bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality and associated factors among hospitalized COVID 19 patients in Lira regional referral hospital, a cross sectional study
Authors: Augustine Ongoli , Bosco Opio , Opollo Marc Sam , Akello Ann Ruth , Francis Kiweewa , Bernard Omech
Published: October 2024

Background

Corona Virus Disease 2019 (COVID-19) caused public emergency with serious morbidity and mortality worldwide between 2020 and 2022, The direct impact of the disease and associated mortality may have been relatively limited in Sub-Saharan Africa (SSA), compared to the impact in other regions. The factors that are considered high risk for acquisition of COVID-19 and associated high mortality rate amongst in-patients are varied in different settings, there are limited data from regional referral designated COVID-19 Treatment Units (CTU) in Uganda. This research assessed the mortality rate, the sub-populations at high risk and characteristics of COVID-19 patients hospitalized in Lira Regional Referral Hospital (LRRH).

Objective

To describe COVID-19 characteristic, mortality and associated risk factors among patients admitted at the Lira Regional referral hospital COVID 19 Treatment Unit in northern Uganda.

Design

Cross Sectional Study with use of Secondary Data

Setting

This study was conducted at Lira RRH between January 2023 and December 2023. The data used were for patients admitted from May 2020 to March 2022.

Participant

In this study all the patients with confirmed COVID-19 were selected by simple census sampling technique, 490 participants were included in the study and these were a) moderately to critically ill patients, b) mild or asymptomatic patients with comorbidity, c) those with positive COVID-19 test and d) those who were admitted in the hospital.

Results

In the final analysis, 490 participants were considered. Out of this, 251 (52%) were females. Majority 203(41%) were older than 60 years of age. Most of the patients presented with cough 369(89.56%), difficulty in breathing (DIB) 293(78.76%), chest pain 237(69.3%), general body weakness (GBW) 199(63.38%) and fever 179(61.3%). Common pre-existing comorbidities were hypertension 139(29.96%), diabetes mellitus 89(19.47%) and HIV 44(10%). Of all the patients admitted, 187(40%) had severe disease and 34(7%) were critically ill.

Overall from May 2020 to March 2022, 142(29%) died. Oxygen saturation (SPO2) 92-100% had 89% decreased mortality (aOR-0.11, 95% CI 0.03-0.44, p-value-0.002). Body temperature 35.5-37.5 degrees Celsius had 78% decreased mortality (aOR-0.22, 95% CI 0.05-0.99, p-value-0.049). Those without Chronic Liver Disease (CLD) had 99% decreased mortality (aOR-0.01, 95% CI 0.001-0.46, p-value-0.017). Age 31-45yrs had 86% decreased mortality (aOR-0.14, 95% CI 0.03-0.74, p-value-0.021)

Conclusion

The in-hospital mortality rate in our cohort of COVID 19 patients admitted at LRRH was high. Not having chronic liver disease, normal oxygen saturation, normal body temperature and younger age were associated with decreased likelihood of death.
UTILIZATION OF PRECONCEPTION CARE AND ASSOCIATED FACTORS AMONG REPRODUCTIVE AGE WOMEN IN POKHARA METROPOLITAN, KASKI, NEPAL
Authors: Aryal Sita , Wagle Saroj , Marasini Yamuna , Bhandari Tulsi Ram
Published: October 2024

Background

Preconception care refers to specific actions taken by an individual or couple to improve their health before becoming pregnant. Preconception care (PCC) is considered primary prevention for the future baby and secondary prevention for prospective mothers. Preconception care utilization in Nepal was very low. Studies on these issues are a newer concept in Nepal and also in Pokhara Metropolitan.

Objectives

To assess the utilization of preconception care and associated factors among reproductive-age group women in Pokhara Metropolitan.

Methods

A community-based cross-sectional study was conducted from January 2024 to September 2024. The total study participants were 384 reproductive-age women. Data were collected using pre-tested, interviewer-administered questionnaires and analyzed with SPSS after entry into Epi-Data. Descriptive analysis was conducted to show frequencies and percentages, while bivariate analysis was performed using a chi-square test and multivariate analysis was done using binary logistic regression to identify factors associated with the utilization of preconception care. Lastly, odds ratios and 95% confidence intervals were used to evaluate the statistical significance between the dependent and independent variables.

Results

Only 0.3% of participants utilize all preconception care components before their last pregnancy. The acceptance level of utilization of the PCC component was 44.5%. The commonest item received by the participants was taking a healthy diet (49.2%), checking weight (43.8%), and blood group screening (53.4%). Age of the respondent AOR=13.89; (CI:2.49-77.33), religion AOR=3.1;CI(1.43-6.95), occupations of respondents AOR=2.58; CI(1.67-3.99), knowledge of PCC AOR=5.12; CI(2.99-8.77), attitude towards PCC AOR=1.92; CI(1.18-3.12), heard about PCC AOR=3.15; CI(1.77-5.59) minutes to reach health facilities AOR=2.4; CI (1.32-4.35) health insurance use before pregnancy AOR=2.68 ;CI(1.71-4.19), and waiting time at health facilities AOR=1.60;CI(1.02-2.50) were identified as a factors associated with utilization of PCC.

