bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV Pre-exposure Prophylaxis Prescription Initiation and Maintenance Among Homeless-Experienced People Who Use Drugs
Authors: Eger William H. , Shaw Leah C. , Biello Katie B. , Lopez Claudia , Brody Jennifer K. , Bazzi Angela R.
Published: November 2024

Background:

HIV pre-exposure prophylaxis (PrEP) remains particularly underused among homeless-experienced people who use drugs (PWUD).

Setting:

Boston Health Care for the Homeless Program, a Federally Qualified Health Center serving homeless-experienced individuals in Boston, Massachusetts.

Methods:

To identify determinants of PrEP prescription initiation and continuation, we analyzed electronic medical records and pharmacy data between April 2018 and March 2022. Participants were HIV-negative and reported sexual, drug, or community-related HIV exposures. Adjusted multinomial logistic regression explored associations between sociodemographics, social vulnerabilities, behavioral factors (eg, injection drug use), and mental health and substance use disorder diagnoses with filling of 1 and more than 1 PrEP prescription.

Results:

Among 509 participants, mean age was 38 years, 28% were women, 19% were Black, and 24% were Hispanic/Latino. At program enrollment, most were experiencing homelessness (92%), injecting drugs (78%), and living with a mental health disorder (71%). In multivariable-adjusted models, injection drug use was positively associated with filling 1 and more than 1 PrEP prescription (adjusted odds ratio [AOR]: 2.88, 95% confidence interval [CI]: 1.33 to 6.26; and AOR: 3.60, 95% CI: 2.02 to 6.42, respectively). Participants with opioid use disorder and generalized anxiety disorder were more likely to fill 1 and more than 1 prescription, whereas those with bipolar disorder were less likely to fill 1 prescription. No sociodemographic characteristics, sexual behaviors, or other mental health or substance use disorders were associated with study outcomes.

Conclusions:

A low-threshold, harm reduction-oriented PrEP program supported prescription initiation and continuation for homeless-experienced PWUD. Implementation research is needed to facilitate scale-up of this approach.
Pharmacokinetics and Safety of Bictegravir in Pregnant and Postpartum Persons With HIV and Their Infants
Authors: Powis Kathleen M. , Pinilla Mauricio , McMorrow Flynn , Stek Alice , Brooks Kristina M. , Shapiro David E. , Knowles Kevin , Eke Ahizechukwu C. , Greene Elizabeth , Agwu Allison , Topete Lourdes , Browning Renee , Chakhtoura Nahida , Arora Priyanka , Huang Xiaoying , Best Brookie M. , Mirochnick Mark , Momper Jeremiah D. ,   the IMPAACT 2026 Protocol Team
Published: November 2024

Background:

Limited data exist on bictegravir pharmacokinetics in pregnancy among persons with HIV (PWH) and infant washout.

Setting:

Nonrandomized, open-label, multicenter phase-IV prospective study of bictegravir pharmacokinetics and safety in pregnant PWH and their infants.

Methods:

Steady-state 24-hour pharmacokinetic sampling of oral bictegravir 50 mg once daily (a component of fixed-dose combination bictegravir/emtricitabine/tenofovir alafenamide) during the second and third trimesters and postpartum was performed. Cord blood and infant washout samples were collected. Total and free bictegravir concentrations were measured by validated liquid chromatography with tandem mass spectrometry methods. Within-participant geometric mean ratios (GMR) with 90% confidence intervals (CI) were calculated to compare pharmacokinetics between second and third trimester versus postpartum. Infant HIV testing results were obtained.

Results:

Twenty-seven maternal–infant pairs were enrolled. Bictegravir area under the concentration–time curve from time 0 through 24 hours post-dose was 46% lower in the second trimester (n = 12; P = 0.002; GMR 0.54; 90% CI: 0.43 to 0.69) and 52% lower in the third trimester (n = 24; P < 0.0001; GMR 0.48; 90% CI: 0.43 to 0.55), compared with postpartum. C24 concentrations were above the estimated bictegravir protein-adjusted 95% effective concentration of 0.162 μg/mL. The median ratio of cord-to-maternal blood concentration was 1.38 (n = 17; quartiles: 1.17–1.63). Median T1/2 for infant bictegravir washout was 33.2 hours (quartiles: 25.7–45.9) with a Cmax of 2.06 μg/mL (quartiles: 1.37–2.72). Overall, 88%–92% of participants maintained suppression <40 copies/mL throughout pregnancy and postpartum. All available infant HIV testing results were negative. The safety profile for pregnant PWH and infants was acceptable.

Conclusions:

Bictegravir exposure was lower during pregnancy compared with postpartum, yet C24 concentrations were greater than the bictegravir protein-adjusted 95% effective concentration.
Disseminated Extranodal Natural Killer/T-Cell Lymphoma Mimicking a Paraneoplastic Polymyositis
Authors: Mumtaz Mudassir , Rayamajhi Sampanna
Published: November 2024

Extranodal natural killer/T-cell lymphoma (ENKTCL) is an aggressive EBV-associated non-Hodgkin lymphoma, most commonly arising from within the mucosa of the upper aerodigestive tract, typically with nasal presentation. Here, we present an interesting case of a 36-year-old man with ENKTCL with an atypical pattern of disease progression despite 3 cycles of SMILE chemotherapy. Restaging 18F-FDG PET/CT demonstrated widespread uptake within the skeletal musculature in a distribution concerning for a paraneoplastic polymyositis. However, muscle biopsy confirmed ENKTCL dissemination.
Clinical Efficacy of Endoscopic Retrograde Cholangiopancreatography Combined With Traditional Chinese Medicine Comprehensive Nursing in the Treatment of Biliary Tract Complications After Liver Transplantation
Authors: Li Yingjia
Published: November 2024

Objective:

This study explored the clinical efficacy of endoscopic retrograde cholangiopancreatography (ERCP) combined with traditional Chinese medicine (TCM) comprehensive nursing in treating biliary tract complications (BTCs) after liver transplantation (LT).

