R3B2, the causal agent of brown rot disease on potato, is extremely damaging, causing great economical losses to potato in temperate regions. It is thought that members of Ralstonia pseudosolanacearum (phy I) are not pathogenic at low temperatures and are usually found in warmer climates. R. pseudosolanacearum strain PD 7123 (seq 33) isolated from roses in the Netherlands, strain P824 (seq 13) isolated from blueberry, and strain P781 (seq 14) from mandevilla in Florida are phylogenetically closely related and could share the same host. The virulence and ability of these novel strains to multiply latently in potato in temperate regions is unknown. The objective of this work was to assess the virulence and presence of latent infections of the mentioned R. pseudosolanacearum strains on three commercial seed potato cultivars under warmer (28°C) and temperate (20°C) temperatures. At 28°C, all three R. pseudosolanacearum strains caused severe symptoms on all potato cultivars. Overall disease severity on potato was lower at 20°C than 28°C, but major differences in virulence of the three strains were observed at 42 days postinoculation (dpi) among potato cultivars. All asymptomatic potato plants and most of their daughter tubers had latent infections at 20°C. Altogether, these results show that the phy I strains from rose, blueberry, and mandevilla may pose a threat to potato production in temperate climates and the worldwide movement of seed potatoes.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
A Cross-Sectional Evaluation of Publication Bias in the Plastic Surgery Literature
Authors: Wu Shannon S. , Katabi Leila , Desimone Robert , Borsting Emily , Ascha Mona
Published: July 2023

Background:

Publication bias (PB) is the preferential publishing of studies with statistically significant results. PB can skew findings of systematic reviews (SR) and meta-analyses (MA), with potential consequences for patient care and health policy. This study aims to determine the extent by which SRs and MAs in the plastic surgery literature evaluate and report PB.

Methods:

This cross-sectional study assessed PB reporting and analysis from plastic surgery studies published between January 1, 2015 and June 19, 2020. Full-texts of SRs and MAs were assessed by two reviewers for PB assessment methodology and analysis. Post-hoc assessment of studies that did not originally analyze PB was performed using Egger’s regression, Duval and Tweedie’s trim-and-fill, and Copas selection models.

Results:

There were 549 studies evaluated, of which 531 full-texts were included. PB was discussed by 183 (34.5%) studies, and formally assessed by 97 (18.3%) studies. Among SR and MAs that formally assessed PB, PB was present in 24 (10.7%), not present in 52 (23.1%), and inconclusive in 8 (3.6%) studies; 141 (62.7%) studies did not report the results of their PB assessment. Funnel plots were the most common assessment method (n=88, 39.1%), and 60 (68.2%) studies published funnel plots. The post-hoc assessment revealed PB in 17/20 (85.0%) studies.

Conclusion:

PB is inadequately reported and analyzed amongst studies in the plastic surgery literature. Most studies that assessed PB found PB, as did post-hoc analysis of non-reporting studies. Increased assessment and reporting of PB amongst SRs and MAs would improve quality of evidence in plastic surgery.
Impact of health disparity on pediatric infections
Authors: Rogo Tanya , Holland Sabina
Published: July 2023

Purpose of review

The COVID-19 pandemic highlighted the health disparities among minoritized children due to structural racism and socioeconomic inequalities. This review discusses how health disparities affect pediatric infections and how they can be addressed.

Recent findings

In addition to disparities in healthcare access due to poverty, geography, and English-language proficiency, implicit and explicit bias affects the healthcare quality and subsequent outcomes in children and adolescents with infections. Disparities in clinical trial enrollment affect the generalizability of research findings. Physicians who understand their patients’ languages and the contexts of culture and socioeconomic conditions are better equipped to address the needs of specific populations and the health disparities among them.