Conclusion

The utilization of preconception care among the women was very low compared to the recommended services and was influenced by various factors.

Community-based advocacy and awareness are needed for women with low levels of knowledge and attitudes towards preconception care components, as well as those facing challenges such as time to reach health facilities, lack of insurance use before pregnancy, and long waiting times at health facilities. Health promotion strategies focused on preconception care and pre-pregnancy planning may increase utilization rates and improve maternal health.
A playbook for harmonization of standards for emergent viral pathogens
Authors: Suliman Sara , Fuchs Sebastien , Catoe David , Hansen Loren , Eveleigh Deepa , Crone Michael A. , Freemont Paul S. , Kammel Martin , Zeichhardt Heinz , Anfora Andrew T. , Garlick Russell , Almond Neil , Page Mark , Beck Brian , Wang Hui , Sharma Karuna , Pestano Gary , Vancann Joannes , Vandesompele Jo , Corner Adam S , Albrecht Jeffrey , Boles Deborah J. , Eisenberg Marcia , Harris Ayla B. , Krueger Brian J. , Suchanek Amanda L. , Urban Thomas J. , Williams Jonathan D. , Chain Patrick , Deshpande Alina , Hollander Attelia , Chalise Sujata , Walt David R. , Germer Jeffrey , Yao Joseph D. , Pritt Bobbi S. , Nolte Frederick S. , Košir Alexandra Bogožalec , Milavec Mojca , Cleveland Megan H. , Vallone Peter M. , Busby Eloise J. , Huggett Jim F. , O’Sullivan Denise M. , Marlowe Elizabeth M. , Pinsky Benjamin A. , Kealiher Annaleise , Lunshof Jeantine E. , Mason Christopher E. , Sninsky John , Tato Cristina , Mercer Timothy , White Thomas J. , Salit Marc
Published: October 2024

Effective clinical and public health decision-making during a pandemic depends on reliable and interoperable clinical diagnostic test results. To ensure trustworthy outcomes, we need widely available and harmonized calibration standards on a shared scale. We present a ‘playbook’ for an inter-laboratory harmonization study that calibrates any available standards against a limited-availability standard issued by a global authority like the World Health Organization (WHO).
Self-assembly of hybrid 3D cultures by integrating living and synthetic cells
Authors: Piernitzki Nils , Gao Ning , Gasparoni Gilles , Schulze-Hentrich Julia , Dustin Michael , Győrffy Balázs , Mann Stephen , Staufer Oskar
Published: October 2024

Self-assembly, a fundamental property of living matter, drives the interconnected cellular organization of tissues. Synthetic cell models have been developed as bionic materials to mimic inherent cellular features such as self-assembly. Here, we leverage co-assembly of synthetic and natural cells to create hybrid living 3D cancer cultures. We screened synthetic cell models, including giant unilamellar vesicles, coacervates, microdroplet emulsions, proteinosomes, and colloidosomes, for their ability to form hybrid tumoroids. Our results identify the balance of inter- and extracellular adhesion and synthetic cell surface tension as key material properties driving successful co-assembly of hybrids. We further demonstrate that these synthetic cells can establish artificial tumor immune microenvironments (ART-TIMEs), mimicking immunogenic signals within tumoroids. Using the ART-TIME approach, we identify co-signaling mechanisms between PD-1 and CD2 as a driver in immune evasion of pancreatic ductal adenocarcinoma. Our findings demonstrate the 3D bottom-up self-assembly of hybrid cancer microenvironments to replace immune components with defined bionic materials, pushing the boundaries to functionally integrating living and non-living matter.
Garlic (Allium sativum L.) yield and quality as affected by different integrated fertilizer levels at Wachemo university, southern Ethiopia
Authors: Abrham S. , Mihret J. , Abraham B.
Published: October 2024

Production and productivity of garlic was constrained by many factors, among which lack of integrated nutrient recommendation is the most important in Ethiopia. Thus, on site trial was executed at Wachemo University Lembuda demonstration field during 2021/2022 with the aims to identify the effects of NPS fertilizer and chicken manure levels on growth, bulb yield and quality; to determine the economic optimum combination of NPS and chicken manure rate for garlic productivity in the target location. The treatments included four levels of chicken manure (0, 5, 10 and 15 t/ha) and five levels of NPS fertilizer (0, 50,100, 150 and 200 kg/ha) arranged factorially using a randomized complete block design (RCBD) and replicated three times. Growth, bulb yield and quality data were collected and subjected to analysis using SAS version 9.4. With the exception of days to maturity, leaf number and non-marketable bulb yield in the case of chicken manure, the majority of the investigated parameters were significantly (P < 0.05) impacted by the main effects of chicken manure and NPS fertilizer. Exception marketable and total bulb yield, the interaction impact was not significant for nearly all of the examined variables. On the other hand, the bulb yield was considerably raised by raising the rate of chicken manure in combination with NPS fertilizer. As a result, combined application of 15 t/ha chicken manure and 150 kg/ha NPS fertilizer produced the maximum marketable bulb (19.52 t/ha) and total yield (20.27 t/ha), followed by marketable yield (18.53 t/ha) and total yield (19.55 t/ha) obtained from plants treated with 200 kg/ha of NPS fertilizer and 15 t/ha of chicken manure, with a 927 % yield advantage over plants receiving no fertilizer. On the other hand, the control treatment produced the lowest total yield (3.89 t/ha) and marketable yield (1.90 t/ha). Plots with 15 t/ha chicken manure had the highest bulb dry matter (35.31%) and TSS (22.47° Brix). In terms of economic analysis, the plants that got 15 t/ha of chicken manure and 150 kg/ha of NPS fertilizer had the highest net benefit (524224.8 ETB/ha) with an MRR of 10,159.1%. Hence, this combination was found to be the best and cost-effective one for smallholder farmers in the study area that could be recommended to boost garlic production and productivity.
Genetic variation in male mate choice for large females inDrosophila melanogaster
Authors: Freed Grace S. , Martinez Isabella G. , Lev Avigayil , Cuadrado Ana-Maria Anthony , Pischedda Alison
Published: October 2024