Materials and Methods:

A total of 124 patients with BTCs after LT were screened and randomly divided into a control group and an experimental group. Both groups of patients underwent ERCP treatment and patients in the control group received conventional nursing, and those in the experimental group received TCM comprehensive nursing on top of the control group. The clinical efficacy after 1 month of intervention was recorded. Before intervention and 1 month after intervention, fasting venous blood was collected to detect the levels of hepatic function indicators alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The negative emotions of the patients were evaluated by using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS), and the quality-of-life scores were determined by using the Quality-of-Life Scale. Postintervention complications, such as pancreatitis, hyperamylasemia, and reflux cholangitis, were recorded.

Results:

The total effective rate in the experimental group (90.32%) was higher than that in the control group (72.58%). ALT, AST, SAS, and SDS scores of the 2 groups after treatment were lower than before treatment, and the scores of quality of life were higher. Greater improvements were observed in the experimental group. The complication rate of the experimental group (3.23%) was lower than that of the control group (22.58%) (P<0.05).

Conclusion:

ERCP combined with TCM comprehensive nursing for patients with BTCs after LT can effectively reduce anxiety and depression, improve the quality of life, and reduce the incidence of complications.
Predicting morbidity and mortality after surgery for isolated traumatic spinal injury without spinal cord injury
Authors: Mohammad Ismail Ahmad , Forssten Maximilian Peter , Cao Yang , Ioannidis Ioannis , Forssten Sebastian Peter , Sarani Babak , Mohseni Shahin
Published: November 2024

BACKGROUND

Traumatic spinal injuries are associated with a high risk of morbidity and mortality. The aim of this study is to investigate which variables best predict adverse outcomes in patients who had surgery for isolated traumatic spinal injury without spinal cord injury.

METHODS

The American College of Surgeons Trauma Quality Improvement Program database was used to identify adult (18 years or older) surgically managed patients with an isolated traumatic spinal injury, without spinal cord injury admitted between 2013 and 2021. An isolated injury was defined as a spine Abbreviated Injury Scale score ≥2 and an Abbreviated Injury Scale score ≤1 in the remaining body regions, as well as corresponding International Classification of Diseases, Ninth and Tenth Revision, codes. The predictive value of demographic, clinical, and comorbidity data was evaluated using logistic regression models and ranked using the permutation importance method.

RESULTS

A total of 39,457 patients were included in the study, of whom 554 died during hospitalization. The most important variables for predicting in-hospital mortality were age, sex, Glasgow Coma Scale on admission, Orthopedic Frailty Score, and cervical spine injury. The most important variables for predicting complications were age, cervical spine injury, the need for cervical spine surgery, Revised Cardiac Risk Index, and alcohol use disorder. Finally, age, cervical spine injury, sex, Glasgow Coma Scale on admission, and Orthopedic Frailty Score had the highest relative importance when predicting failure to rescue. Models based on the five most important variables for each outcome demonstrated an excellent predictive ability for in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.84; 95% confidence interval [CI], 0.82–0.86) and failure to rescue (AUROC [95% CI], 0.86 [0.84–0.87]) as well as an acceptable predictive ability for complications (AUROC [95% CI], 0.72 [0.71–0.73]).

CONCLUSION

The most important factors identified to predict mortality, complications, and failure to rescue in traumatic spinal injury patients without spinal cord injury who undergo surgery were patients' age, sex, frailty, cervical spine injury that necessitated surgical intervention, and cardiovascular risk.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Cardiorespiratory Fitness From Cardiopulmonary Exercise Testing Is a Comprehensive Risk-stratifying Tool in Liver Transplant Candidates
Authors: Hughes Dempsey L. , Lizaola-Mayo Blanca , Wheatley-Guy Courtney M. , Vargas Hugo E. , Bloomer Pamela M. , Wolf Cody , Carey Elizabeth J. , Forman Daniel E. , Duarte-Rojo Andres
Published: November 2024

Background.

Cardiovascular disease and physical decline are prevalent and associated with morbidity/mortality in liver transplant (LT) patients. Cardiopulmonary exercise testing (CPX) provides comprehensive cardiopulmonary and exercise response assessments. We investigated cardiorespiratory fitness (CRF) and cardiac stress generated during CPX in LT candidates.

Methods.

LT candidates at 2 centers underwent CPX. Standard-of-care cardiac stress testing (dobutamine stress echocardiography, DSE) results were recorded. Physical function was assessed with liver frailty index and 6-min walk test. CPX/DSE double products were calculated to quantify cardiac stress. To better study the association of CPX-derived metrics with physical function, the cohort was divided into 2 groups based on 6-min walk test median (372 m).

Results.

Fifty-four participants (62 ± 8 y; 65% men, Model for End-Stage Liver Disease-Na 14 [10–18]) underwent CPX. Peak oxygen consumption was 14.1 mL/kg/min for an anerobic threshold of 10.2 mL/kg/min, with further CRF decline in the lower 6MWT cohort despite lack of liver frailty index-frailty in 90%. DSE was nondiagnostic in 18% versus 4% of CPX (P = 0.058). All CPX were negative for ischemia. A double product of ≥25 000 was observed in 32% of CPX and 11% of DSE (P = 0.020). Respiratory function testing was normal. No patient presented major cardiovascular events at 30 d post-LT.