Addressing disparities in pediatric infections requires prioritization of efforts to increase physician workforce diversity in Pediatric Infectious Diseases, as well as education in bias reduction and culturally sensitive clinical practice, in addition to socioeconomic interventions that improve healthcare access, delivery, and outcomes.
Validation of the PROMIS-29 Questionnaire as a Measure of Recovery after Pancreatic Surgery
Authors: Pecorelli Nicolò , Guarneri Giovanni , Vallorani Alessia , Limongi Chiara , Licinio Alice W. , Di Salvo Francesca , Tamburrino Domenico , Partelli Stefano , Crippa Stefano , Falconi Massimo
Published: July 2023

Objective:

To contribute evidence for the reliability, construct validity and responsiveness of the PROMIS-29 profile questionnaire as a measure of recovery after pancreatic surgery.

Summary Background Data:

PROMIS questionnaires have been recommended to evaluate post-discharge recovery after surgery. Evidence supporting their measurement properties in pancreatic surgery is missing.

Methods:

An observational validation study designed according to the COSMIN checklist was conducted including data from a prospective clinical trial. Patients undergoing pancreatectomy completed PROMIS-29 preoperatively and on postoperative days (PODs) 15, 30, 90, 180. Reliability was assessed by internal consistency using Cronbach’s alpha. Construct validity was assessed by known-groups comparison. Responsiveness was evaluated hypothesizing that scores would be higher (1) preoperatively versus POD15, (2) on POD30 versus POD15, (3) on POD90 versus POD30, and (4) on POD180 versus POD90.

Results:

Overall, 510 patients were included in the study. Reliability was good to excellent (alpha values ranged from 0.82 to 0.97). Data supported 4 of 5 hypotheses tested for construct validity for five domains (physical function, anxiety, depression, fatigue and ability to participate in social roles) at most time points. Responsiveness hypotheses 1, 2, 3 were supported by the data for physical function, fatigue, sleep disturbance, pain interference and ability to participate in social roles domains.

Conclusion:

PROMIS had excellent reliability, discriminated between most groups expected to have different recovery trajectories and was responsive to the expected trajectory of recovery up to 90 days after surgery. Our findings support the use of PROMIS-29 profile as a patient reported outcome measure of post-discharge recovery after pancreatectomy.
IL-35 Stabilizes Treg Phenotype to Protect Cardiac Allografts in Mice
Authors: Huang Ai , Liu Kewei , Yin Ziyi , Liu Jie , Wei Hongyan , Xing Shijie , Qu Yue , Huang Lei , Li Liancheng , Li Chang , Zhang Lei , Li Xiaoshi , Zheng Cunni , Liu Quan , Jiang Ke
Published: July 2023

Background.

Interleukin-35 (IL-35), secreted by regulatory T cells (Treg) and B cells, is immunosuppressive under both physiological and pathological conditions. However, the role of IL-35 in all responses has yet to be investigated. Here, we demonstrate that IL-35 protects allografts by stabilizing the Treg phenotype and suppressing CD8+ T-cell activation in a mouse heart transplantation model.

Methods.

The effect of IL-35 on immune cell infiltration in grafts and secondary lymphoid organs was examined using mass cytometry, flow cytometry, and immunofluorescence. Moreover, using quantitative real-time polymerase chain reaction, flow cytometry, and phospho-flow assays, we demonstrated that IL-35 maintains Treg phenotypes to restrain CD8+ T cells via the gp130/signal transducer and activator of transcription 1 pathway.

Results.

Mass cytometry analysis of intragraft immune cells showed that IL-35 decreased CD8+ T-cell infiltration and increased Foxp3 and IL-35 expressions in Treg. In vitro, we demonstrated that IL-35 directly promoted Treg phenotypic and functional stability and its IL-35 secretion, generating a positive feedback loop. However, Treg are required for IL-35 to exert its suppressive effect on CD8+ T cells in vitro. After depleting Treg in the recipient, IL-35 did not prolong graft survival or decrease CD8+ T-cell infiltration. Mechanistically, we found that IL-35 sustained Treg stability via the gp130/signal transducer and activator of transcription 1 signaling pathway.

Conclusions.