Males in many species show courtship and mating preferences for certain females over others when given the choice. One of the most common targets of male mate choice in insects is female body size, with males preferring to court and mate with larger, higher-fecundity females and investing more resources in matings with those females. Although this preference is well-documented at the species level, less is known about how this preference varies within species and whether there is standing genetic variation for male mate choice within populations. We used hemiclonal analysis in the fruit fly,Drosophila melanogaster, to test for heritable genetic variation in pre- and post-copulatory components of male mate choice for large females. We found additive genetic variation for both forms of male choice: males from different hemiclone lines varied in the strength of their courtship preferences for large females and the degree to which they extended matings with large females. Although males from hemiclone lines with stronger courtship preferences for large females were more likely to mate with those females, there was no genetic correlation between pre- and post-copulatory components of male mate choice, suggesting that they are under independent genetic control. Genetic variation in male mate choice may be widespread, potentially impacting the fitness of both sexes and the adaptive evolution of populations.
Inhibition of pterygium cell fibrosis by the Rho kinase inhibitor
Authors: Dai Jiannong , Rayana Naga Pradeep , Peng Michael , Sugali Chenna Kesavulu , Harvey Devon Hori , Dhamodaran Kamesh , Yu Eric , Liu Shaohui , Mao Weiming
Published: October 2024

Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and α smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinases inhibitors are a potential post-surgical treatment to prevent pterygium recurrence.
Fluorescence-based CRISPR interference system for controlled genetic repression and live single-cell imaging in mycobacteria
Authors: Laudouze Janïs , Point Vanessa , Achache Wafaa , Crauste Céline , Canaan Stéphane , Santucci Pierre
Published: October 2024

Mycobacterial genetics has played a pivotal role over the last 35 years in our understanding of mycobacterial physiology, pathogenesis and antibiotic resistance. Numerous approaches are now available worldwide to dissect the contribution of genes of interest in biological processes. However, many of these approaches can be fastidious, difficult to perform and time-consuming, especially when working with slow-growing mycobacteria or in bio-safety level two/three settings. The recent development of CRISPRi-mediated targeted gene repression has revolutionized the way research groups can perform genetics in mycobacteria, providing a fast, robust and efficient alternative to study the function of specific genes including essential genes. In this research letter, we report the development and validation of a new subset of fluorescence-based CRISPRi tools for our scientific community. The pJL series is directly derived from the original integrative pIRL2 and pIRL117 CRISPRi vectors and conserved all the elements required to perform inducible targeted gene repression. In addition, these vectors carry two distinct fluorescent markers for which the expression is driven by the strong and constitutive promotorpsmycto simplify the selection of recombinant clones. We demonstrate the functionality of these vectors by targeting the expression of the non-essential glycopeptidolipid translocasemmpL4band the essential genesrpoBandmmpL3. Finally, we describe an efficient single-step procedure to co-transform mycobacterial species with this integrative genetic tool alongside replicative vectors. Such tools and approaches should be useful to foster discovery in mycobacterial research.

Graphical Abstract

Development and validation of a new subset of E. coli-Mycobacteria shuttle vectors that enable simultaneous CRISPRI-mediated gene silencing and fluorescence based single-cell imaging.
Associations Between Female Sex Hormones and Skeletal Muscle Ageing: The Baltimore Longitudinal Study of Aging
Authors: Critchlow Annabel J. , Alexander Sarah E. , Hiam Danielle , Ferrucci Luigi , Scott David , Lamon Séverine
Published: October 2024

Background

To date, most research investigating the influence of circulating sex hormones on ageing female skeletal muscle has been cross-sectional and focused only on dichotomised young and old, or pre-versus post-menopausal groups. This excludes an important transitional period from high to low circulating oestrogen. Using secondary data from the Baltimore Longitudinal Study of Aging, this study aimed to investigate cross-sectional and longitudinal associations between circulating sex hormones and skeletal muscle mass and function across a continuum of ages.