Conclusions.

CPX provided efficient and effective combined cardiopulmonary risk and frailty assessments of LT candidates in a 1-stop test. The CRF was found to be very low despite preserved physical function or lack of frailty.
PCTP: Toxicity, persistence, and safety considerations for potential
contamination
Authors: Park Jeongmin , Kim Jiin , Lee Joon-Goo
Published: November 2024

Pentachlorothiophenol (PCTP) is recognized for its toxicological concerns and
environmental persistence. As a persistent, bioaccumulative, and toxic
substance, PCTP has garnered attention due to its potential adverse impacts on
ecosystems and human health. Despite its significance, research on PCTP remains
relatively sparse, with limited recent literature available on its toxicity,
methods for quantification, and occurrence in environmental matrices. Analytical
methods for detecting PCTP have largely evolved from techniques used for similar
compounds such as hexachlorobenzene, focusing on metabolite analysis in
biological and environmental samples. Recent studies underscore the necessity
for robust analytical techniques to precisely monitor PCTP levels in aquatic
systems and human exposure scenarios. This review consolidates current knowledge
on PCTP, emphasizing its toxicological profile, analytical methodologies, and
occurrence in environmental samples. By synthesizing findings from recent
studies, this paper offers insights into the current understanding of PCTP while
identifying areas that warrant further investigation.
Impact of lactic acid fermentation using Lactiplantibacillus
plantarum on the physicochemical, phytochemical, and biological
properties of Antidesma bunius (L.) Spreng. fruit
juice
Authors: Nituda Jerald P. , Lizardo-Agustin Rona Camille M.
Published: November 2024

Lactic acid fermentation is a transformative method, converting polyphenols in
plant-based juices into bioactive derivatives. Antidesma bunius
(L.) Spreng. fruit, with its high polyphenolic content, presents an opportunity
for innovative functional food products. In this study, changes in
physicochemical properties, polyphenolic contents, and in vitro
biological activities of lactic acid-fermented A. bunius fruit
juice were investigated. Fermentation by Lactiplantibacillus
plantarum resulted in significant changes in the physicochemical,
phytochemical, and biological properties of A. bunius juice.
The initial decline and subsequent increase in LAB count aligned with changes in
total soluble solids, pH, and total titratable acidity, indicating lactic acid
production. Total polyphenols were retained after 48 h, while the total
flavonoids increased after 72 h fermentation. The antioxidant activities in
terms of H2O2 scavenging and Fe3+
reducing power increased at 24 h and 48 h, respectively. Alpha-amylase
inhibition peaked at 48 h fermentation, while α-glucosidase inhibition
declined but remained significant. HPLC analysis showed that gallic acid and
catechin were the specific bioactive compounds that significantly increased
after fermentation. Chemometric analysis showed that gallic acid and catechins
had the most positive effect in the improvement of biological activities
specifically α-amylase and α-glucosidase inhibition, and
H2O2 scavenging activities. The study revealed that
lactic acid fermentation of A. bunius fruit juice enhanced its
physicochemical properties, polyphenolic content, and specific biological
activities.
Comparative study on the nutritional and sensory properties, and
drying kinetics of two Nigerian rice cultivars
Authors: Ogunwale Esther Ayomide , Chikieze Peter Madabuchi , Taiwo Kehinde Adekunbi , Morakinyo Tunde Afolabi , Akanbi Charles Taiwo , Gbadamosi Saka Olasunkanmi , Olawoye Babatunde , Awoleye Micheal Olusegun , Alabi Dorcas Lola , Alagbo Oyebanji Olubunmi , Koya Olufemi Adebola
Published: November 2024

The demand for locally process rice grain has led to the development of improved
processing conditions for maximum nutritional and quality products. This study,
therefore, investigates the effect of parboiling temperature and time on the
nutritional, sensory, and drying kinetics of two Nigerian rice cultivars. Agric
and Ofada rice cultivars were subjected to three different parboiling
temperatures (120, 135, and 150°C) and time (15, 20, and 25 min). The
parboiled rice was analyzed for proximate composition, mineral content, sensory
properties, and drying kinetics. Parboiling the rice cultivars at the three
different temperatures significantly reduces the moisture content, ash, and
crude fat of the rice grain. The total carbohydrate of the rice cultivars
increased with an increase in parboiling temperature. All the mineral elements
analyzed in this study were increased significantly with an increase in the
parboiling temperature. Of all the rice samples, only paddy rice parboiled at
150°C for 25 min was the least accepted by the panelists. The drying
kinetics revealed the Page model best predicts the drying of the two Nigerian
rice cultivars. This study concluded the parboiling process significantly
improved the nutritional, minerals, and sensory properties of the two Nigerian
rice cultivars.
Enzymatic hydrolysis for biotin extraction from animal-derived
foods
Authors: Kim Naeun , Yu Jihyeon , Kim Yoonjeong , Park Eunji , Choi Youngmin , Kim Younghwa
Published: November 2024