Our findings highlight that IL-35 stabilizes the Treg phenotype to ameliorate CD8+ T-cell infiltration in the allograft, which has never been described in the transplanted immunological milieu.
Development of a mobile, high-throughput, and low-cost image-based plant growth phenotyping system
Authors: Yu Li’ang , Sussman Hayley , Khmelnitsky Olga , Ishka Maryam Rahmati , Srinivasan Aparna , Nelson Andrew D.L. , Julkowska Magdalena M.
Published: July 2023

Nondestructive plant phenotyping is fundamental for unraveling molecular processes underlying plant development and response to the environment. While the emergence of high-through phenotyping facilities can further our understanding of plant development and stress responses, their high costs significantly hinder scientific progress. To democratize high-throughput plant phenotyping, we developed sets of low-cost image- and weight-based devices to monitor plant growth and evapotranspiration. We paired these devices with a suite of computational pipelines for integrated and straightforward data analysis. We validated the suitability of our system for large screens by evaluating a cowpea diversity panel for responses to drought stress. The observed natural variation was subsequently used for Genome-Wide Association Study, where we identified nine genetic loci that putatively contribute to cowpea drought resilience during early vegetative development. We validated the homologs of the identified candidate genes in Arabidopsis using available mutant lines. These results demonstrate the varied applicability of this low-cost phenotyping system. In the future, we foresee these setups facilitating identification of genetic components of growth, plant architecture, and stress tolerance across a wide variety of species.
DNA satellite and chromatin organization at house mouse centromeres and pericentromeres
Authors: Packiaraj Jenika , Thakur Jitendra
Published: July 2023

Centromeres are essential for faithful chromosome segregation during mitosis and meiosis. However, the organization of satellite DNA and chromatin at mouse centromeres and pericentromeres is poorly understood due to the challenges of sequencing and assembling repetitive genomic regions. Using recently available PacBio long-read sequencing data from the C57BL/6 strain and chromatin profiling, we found that contrary to the previous reports of their highly homogeneous nature, centromeric and pericentromeric satellites display varied sequences and organization. We find that both centromeric minor satellites and pericentromeric major satellites exhibited sequence variations within and between arrays. While most arrays are continuous, a significant fraction is interspersed with non-satellite sequences, including transposable elements. Additionally, we investigated CENP-A and H3K9me3 chromatin organization at centromeres and pericentromeres using Chromatin immunoprecipitation sequencing (ChIP-seq). We found that the occupancy of CENP-A and H3K9me3 chromatin at centromeric and pericentric regions, respectively, is associated with increased sequence abundance and homogeneity at these regions. Furthermore, the transposable elements at centromeric regions are not part of functional centromeres as they lack CENP-A enrichment. Finally, we found that while H3K9me3 nucleosomes display a well-phased organization on major satellite arrays, CENP-A nucleosomes on minor satellite arrays lack phased organization. Interestingly, the homogeneous class of major satellites phase CENP-A and H3K27me3 nucleosomes as well, indicating that the nucleosome phasing is an inherent property of homogeneous major satellites. Overall, our findings reveal that house mouse centromeres and pericentromeres, which were previously thought to be highly homogenous, display significant diversity in satellite sequence, organization, and chromatin structure.
Response Surface Methodology-Based High-Throughput BioLector Fermentation Screening of Rosetta™-2 for Enhanced Production of Insulin Variant: Towards Improved Production Efficiency
Authors: Ayan Esra , Aytekin Ali Özhan , Kati Ahmet , DeMirci Hasan
Published: July 2023

Background

In order to obtain high yields of recombinant insulin and advancing therapeutic avenues for diabetes patients, the development of innovative designer insulin analogs have critical importance. The modified insulin analog presents a cost-effective remedy by being produced as inclusion bodies (IBs) withinEscherichia coliBL21 (DE3) Rosetta-2 strain. This approach to production not only offers reduced production time but also yields high recovery rates. The prime aim of this investigation was to optimize the composition of the cultivation media, thereby accomplishing higher cell density fermentation of the proinsulin, that is fused with a cleavable hexa histidine purification tag.