Methods

Multiple and binomial linear regression was used to map cross-sectional (n=319) and longitudinal (n=83) associations between circulating sex hormones (oestradiol (E2), free oestradiol index (FEI), free (TT) and bioavailable testosterone (BioT), testosterone/oestradiol ratio (TT/E2)) and skeletal muscle mass and function in healthy females. Cross-sectional models analysed females across an ageing continuum (24-89 years) and longitudinal associations were tested across 4-6 years of ageing in females over 50 years old. Models were adjusted for age, height, physical activity, comorbidities, and ethnicity.

Results

Cross-sectionally, serum E2 and FEI were positively associated with relative appendicular lean mass (ALM; β=0.28 and 0.20, respectively,p<0.05) and thigh muscle percentage (β=0.19 and 0.15, respectively,p<0.05). E2 and FEI were negatively associated with total body fat percentage (β=-0.30 and -0.21, respectively,p<0.05). BioT was positively associated with absolute ALM (β=0.13,p<0.05) and total body fat percentage (β=0.18,p<0.05). TT was negatively associated with total body fat percentage (β=-0.14,p<0.05). The TT/E2 ratio was negatively associated with thigh muscle CSA (β=-0.08,p<0.05) and hamstring strength (β=-0.12,p<0.05). Across 4-6 years, a decrease in E2 and FEI were associated with a decrease in ALM (β=0.29 and 0.42, respectively,p<0.05), and decrease in FEI was associated with a decrease in handgrip strength (β=0.17,p<0.05). A decrease in TT and BioT were associated with an increase in relative ALM (β=-0.25 for both,p<0.05) and relative quadriceps strength (β=-0.12 and -0.27, respectively,p<0.05)

Conclusion

This study demonstrates novel associations between sex hormone levels and skeletal muscle in females across a wide continuum of ages. We also demonstrate that longitudinal fluctuations in circulating sex hormones must be considered to gain a comprehensive understanding of female muscle ageing.
An ancient lysozyme in placozoans
Authors: Berndt Henry , Duarte Igor , Repnik Urska , Struwe Michel , Abukhalaf Mohammad , Scheidig Axel , Tholey Andreas , Gruber-Vodicka Harald , Leippe Matthias
Published: October 2024

Lysozymes are an essential part of nutrition and antibacterial immunity in metazoans, executing the breakdown of bacterial cell walls via the hydrolysis of peptidoglycan. Although various lysozymes have been reported for several bilaterian phyla, the origin of metazoan lysozymes remains elusive as they seem to be lacking in non-bilaterian animals. In this study, we investigated a putative goose-type lysozyme (PLys, glycoside hydrolase family 23, GH23) of the placozoanTrichoplaxsp. H2 which we localized to gland cells of the ventral epithelium. N-terminal of the conserved GH23 lysozyme domain, PLys contains a non-conserved cysteine-rich domain. We could show a truncation of this N-terminal domain in the maturation process of PLys and a drastic increase in enzymatic activity at the cost of stability using recombinantly expressed physiological proteoforms of PLys. Phylogenetic analysis of GH23 lysozymes from all domains of life revealed a monophyletic radiation in animals. Based on structural comparisons and their distribution in the animal tree of life, metazoan g-type GH23 lysozymes appear to have originated from a horizontal gene transfer event from bacteria to an early pre-bilaterian ancestor. GH23 lysozymes have then been retained and expanded in many phyla, including Porifera, Cnidaria, Placozoa and chordates, acting as key component in the antibacterial arsenal since early metazoan evolution.
Reactive nitrogen species (RNS) and its reaction intermediates with reactive oxygen species (ROS) in pH-neutral high-strength plasma-activated water determines the antimicrobial activity against ESKAPE Pathogens
Authors: Mukherjee Debapriya , Roy Chowdhury Atish , Ghosh Pallab , Vishwa Nishanth , Rao Lakshminarayana , Chakravortty Dipshikha
Published: October 2024

Plasma activated water (PAW) has gained significant global recognition due to its diverse applications in the biomedical and food preservation industries. The interaction between plasma’s ionized particles, comprising ions, electrons, and neutral atoms, and water molecules results in high concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS), making PAW effective across various medical and agricultural fields. Previous research has demonstrated that effectiveness of PAW largely depends on its acidic pH, which generates several nucleophilic oxidants or secondary reactive nitrogen intermediates, such as peroxynitrite, derived from primary ROS and RNS. In one of our earlier studies, we were successful in generation of PAW at a neutral pH, which is more practical for real world applications. In this research, we explored the potential of the neutral pH high strength buffered PAW (hsPAbW) as an antimicrobial agent against ESKAPE pathogens and investigated its mechanism of action. Our findings revealed that hsPAbW effectively reduced bacterial viability during their exponential growth phase. We demonstrated that the ROS in hsPAbW are insufficient to independently kill the bacteria. Instead, the RNS components of hs-PAbW can exert microbicidal effects either independently or through the formation of peroxynitrite intermediates, which lead to nitrotyrosine production. As a result, we eliminated the need for low pH to induce the antimicrobial effects of hsPAbW, making it more practical for real world applications. Finally, our study showed that hs-PAbW is more effective at killing bacteria than high doses (50 microgram/mL) of antibiotics like ceftazidime, ciprofloxacin, and meropenem. Overall, our research highlights the promising potential of neutral pH PAW as a sustainable solution for combating ESKAPE pathogens.
Identification of a newPlasmodium falciparumE2 ubiquitin conjugating enzyme
Authors: Smith Cameron , Hajisadeghian Mohsen , van der Heden van Noort Gerbrand J. , Pinto-Fernández Adán , Kessler Benedikt M , Artavanis-Tsakonas Katerina
Published: October 2024