Biotin exists as free or covalently bound to protein through a lysine residue.
Therefore, the extraction of free biotin form is difficult in foodstuffs. Thus,
the aim of this study was to investigate the extraction method of biotin in
animal-derived foods by enzymatic hydrolysis (pepsin) using autoclave extraction
or sonication extraction. Biotin contents of animal origin foods such as meat
(beef, foreshank), fish and shells (mackerel), and egg (yolk, raw) were
significantly higher in the autoclave extraction method with pepsin treatment.
Therefore, these methods were selected for further applications in this study.
As a result, pepsin-assisted extraction methods showed significantly higher
contents of biotin compared with non-enzyme-treated samples in most of meat,
fish, shellfish, and egg. The performed extraction methods in this study were
validated according to AOAC guideline. An excellent linearity of biotin standard
was observed over R2=0.999. All analytical methods for biotin
showed the acceptable accuracy (97-101% recovery) and the precision
(1-4% RSD for the repeatability, 0-4% RSD for the
reproducibility). The limits of detection and quantification for biotin analysis
were 0.009 and 0.024 μg/100 g, respectively. These results may be useful
for providing reliable data about the biotin contents in commonly consumed foods
in Korea.
Hypertension Management Dynamics in Pediatric CKD: Insights from the 4C Study
Authors: Doyon Anke , Bayazit Aysun Karabay , Duzova Ali , Thurn Daniela , Canpolat Nur , Kaplan Bulut Ipek , Azukaitis Karolis , Obrycki Lukasz , Ranchin Bruno , Shroff Rukshana , Candan Cengiz , Erdogan Hakan , Paripovic Dusan , Donmez Osman , Lugani Francesca , Arbeiter Klaus , Yilmaz Ebru , Zaloszyc Ariane , Wühl Elke , Melk Anette , Querfeld Uwe , Schaefer Franz ,   4C Study Consortium
Published: November 2024

Rationale

To investigate blood pressure (BP) trajectories, and the impact of pharmacological intervention in children with chronic kidney disease (CKD).

Methods

Analysis of antihypertensive treatment (AHT) and BP slopes in 320 patients of the 4C Study cohort with CKD prior to renal replacement therapy, based on a minimum of three individual observations and two years of follow-up.

Results

At enrollment, 70 patients (22%) had uncontrolled or untreated hypertension, 130 patients (41%) had controlled hypertension, and 120 patients (37%) had normotension without antihypertensive treatment. AHT medication was prescribed in 53% of patients at baseline and initiated or added in 91 patients (AHT-I, 28%) during follow-up.

Overall BP standard deviation score (SDS) remained stable over time in the cohort (ß= -0.037±0.034, p=0.34 and -0.029± 0.348, p=0.093 per year for systolic and diastolic BP SDS). In the AHT-I group, systolic and diastolic BP SDS was higher at baseline and decreased significantly during follow-up (−0.22±0.07, p<.003 and -0.12±0.05 SDS per year, p=0.01). Only 8/70 (11%) patients of the previously untreated/uncontrolled group remained untreated at the last observation, while 31 (44%) were controlled during follow-up. Of the 120 normotensive patients at baseline, 60% remained normotensive while 40% progressed to uncontrolled/untreated (n=23, 19%) or controlled (n=24, 20%) hypertension.

Conclusions

The study provides comprehensive real-world evidence on long-term management of blood pressure in children with CKD from the 4C Study. Although blood pressure control improved significantly with the intensification of antihypertensive therapy, a notable proportion of previously normotensive patients developed de novo hypertension over the observation period.
A TORC1-PHR1 signaling axis regulates phosphorus starvation and immunity signaling network in Arabidopsis
Authors: Awasthi Prakhar , Muhammed Jamsheer K , Kumar Manoj , Mishra Shruti , Tiwari Archna , Jindal Sunita , Saksena Harshita B. , Singh Dhriti , Vadassery Jyothilakshmi , Rouached Hatem , Meyer Christian , Laxmi Ashverya
Published: November 2024

The Target of Rapamycin Complex 1 (TORC1) is a crucial eukaryotic kinase that modulates growth in response to nutrient availability. Phosphorus (P) is an essential macronutrient, and its deficiency induces extensive reprogramming of growth and defense strategies in plants. This process involves Phosphate Starvation Response 1 (PHR1), a master regulator of the Phosphate Starvation Response (PSR). In this study, we identify a novel, non-canonical role for TORC1 in regulating P starvation responses in Arabidopsis. We demonstrate that P limitation activates TORC1, leading to the stabilization of PHR1. Inhibition of TORC1 increased sensitivity to P starvation, accompanied by disruption of starvation-induced transcriptional reprogramming. Additionally, our results reveal that the TORC1-PHR1 signaling axis plays a crucial role in reprogramming the expression of genes involved in the plant immune signaling network. This regulation is critical for the symbiotic association with the endophytic fungusPiriformospora indicaunder P starvation. These findings underscore the significant role of the TORC1-PHR1 module in orchestrating the PSR and highlight the evolutionary adaptation of TORC1 signaling pathways in plants.
Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach
Authors: Rai Archana , Klonowski Jonathan , Yuan Bo , Coveler Karen J. , Dardas Zain , Egab Iman , Xu Jiaoyang , Lupo Philip J. , Agopian A. J. , Kostka Dennis , Lo Cecilia W. , Yi Stephen (Song) , Gelb Bruce D. , Seidman Christine E. , Boerwinkle Eric , Posey Jennifer E. , Gibbs Richard A. , Lupski James R. , Morris Shaine A. , Coban-Akdemir Zeynep
Published: November 2024