Result

Various factors, including carbon and nitrogen sources, salts, metal ions, and pH, were systematically investigated through experimental screening using the BioLector multiwell bright plate. Additionally, computational analysis employing thePlackett-Burman Designwithin theDesign Expertsoftware was utilized to assess their effectiveness in terms of insulin concentration as a surrogate measure of insulin yield. Among the tested variables, glucose, glycerol, MgSO4, and lower Luria-Bertani mix concentration have a significant influence on insulin production, as determined by the screening experiment. Subsequently, theCentral Composite Designapproach was operated to further evaluate and optimize the precise levels of these influential variables. This systematic methodology achieved an optimized cultivation media formulation, resulting in a remarkable enhancement of insulin production, with levels reaching up to 13 mg/ml when applied in BioLector fermentation.

Conclusion

The formulated cultivation media exhibited suitability for promoting high cell density fermentation of the modified insulin, thereby facilitating the attainment of optimal yields for the proinsulin expression.
afila, the origin and nature of a major innovation in the history of pea breeding
Authors: Tayeh Nadim , Hofer Julie , Aubert Grégoire , Jacquin Françoise , Turner Lynda , Kreplak Jonathan , Paajanen Pirita , Le Signor Christine , Dalmais Marion , Pflieger Stéphanie , Geffroy Valérie , Ellis Noel , Burstin Judith
Published: July 2023

Theafila(af) mutation ofPisum sativumL. (pea) is characterised by leaves that are composed of a basal pair of stipules, a petiole and a branched mass of tendrils. These are bipinnate leaves in which the leaflet primordia are replaced by midrib-like, or terminal tendril, primordia. The phenotype was first reported as a spontaneous mutation in 1953, and several reports of spontaneously occurringafmutants and induced mutations have been published since then. Despite its wide-scale introgression to improve standing ability in combine-harvested dry pea crops, the molecular basis ofafhas remained unknown. Here, we show that the deletion of two tandemly-arrayed Q-type Cys(2)His(2)-zinc finger transcription factors, viz.PsPALM1aandPsPALM1b, is responsible for the af phenotype. Based on molecular evidence for the presence/absence of seven consecutive pea genes, we identified eight haplotypes in the genomic region of chromosome 2 that harboursaf. These haplotypes differ in the presence or absence ofPsPALM1a-band close genes and in the size of the deletion. Representative cultivars and spontaneous or induced mutants were assigned to the different haplotypes. The hitherto unrecognised diversity at theaflocus reveals highly rich, unexplored, potential for pea improvement and sheds light on the breeding history of pea. This knowledge can also be used to breed innovative cultivars in related crops.
The human genome’s vocabulary as proposed by the DNA language model GROVER
Authors: Sanabria Melissa , Hirsch Jonas , Poetsch Anna R.
Published: July 2023

Large Language Models (LLMs) on natural language have achieved a level of performance that allows the generation of coherent and syntactically correct text. DNA sequence of genomes follows rules similar to natural language, but a distinguishing factor is the absence of a concept analogous to words. We established byte-pair tokenization on the human genome and trained a foundation language model called GROVER (“GenomeRulesObtainedViaExtractedRepresentations”) to select the optimal vocabulary with a custom fine-tuning task of next-k-mer prediction. We thus defined a dictionary of words/tokens in the human genome that best carries the information content for DNA language models. Analyzing GROVER’s learned representations, we observed that token embeddings primarily encode information related to their frequency, sequence content, and length. Some tokens are almost exclusively localized in repeats, while the vast majority widely distributes over the genome. The model also learns context and lexical ambiguity. Average embeddings of genomic regions relate to functional genomics annotation and thus indicate that GROVER has learned these structures purely from the contextual relationships of tokens. That we can extract functional annotations from the genome, purely based on sequence representation to the trained model, highlights the extent of information content encoded by the sequence. This is supported by fine-tuning tasks on genome biology with questions of promoter identity and protein-DNA binding. GROVER learns sequence context, a sense for grammatical structures and language rules in the genome. This knowledge can be extracted and used to compose a grammar book for the code of life.