The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum survival and represents a potential target for antimalarial therapies. We utilised a ubiquitin-activity based probe (Ub-Dha) to capture active components of the ubiquitin conjugating machinery during asexual blood-stage development. Several E2 ubiquitin-conjugating enzymes, the E1 activating enzyme, and the HECT E3 ligase PfHEUL were identified and validated through in vitro ubiquitination assays. We also demonstrate selective functional interactions between PfHEUL and a subset of both human andP. falciparumE2s. Additionally, the Ub-Dha probe captured an uncharacterized protein, PF3D7_0811400 (C0H4U0) with no known homology to ubiquitin-pathway enzymes in other organisms. Through structural and biochemical analysis, we validate it as a novel E2 enzyme, capable of binding ubiquitin in a cysteine-specific manner. These findings contribute to our understanding of theP. falciparumUPS, identifying promising novel drug targets and highlighting the evolutionary uniqueness of the Ub-proteasome system in this parasite.
Novel mechanism of inflammatory activation by Ebola virus matrix protein linked to the ebolavirus virulence
Authors: Yamaoka Satoko , M’Hamdi Zeineb , Wang Lin , Swenson Vaille A. , McNally Kristin L. , Lu Shao-Chia , Singh Reema , Saundh Stephanie L. , Zell Brady N. , Best Sonja M. , Barry Michael A. , Rasmussen Angela L. , Ebihara Hideki
Published: October 2024

Uncontrolled systemic inflammatory responses are a critical pathological feature of fatal Ebola virus (EBOV) infection. While some inflammatory responses may originate from mononuclear phagocytes (MNPs), non-immune cells vastly outnumber MNPs and may be an important source of inflammation. Here, we demonstrated that highly virulent EBOV induced a high and sustained pro-inflammatory response compared to less virulent ebolaviruses in non-MNPs through TLR4-independent NF-κB activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-κB in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a novel virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-κB signaling pathway, primarily via TNFR1 using a ligand-independent mechanism. These findings reveal mechanisms that may drive systemic inflammation and promote EBOV pathogenesis, suggesting potential therapeutic strategies to mitigate immune dysregulation in severe EBOV infections.
Loss of the Inv(16) OncogeneCBFB::MYH11Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow
Authors: Panda Sipra , Wang Yiqian , Becker Michelle , Dhir Arjun , Lam Calvin , Rivas Cecilia , Alemu Lemlem , Garrett Lisa , Swenson Samantha , Hyde R. Katherine
Published: October 2024

Inversion of chromosome 16 [inv(16)] is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML) and generates the fusion geneCBFB::MYH11 (CM), which initiates leukemogenesis. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption thatCMis required after leukemic transformation. However, this has yet to be shown experimentally. Using a knock-in mouse that allows for deletion ofCMafter leukemia development, we found that loss of the fusion gene increased apoptosis and decreased colony growthin vitro. Interestingly, 5-20% of the colonies had successfully deletedCM. To test the role ofCM in vivo, we used an inducible shRNA knockdown (KD) construct against the fusion gene. We found that decreasedCMexpression eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite these cells showing significant knockdown ofCMat the mRNA and protein levels. Furthermore, with prolonged KD ofCM, ∼40% of mice re-established disease while maintaining KD of the fusion gene. Our work indicates thatCMis required by leukemia cells in the spleen and blood, but that cells in the bone marrow can survive and re-establish disease independent of the fusion protein.
Tumor suppressor NME1/NM23-H1 modulates DNA binding of NF-κB RelA
Authors: Shahabi Shandy , Maurya Mano , Subramaniam Shankar , Ghosh Gourisankar
Published: October 2024

The dimeric NF-κB family of transcription factors activates transcription by binding sequence-specifically to DNA response elements known as κB sites, located within the promoters and enhancers of their target genes. While most NF-κB remain inactive in the cytoplasm of unstimulated cells, a small amount of RelA, one of its members, persists in the nucleus, ensuring low-level expression of genes essential for homeostasis. Several cofactors have been identified that aid in DNA binding of RelA. In this study, we identify NME1 (nucleoside diphosphate kinase 1) as a cofactor that enhances RelA’s ability to bind κB sites within the promoters of a subset of its target genes, promoting their expression under both unstimulated and stimulated conditions. Depletion of NME1 influences activation or repression of several genes that are unresponsive to TNFα, despite containing κB sites in their promoters but not in clusters. This suggests that clustering of kB sites may be necessary for RelA-dependent transcription complex assembly. NME1 appears to act as a cofactor for other transcription factors to regulate these genes. NME1 does not directly contact κB DNA but interacts with RelA, with this interaction being further strengthened in the presence of κB DNA. Notably, NME1 alone has a marginal effect in enhancing RelA’s DNA binding, suggesting that NME1 likely cooperate with other cofactors to regulate DNA binding and transcription through RelA. These observations underscore the intricate assembly of transcription complexes centered on NF-κB.
Alzheimer’s disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine activity in aged mice
Authors: Knox Kevin M. , Davidson Stephanie , Lehmann Leanne M. , Skinner Erica , Lo Alexandria , Jayadev Suman , Barker-Haliski Melissa
Published: October 2024