Laterality defects are defined by perturbations in the usual left-right asymmetry of organs. Due to low known genetic etiology of congenital heart disease (CHD) cases (less than 40%), we used a digenic model approach for the identification of contributing variants in known laterality defect genes (N = 115) in the exome/genome sequencing (ES/GS) data from individuals with clinically diagnosed laterality defects. The unsolved ES/GS data were analyzed from three CHD cohorts: Baylor College of Medicine-Genomics Research to Elucidate the Genetics of Rare Diseases (BCM-GREGoR; N = 247 proband ES), Gabriella Miller Kids First Pediatric Research program (Kids First; N = 158 trio GS), and Pediatric Cardiac Genomics Consortium (PCGC; N = 163 trio ES), and trans-heterozygous digenic variants were identified in 2.8% (inherited digenic variants in 0.4%), 8.2%, and 13.5% cases respectively, which was significantly higher as compared to 602 control trios provided by the 1000 Genomes Project(p =0.001, 1.4e-07, and 8.9e-13, respectively). Trans-heterozygous digenic variants were also identified in 0.4%, and 1.4% cases with non-laterality CHD in Kids First and PCGC datasets, respectively, which was not statistically significant as compared to control trios (p= 1, and 0.059, respectively). Altogether, in laterality cohorts, 23% of digenic pairs were in the same structural complex of motile cilia. Out of 39 unique digenic pairs in laterality CHD, 29 are more likely to be potential digenic hits as predicted by DiGePred tool. These findings provide further evidence that digenic epistatic interaction can contribute to the complex genetics of laterality defects.
Rotation-direction-dependent regulation of ATPase inhibitory factor 1 for mitochondrial ATP synthase from atomistic simulation
Authors: Kobayashi Ryohei , Okazaki Kei-ichi
Published: November 2024

ATPase inhibitory factor 1 (IF1) is an endogenous regulatory protein for mitochondrial FoF1-ATP synthase. It blocks the catalysis and rotation of the F1part by deeply inserting itself into the rotor-stator interface. Recent single-molecule manipulation experiments have elucidated that forcible rotations only in the ATP-synthesis direction eject IF1, rescuing F1from the IF1-inhibited state. However, the molecular mechanism of the rotation-direction-dependent process at an atomic resolution is still elusive. Here, we have performed all-atom molecular dynamics (MD) simulations of the IF1-bound F1structure with a torque applied to the rotor γ subunit. In the torque-applying simulations, we first found that the core part of the γ subunit rotated more in response to an external torque in the synthesis direction than in the hydrolysis direction. Further rotations of the γ subunit up to 120° revealed that the conformational change of the IF1-bound αβ was only allowed in the synthesis direction. Also, the 120° rotation in the synthesis direction disrupted its contacts with IF1, destabilizing the short helix of IF1. After additional rotation up to the synthetic 240° state, the closed-to-open conformational change of the IF1-bound β subunit pulled IF1outwardly, deforming the long helix of IF1. These stepwise destabilizations of the IF1helices should be crucial for IF1ejection. Our simulations also provided insight into the nullification mechanism of the hydrolytic rotation, highlighting the steric clash between F22 of IF1and the βTPsubunit. Finally, we discussed a sufficient proton motive force to rescue FoF1-ATP synthase from the IF1-inhibited state.
Targeting STING in experimental peritoneal damage: a novel approach in peritoneal dialysis therapy
Authors: Marchant Vanessa , García-Giménez Jorge , González-Mateo Guadalupe T. , Sandoval Pilar , Tejedor-Santamaria Lucía , Rayego-Mateos Sandra , Ramos Ricardo , Jiménez-Heffernan José , Ortiz Alberto , Raby Anne-Catherine , López-Cabrera Manuel , Ramos Adrián M. , Ruiz-Ortega Marta
Published: November 2024

Peritoneal dialysis (PD) is a widely used kidney replacement therapy for end-stage kidney disease (ESKD) patients. However, long-term exposure to PD fluids (PDF) can lead to peritoneal membrane (PM) damage, causing ultrafiltration failure and thus PD discontinuation. Investigating the molecular mechanisms underlying this damage is crucial for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. Therefore, in this work we study the role of STING in peritoneal inflammation and fibrosis. To this aim, we performed different preclinical mouse models of peritoneal inflammation, fibrosis, and adhesions. In a chlorhexidine gluconate (CHX)-induced inflammation model, we found changes in the peritoneal transcriptomic profile, and cytosolic DNA-sensing signaling was one of the most enriched KEGG pathways. STING, as a conspicuous member of this pathway, was upregulated in CHX-and PDF-exposed mice, and in peritoneal biopsies from PD patients. STING genetic deficiency diminished peritoneal inflammation, by downregulating inflammatory gene expression, preventing NF-κB pathway activation, and decreasing cell infiltration, in early (10 days) and advanced (30 days) stages of the CHX model. STING absence also decreased PM thickness and fibrosis in the advanced CHX model, reduced adhesion scores in a post-surgical intra-abdominal adhesion model, and decreased inflammation in anS. epidermidis-induced peritonitis model. Furthermore, pharmacological inhibition of STING with C-176 decreased inflammation and macrophage-mediated mesothelial-to-mesenchymal transition in cultured mesothelial cells, and reduced CHX-induced PM thickness and inflammation in mice. Altogether, these findings highlight STING as a key mediator of peritoneal damage and suggest it may be a novel therapeutic target for preventing PD-associated peritoneal deterioration.
Use of deep learning algorithms for segmentation of microelectrode arrays electrograms in the study of changes in myocardial bioelectrical activity
Authors: Kotikhina Elena , Karchkov Denis , Moskalenko Viktor , Rybkin Anton , Smirnov Ruslan , Osipov Grigory , Smirnov Lev
Published: November 2024

The using of modern electrophysiological methods during scientific research implies processing of huge data sets which becomes a significant problem. Progress in the development of equipment for registration of multiple local field potentials from the tissue surface contributes to the study of spatio-temporal characteristics of myocardial bioelectrical activity at a more detailed level. But it also raises the need for automation of data analysis, which can be accomplished by algorithms based on machine learning. New scientific approaches can contribute to the discovery of new facts about substances widely used but with under-researched efficacy. The paper presents the results of epicardial mapping by flexible microelectrode arrays of myocardium of isolated rat heart perfused with a solution containing L-carnitine, nutritional supplement that may be recommended for people suffering from cardiovascular disease. Electrograms from microelectrode arrays were analyzed using a neural network model based on U-Net architecture adapted for segmentation of one-dimensional signal. It was shown that the presence of L-carnitine in the perfusion solution caused a decrease in heart rate, myocardial excitation conduction velocity, coronary blood flow intensity of the isolated rat heart and suppressed physiological responses of the heart to adrenaline stimulation.
Negative resilience trends to more frequent extreme droughts in Mediterranean oak species
Authors: Borreguero I. J. , Sánchez-Miranda Á. , Martínez-Sancho E. , Rubio-Casal A. E. , Sánchez-Salguero R. , Matías L.
Published: November 2024

Recent changes in climate have triggered widespread mortality events in oak forests worldwide. Despite the ecological importance of these ecosystems, limited information exists on the long-term resilience of oak forests in response to extreme climate events.Quercus canariensis, a semi-deciduous oak sensitive to summer drought characteristic of the Mediterranean climate, is currently showing defoliation and mortality episodes in the drier areas of its natural range. Here, we investigated the long-term impacts of climate on the radial growth ofQ. canariensisand assessed changes in resilience to extreme droughts across eight populations in S Spain following an environmental gradient. We observed a clear latitudinal gradient in growth performance, as reflected by resilience indices across populations. Since 1970,Q. canariensishas shown a marked decline in resilience to extreme drought events at the wettest region, resulting in a diminished capacity to recover pre-drought growth levels. This trend has preceded growth declines in certain populations, suggesting increased vulnerability to the increasing frequency of extreme climatic events. Through growth analyses, we identified early-warning signals of forest decline in this Mediterranean oak species, highlighting the most sensitive populations and its high susceptibility to extreme droughts impacts.
Combining the CRISPR Activation and Interference Capabilities Using dCas9 and G-Quadruplex Structures
Authors: Kabir Mohammad Lutful , Kodikara Sineth G. , Hoque Mohammed Enamul , Shiekh Sajad , Alfehaid Janan , Basu Soumitra , Balci Hamza
Published: November 2024

We demonstrate that both CRISPR interference and CRISPR activation can be achieved at RNA and protein levels by targeting the vicinity of a putative G-quadruplex forming sequence (PQS) in thec-Mycpromoter with nuclease-dead Cas9 (dCas9). The achieved suppression and activation in Burkitt’s Lymphoma cell line and inin vitrostudies are at or beyond those reported with alternative approaches. When the template strand (contains the PQS) was targeted with CRISPR-dCas9, the G-quadruplex was destabilized andc-MycmRNA and protein levels increased by 2.1-fold and 1.6-fold, respectively, compared to controls in the absence of CRISPR-dCas9. Targeting individual sites in the non-template strand with CRISPR-dCas9 reduced both thec-MycmRNA and protein levels (by 1.8-fold and 2.5-fold, respectively), while targeting two sites simultaneously further suppressed both the mRNA (by 3.6-fold) and protein (by 9.8-fold) levels. These were consistent with cell viability assays when single or dual sites in the non-template strand were targeted (1.7-fold and 4.7-fold reduction in viability, respectively). We also report extensivein vitrobiophysical studies which are in quantitative agreement with these cellular studies and provide important mechanistic details about how the transcription is modulated via the interactions of RNA polymerase, CRISPR-dCas9, and the G-quadruplex.
Desmoplakin is a desmosomal mechanosensor
Authors: Dong Yinchen , Elgerbi Ahmed , Xie Bin , Choy John S. , Sivasankar Sanjeevi
Published: November 2024

Desmosomes are essential cell-cell adhesion organelles that enable tension-prone tissue, like the skin and heart, withstand mechanical stress. Desmosomal anomalies are associated with numerous epidermal disorders and cardiomyopathies. Despite their critical role in maintaining tissue resilience, an understanding of how desmosomes respond to mechanical stimuli is lacking. Here we demonstrate, in human breast cancer MCF7 cells, that actomyosin forces induce a conformational change in the N-terminal region of desmoplakin, a critical cytoplasmic desmosomal protein. Using super-resolution fluorescence microscopy, biochemical assays, and atomistic computer simulations, we show that actomyosin forces are directed to desmoplakin along keratin-19 filaments. These forces induce a conformational change in the N-terminal plakin domain of desmoplakin, converting this domain from a folded (closed) to an extended (open) conformation. Functional adhesion assays show that MCF7 cells with desmoplakin in an open conformation are more adhesive than cells with desmoplakin in a closed state. Our findings establish that desmoplakin is mechanosensitive and undergoes force-induced conformational changes which enhance the mechanical resilience of desmosomes.