Structured Abstract

INTRODUCTION

Alzheimer’s disease (AD) patients are at greater risk of focal seizures than similarly aged adults; these seizures, left untreated, may worsen functional decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled mouse model of acquired chronic secondarily generalized focal seizures allows for precisely timed drug administration studies to quantify the efficacy and tolerability of ASMs in an AD-associated genetic model. We hypothesized that mechanistically distinct ASMs would exert differential anticonvulsant activity and tolerability in aged AD mice (8-15 months) to define whether rational ASM selection may benefit specific AD genotypes.

METHODS

Aged male and female PSEN2-N141I versus age-matched non-transgenic control (PSEN2 control) C57Bl/6J mice, and APPswe/PS1dE9versus transgene negative (APP control) littermates underwent corneal kindling to quantify latency to fully kindled criterion. Dose-related ASM efficacy was then compared in each AD model versus matched control over 1-2 months using ASMs commonly prescribed in older adults with epilepsy: valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin.

RESULTS

Sex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more stimulations to attain kindling criterion (X2=5.521; p<0.05). Male APP/PS1 mice did not differ in kindling rate versus APP control mice, but they did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive than APP controls to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive than PSEN2 controls to valproic acid and lamotrigine.

DISCUSSION

AD genotypes may differentially impact ASMs activity and tolerability in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD, thus reducing functional decline.
Effect of Neoadjuvant Chemotherapy on Breast Conservative Surgery of Breast Cancer
Authors: Ahmed Mohamed Mostafa M , Abosenna Kamal Abdelrahman , Mohamed Basma Ahmed , Nagla Noha Mohamed
Published: October 2024

Background

Breast conserving surgery (BCS) has been established as a safe and effective alternative way of total (modified radical) mastectomy for achieving loco regional control of female invasive breast cancer. There are still obstacles on generalizing neoadjuvant chemotherapy as a primary treatment of breast cancer even on early tumors, including large presenting tumors size relative to breast size especially on small breast sizes. Introducing preoperative (neoadjuvant) chemotherapy (NACT) has been argued to increase rates of neoadjuvant chemotherapy because of decreasing the overall tumor’s size.

Aim of this study

The aim of this work is to evaluate the efficacy of neoadjuvant chemotherapy on rates of breast conserving surgery on different molecular subgroups of breast cancer.

Patients and methods

Record of total of 44 patients with pathologically proven invasive breast cancer, who received neoadjuvant chemotherapy were included in this study. Eligibility of patients for breast conserving surgery before and after receiving neoadjuvant chemotherapy was measured in different molecular subtypes of breast cancer.

Results

Neoadjuvant chemotherapy increased eligibility for breast conserving surgery from 29% pre neoadjuvant chemotherapy to 77% post neoadjuvant chemotherapy. Highest rates of eligibility to neoadjuvant chemotherapy post neoadjuvant chemotherapy were achieved in HER-2 positive and Luminal A patients. Downstaging of the whole TNM disease stage decreased secondary to neoadjuvant chemotherapy in 89% of total study population. Luminal B patients showed the highest rates of downstaging. The average decrease in tumor size was 65.8% in response to neoadjuvant chemotherapy. HER-2 positive and triple negative patients showed the highest complete pathological response rates at 60.0% and 54.5% (p = 0.008).

Conclusion

Neoadjuvant chemotherapy increased the rate of breast conserving surgery with variation in response depending on the molecular subtype of the tumor. Her2+ tumors were the most sensitive subtypes to neoadjuvant chemotherapy with the highest breast conserving surgery eligibility following neoadjuvant chemotherapy.
Functional respiratory abnormalities in adults who vape daily
Authors: Lechasseur Ariane , Fortin Marc , Godbout Krystelle , Boulay Marie-Ève , Bergeron Keven , Routhier Joanie , Parent-Racine Geneviève , Roy Annie , Boutin Geneviève , Maltais François , Côté Andréanne , Morissette Mathieu C.
Published: October 2024

Despite the widespread use of vaping, a very limited number of clinical studies have investigated the effects of this habit on the lungs of healthy individuals. Our group recently initiated theVapingAdverseLung and HeartEvents Cohort(VapALERT), a prospective study aiming to identify the impacts of vaping on respiratory and cardiovascular health. We elected to report early findings from the pulmonary function tests performed at the initial visit of the first 83 participants recruited so far. Almost 80% of volunteers with no diagnosis of lung disease and who vape daily have an abnormal airway reactivity to metacholine and/or lung clearance index and/or diffusion capacity. We can conclude from this study that adult individuals who vape daily are very likely to present asymptomatic functional respiratory abnormalities, especially airway hyperresponsiveness, ventilation heterogeneity and reduced gas diffusion regardless of past or current tobacco and/or cannabis smoking. Longitudinal studies are crucial to determine how respiratory abnormalities observed in individuals who vape will progress over time.
The Hunchback temporal transcription factor determines interneuron molecular identity, morphology, and presynapse targeting in theDrosophilaNB5-2 lineage
Authors: Pollington Heather Q. , Doe Chris Q.
Published: October 2024