Significance Statement

Desmosomes are essential cell-cell adhesion junctions that enable tension-prone tissue, like the skin and heart, withstand mechanical stress. Despite their critical role in maintaining tissue integrity, it is unclear how desmosomes respond to mechanical forces. Here we demonstrate that force induces a conformational change in desmoplakin, a critical intracellular desmosomal protein. This force-induced change in the desmoplakin’s structure enhances the resilience of desmosomes and enables them to withstand mechanical stress.
Deep Kernel Inversion: Rapid and Accurate Molecular Interaction Prediction for Drug Design
Authors: Myers Seth A. , Miller Chad , Lugo Kyler , Trinh Thi , Lee Chang-wook , Arunachalam Naveen , Chen Hannah , Drygin Denis , Martineau James
Published: November 2024

Computational drug design offers the opportunity to dramatically accelerate novel therapeutics for untreated diseases. Designing compounds with optimal efficacy and specificity, however, requires understanding and optimizing immense numbers of molecular interactions. While advances in predicting one-to-one molecular interactions continue, there has been limited progress in scaling one-to-many or many-to-many molecular interaction models. In this paper, we introduce a deep learning framework that embeds molecules into a high-dimensional vector space, which we have named Deep Kernel Inversion. In this framework, the dot product between vectors accurately predicts molecular interactions. This approach reduces the complexity of predicting an entire molecular interaction network fromO(n2) toO(n), enabling new molecular design tasks previously inaccessible to computational approaches. In the case of human protein-protein interactions (PPI), we demonstrate a100,000 folddecrease in the computation required to map the full human PPI network. We also demonstrate best-in-class performance across multiple molecular interaction tasks with this approach. This work offers a new way forward in scaling accurate molecular interaction predictions with applications in mapping biological pathways, target discovery, drug design, and therapeutic development.
Mapping object space dimensions: new insights from temporal dynamics
Authors: Kidder A. , Quek G. L. , Grootswagers T.
Published: November 2024

How is object information organized in high-level visual cortex? Recently, a comprehensive model of object space in macaques was proposed, defined by the orthogonal axes of animacy and aspect ratio (Bao et al., 2020). However, when using stimuli that dissociated category, animacy, and aspect ratio in humans, no tuning of aspect ratio was observed in fMRI data (Yargholi & Op de Beeck, 2023). This difference could be a result of different stimuli, the limited temporal resolution of fMRI, or information available about the presented stimuli. Here, we asked if and when information about aspect ratio, animacy, and category is available over time. We collected whole-brain electroencephalography (EEG) data while participants (N = 20) viewed the stimulus set used by Yargholi & Op de Beeck (2023). To mask object details and increase reliance on shape information, we also presented silhouette versions of the stimuli. Stimuli were presented in 5Hz streams using rapid serial visual presentation, with intact and silhouette stimuli sets were shown in separate streams. Using standard multivariate decoding pipelines and representational similarity analysis, we found that aspect ratio, category, and animacy were represented during visual object processing. The dominant dimension was modulated by stimulus type, demonstrating that the observable dimensions of object space depend on the nature of the stimuli presented. Taken together, these findings demonstrate that aspect ratio is represented during object processing, however earlier and more transiently than categorical dimensions, such as animacy. By focusing on underlying temporal dynamics, our results provide clear new insights into the contradicting findings reported in previous work and reveal a more nuanced understanding of how object space evolves over time.
Index Case Testing in Mozambique: a descriptive analysis of 7 years of implementation
Authors: Honwana Nely , Amane Guita , Lisboa Miguelhete , Templin Lindsay , Swor Meghan , Simbine Ana Paula , Samussone Ema , Couto Aleny
Published: November 2024

Introduction

In 2014, Mozambique introduced index case testing (ICT) to increase the identification of people living with HIV (PLHIV), including among hard-to-reach populations. The strategy elicits PLHIV’s sexual contacts and biological children for testing at the community and facility levels, improving testing efficiency in detecting HIV among people. We analyzed HIV program data to understand ICT contributions to case identification since 2017.

Methods

Routine aggregated program data from the President’s Emergency Plan for AIDS Relief (PEPFAR) Monitoring, Evaluation, and Reporting data were abstracted for 2017–2023. Test positivity was calculated as positive tests over the total number of tests conducted by modality. Data were analyzed by calendar year (January–December), sex, age group (<15, 15– 49, ≥50 years), and ICT setting (community-based, facility-based).

Results

During 2017–2023, overall test positivity for all modalities combined decreased from 5.7% (410,430/7,207,532) to 2.9% (297,012/10,190,365), and ICT increased by 92% (from 389,940 tests done in 2017 to 748,265 in 2023). The contribution of ICT to the total number of positive tests increased from 9.0% to 24.5% (37,076/410,430 to 72,622/297,012); among men tested, the contribution of ICT to positive tests increased from 10.2% to 29.9%; among children <15 years tested, from 20.3% to 35.3%; and among 15–49-year-olds tested, from 10.3% to 25.3%. Almost two-thirds (65.3%) of positive tests through ICT were community-based (276,356/ 423,166), with a testing positivity rate of 10.5% (276,356/2,632,862). The overall ICT test positivity rate was 12.0% (423,166/3,535,787) compared to the overall test positivity rate of 4.1% (2,373,985/57,909,176).