Interneuron diversity within the central nervous system (CNS) is essential for proper circuit assembly. Functional interneurons must integrate multiple features, including combinatorial transcription factor (TF) expression, axon/dendrite morphology, and connectivity to properly specify interneuronal identity. Yet, how these different interneuron properties are coordinately regulated remains unclear. Here we used theDrosophilaneural progenitor, NB5-2, known to generate late-born interneurons in a proprioceptive circuit, to determine if the early-born temporal transcription factor (TTF), Hunchback (Hb), specifies early-born interneuron identity, includingmolecular profile,axon/dendrite morphology, andpresynapse targeting. We found that prolonged Hb expression in NB5-2 increases the number of neurons expressing early-born TFs (Nervy, Nkx6, and Dbx) at the expense of late-born TFs (Runt and Zfh2); thus, Hb is sufficient to promote interneuron molecular identity. Hb is also sufficient to transform late-born neuronal morphology to early-born neuronal morphology. Furthermore, prolonged Hb promotes the relocation of late-born neuronal presynapses to early-born neuronal presynapse neuropil locations, consistent with a change in interneuron connectivity. Finally, we found that prolonged Hb expression led to defects in proprioceptive behavior, consistent with a failure to properly specify late-born interneurons in the proprioceptive circuit. We conclude that the Hb TTF is sufficient to specify multiple aspects of early-born interneuron identity, as well as disrupt late-born proprioceptive neuron function.
Presynaptic filopodia form kinapses and modulate membrane mechanics for synchronous neurotransmission and seizure generation
Authors: Jain Akanksha , Kroll Jana , Webster Jack F. , Moss Jon , Ultanir Sila K. , Gonzalez-Sulser Alfredo , Rosenmund Christian , Cousin Michael A. , Ivanova Daniela
Published: October 2024

The structural stability of synapses directly contrasts with their functional plasticity. This conceptual dichotomy is explained by the assumption that all synaptic plasticity is generated via either electrical and/or biochemical signaling. Here, we challenge this dogma by revealing an activity-dependent presynaptic response that is physical in nature. We show that dynamic filopodia emerge during action potential discharge and transiently deform synaptic boutons to enhance connectivity. Filopodia generation requires neuronal activity, calcium and actin, and occurs in intact brain circuits and human brain. Mechanistically, their extension preserves synchronous neurotransmitter release by increasing presynaptic membrane tension. However, filopodia generation becomes maladaptive during dysregulated brain activity, exacerbating seizuresin vivo. Therefore, we provide direct evidence that presynaptic mechanical forces determine the extent and timing of synaptic signals.
Magnetic dipole contribution to the
γ
spectrum from
d−t
collisions
Authors: Timofeyuk N. K.
Published: October 2024

One in about a few 105 sub-Coulomb d−t collisions is accompanied by the emission of a γ photon. The γ spectrum from these collisions is dominated by a 16.7 MeV peak, corresponding to the population of the p-wave 3/2− α−n ground-state resonance in the E1 transition from an intermediate d-wave α−n state, corresponding to the He5 excited state around 16.7 MeV. The strength of this spectrum at the large γ-energy endpoint decreases fast both due to kinematic factors and due to centrifugal repulsion between neutron and α particle at near-zero relative energies. However, no centrifugal repulsion would occur if s-wave α−n states were populated in a magnetic dipole transition. Therefore, one can expect that close to the

γ

-spectrum endpoint around 17.5 MeV the M1 transition could dominate, leading to additional counts in experimental spectra which could be easily misinterpreted as a background. This work presents calculations of the M1 contribution to the d+t→α+n+γ cross section caused both by convection and magnetization currents. While the first contribution was found to be negligible, the one from magnetization depends strongly on the choice of the model for the d−t channel scattering wave function. Using d−t interaction models from the literature, represented either by a gaussian of by a square well, resulted in unrealistically strong M1 contribution. Withoptical folding potential constructed in the present work, correctly representing the sizes of deuteron and triton, the M1 contribution near the endpoint is reduced to about 2% of the 16.7-MeV E1 peak. Arguments in favor of more detailed calculations, that could potentially change this number, are put forward.

Published by the American Physical Society
2024
CGC and saturation approach: Impact-parameter dependent model of perturbative QCD and combined HERA data
Authors: Roa Michael , Garrido José , Guevara Miguel
Published: October 2024

In this paper we confront the color glass condensate and saturation approach of Contreras [Non-linear equation in the re-summed next-to-leading order of perturbative QCD: The leading twist approximation, ] with the experimental combined HERA data and obtain its parameters. The model includes two features that are in accordance with our theoretical knowledge of deep inelastic scattering. These consist of: (i) the use of analytical solution for the nonlinear Balitsky-Kovchegov evolution equation and () the exponential behavior of the saturation momentum on the impact parameter b-dependence, characterized by Qs∝exp(−mb) which reproduces the correct behavior of the scattering amplitude at large b in accord with Froissart theorem. The model results are then compared to data at small-x for the structure function of the proton F2, the longitudinal structure function FL, the charm structure function F2cc¯, the exclusive vector meson (J/ψ,ϕ,ρ) production and deeply virtual Compton scattering. We obtain a good agreement for the processes in a wide kinematic range of Q2 at small-x. Our results provide a strong guide for finding an approach, based on color glass condensate and saturation effective theory for high-energy QCD, to make reliable predictions from first principles and for forthcoming experiments like the Electron Ion Collider and the LHeC.

Published by the American Physical Society
2024
Lepton flavor violation in exclusive
b→dℓiℓj
and
b→sℓiℓj
decay modes
Authors: Bečirević D. , Jaffredo F. , Pinheiro J. P. , Sumensari O.
Published: October 2024

We discuss the exclusive lepton flavor violating (LFV) decays modes based on b→dℓiℓj and b→sℓiℓj by considering the ground state mesons and baryons. After spelling out the expressions for such decay rates in a low energy effective theory which includes generic contributions arising from physics beyond the Standard Model, we show that the experimental bounds on meson decays can be used to bound the corresponding modes involving baryons. We find, for example, B(Λb→Λμτ)≲4×10−5. We also consider two specific models and constrain the relevant LFV couplings by using the low energy observables. In the first model, we assume the Higgs mediated LFV and find the resulting decay rates to be too small to be experimentally detectable. We also emphasize that the regions favored by the bounds B(h→μτ)Atlas and B(h→eτ)Atlas are not compatible with B(μ→eγ)MEG to 1σ. In the second model, we assume LFV mediated by a heavy Z′ boson and find that the corresponding b-hadron branching fractions can be O(10−6), thus possibly within experimental reach at LHCb and Belle II.

Published by the American Physical Society
2024
Concept study of a storage ring-based gravitational wave observatory: Gravitational wave strain and synchrotron radiation noise
Authors: Schmirander Thorben , Miltchev Velizar , Rao Suvrat , Brüggen Marcus , Grüner Florian , Hillert Wolfgang , Liske Jochen
Published: October 2024

This work for the first time addresses the feasibility of measuring millihertz gravitational waves (mHz GWs) with a storage ring-based detector. While this overall challenge consists of several partial problems, here we focus solely on quantifying design limitations imposed by the kinetic energy and radiated power of circulating ions at relativistic velocities. We propose an experiment based on the measurement of the time-of-flight signal of an ion chain. One of the dominant noise sources inherent to the measurement principle for such a GW detector is the shot noise of the emitted synchrotron radiation. We compute the noise amplitude of arrival time signals obtained by analytical estimates and simulations of ions with different masses and velocities circulating in a storage ring with the circumference of the Large Hadron Collider. Thereby, we show that our experiment design could reduce the noise amplitude due to the synchrotron radiation in the frequency range 10−4–10−2  Hz to one or two orders of magnitude below the expected GW signals from of astrophysical sources, such as supermassive binary black holes or extreme mass-ratio inspirals. Other key requirements for building a working storage ring-based GW detector include the generation and acceleration of heavy ion chains with the required energy resolution, their injection and continued storage, as well as the detection method to be used for the determination of the particle arrival time. However, these are not the focus of the work presented here, in which we instead concentrate on the definition of a working principle in terms of ion type, kinetic energy, and ring design, which will later serve as a starting point when addressing a more complete experimental setup.

Published by the American Physical Society
2024
Isospinning
CP2
solitons
Authors: Amari Yuki , Antsipovich Sergei , Nitta Muneto , Shnir Yakov
Published: October 2024

We study stationary rotating topological solitons in a (2+1)-dimensional CP2 nonlinear sigma model with a stabilizing potential term. We find families of U(1)×U(1) symmetric solutions with topological degrees equal or larger than 1, which have two angular frequencies and are labeled by two (one topological and the other nontopological) winding numbers k1≥k2. We discuss properties of these solitons and investigate the domains of their existence.

Published by the American Physical Society
2024
Electrotaxis of Self-Propelling Artificial Swimmers in Microchannels
Authors: Buness Carola M. , Rana Avi , Maass Corinna C. , Dey Ranabir
Published: October 2024

Biological microswimmers alter their swimming trajectories to follow the direction of an applied electric field, exhibiting electrotaxis. We show that synthetic active droplet microswimmers also autonomously change swimming trajectories in microchannels, even undergoing “U-turns,” in response to an electric field, mimicking electrotaxis. We exploit such electrotaxis, in the presence of an external flow, to robustly tune the swimming trajectory of active droplets between wall-adjacent, oscillatory, and channel centerline swimming. A general hydrodynamic model demonstrates that the electrotactic dynamics is governed by the electrical effects due to the swimmer’s inherent surface charge, besides its motility, hydrodynamic wall interactions, and relative orientations of the electric field and imposed flow. Our study demonstrates a simple method for controlling active agents in complex geometries for microrobotic applications, like autonomous cargo delivery.

Published by the American Physical Society
2024