Conclusion

Over the 7-year period, HIV testing through ICT almost doubled, and one of every four people who tested positive for HIV was detected through ICT. ICT efficiency is demonstrated by a test positivity that is three times higher (12%) than the overall test positivity (4%), with particular efficiencies among hard-to-reach age and sex groups.
“CD4+T Cells drive Inflammation in Type 2 Diabetes Mellitus via the TNF-α/STAT-3 Signaling Pathway”
Authors: Shaw Shubham K , Sengupta Soumya , Jha Rohila , Pattanaik Chandrasekhar , Behera Harapriya , Barik Prakash K , Meher Dayanidhi , Sarangi Rajlaxmi , Devadas Satish
Published: November 2024

1)

Objectives

To establish adaptive immune cells specifically T helpers as mediators of meta-inflammation in Type 2 Diabetes Mellitus, correlate biochemical and immunological parameters and delineate the specific signaling proteins responsible for it.

2)

Research Design and Methods

100 T2DM patients with no other clinical disease, autoimmunity or infection were recruited and analyzed for their biochemical and immune parameters. Bioplexing and flow cytometry was employed to analyse total and cell specific protein secretion respectively.Ex-vivoinhibition studies were performed using targeted monoclonal antibodies or small molecule STAT inhibitors.

3)

Results

CD4+T-cells were found to be the primary source for meta-inflammation in T2DM patients with multiple pro-inflammatory cytokines and antibody isotypes. TNF-α acting through STAT-3 was shown as the primary pathway implicating meta-inflammation through CD4+T-cells, wherein inhibitor studies revealed subtle pathways differences between TNF-α or STAT-3 inhibition.

4)

Conclusions

Our result suggests that chronic meta-inflammation with a dysregulated biochemical profile have severe implications on immune function. Additionally, TNF-α and STAT-3 inhibition are good therapeutic targets for better T2MD treatment in ameliorating meta-inflammation.
Prevalence of Physical Activity Initiatives in Australian Primary Schools: A Cross-Sectional Survey
Authors: O’Brien Kate M , Bell Jessica , Wolfenden Luke , Nathan Nicole , Yoong Serene , Bauman Adrian , Lecathelinais Christophe , Leigh Lucy , Hodder Rebecca K
Published: November 2024

Introduction

Schools play a significant role in influencing children’s physical activity and sedentary behaviours and are a key recommended setting for physical activity initiative globally. To achieve population-wide health benefits, they must be guideline-informed and widely adopted. However, evidence on their implementation in Australian primary schools is limited.

Objective

To assess the reported implementation of recommended physical activity initiatives in Australian primary schools and explore their associations with school characteristics.

Methods

A cross-sectional study surveyed a nationally representative sample of Australian primary school principals (August 2022-October 2023). Principals reported on 33 physical activity initiatives categorised by delivery context: in the classroom; outside the classroom and during break times; outside of school outside or involving families; or other. Prevalence estimates were weighted to the Australian school population, and logistic regression models assessed associations with school characteristics.

Results

A total of 669 schools participated, with 360 principals completing the survey. Reported implementation rates varied from 4% to 98%. The most frequently implemented initiative in classrooms wasPhysical activity units of work in PDHPE/HPE curriculum across all year groups(98%); outside the classroom/break times wasSchool infrastructure that supports physical activity during breaks everyday (e.g. play areas)(96%); and outside of school/involving families wasSchool provides end of trip facilities to encourage active school travel(75%). Implementation of nine initiatives was associated with school size (n=6), geographic location (n=4), or socio-economic status (n=1).

Conclusion

This first national study provides critical information on current implementation levels individual physical activity initiatives in Australian primary schools and highlights where policy and practice investment in implementation support is required.
Trikafta rescues F508del-CFTR by tightening specific phosphorylation-dependent interdomain interactions
Authors: Wang Guangyu
Published: November 2024

Trikafta is well-known for correcting the thermal and gating defects caused by the most common cystic fibrosis mutation F508del in the human cystic fibrosis transmembrane conductance regulator even at physiological temperature. However, the exact pathway is still unclear. Here, the noncovalent interactions among two transmembrane domains (TMD 1 and TMD2), the regulatory (R) domain and two nucleotide binding domains (NBD1 and NBD2), along with the thermoring structures of NBD1, were analyzed around the active gating center. The results demonstrated that Trikafta binding to TMD1 and TMD2 rearranged their interactions with the R domain, releasing the C-terminal region from NBD1 for its tight ATP-dependent dimerization with NBD2, stabilizing NBD1. Taken together, although the deletion of F508 induces the primary thermal defect of NBD1 and then the gating defect at the TMD1-TMD2 interface, Trikafta rescued them in a reverse manner allosterically. Thus, the thermoring structure can be used to uncover the pathway of a drug to correct the thermal defect of health-related protein.

Significance

Trikafta modulators have been approved by the FDA to treat the most common cystic fibrosis– causing mutation F508del CFTR. However, the molecular action mechanisms of these modulators are still unknown. Following the identification of the gating center in CFTR, this study further revealed that the specific noncovalent interactions of the phosphorylated S813 site with cytoplasmic loops 1 and 4 and N-/C- terminal tails of TMD1 upon Trikafta-triggered tight TMD1- TMD2 interactions at the gating center play a pivotal role in rescuing the primary gating defect and then the thermal defect of F508del CFTR.

Highlights

Trikafta strengthened TMD1-TMD2 interactions at the gating center of ΔF508-CFTR Tight TMD1-TMD2 interactions allowed specific interactions of the R domain with the ICL1- ICL4 interface and the N-/C- terminal tails of TMD1 Subsequently, the C-terminal region was released from NBD1 for tight ATP-dependent NBD1-NBD2 dimerization, stabilizing NBD1 of ΔF508-CFTR