bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic Cancer Risk and Screening Outcomes in Li-Fraumeni Syndrome
Authors: Fernandes Conrad J. , Du Yun K. , Naumer Ann , Kagami Laura A. , Le Anh , Good Madeline , Duvall Melani , Powers Jacquelyn , Zelley Kristin , Maese Luke , MacFarland Suzanne , Kohlmann Wendy , Maxwell Kara N. , Katona Bryson W.
Published: February 2025

Objectives:

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome that may confer increased pancreatic cancer (PC) risk. This study assesses PC risk and the rate of pancreatic imaging abnormalities in LFS.

Methods:

PC prevalence in LFS was calculated for individuals with a known TP53 variant from the IARC/NCI database. Pancreatic imaging studies across three institutional LFS cohorts were reviewed and compared using Fisher’s Exact test.

Results:

Of 3043 individuals with LFS in the IARC/NCI database 46 (1.5%) had PC and 42/1243 (3.4%) LFS families had a member with PC. Amongst PCs with a known age of diagnosis, 2.6% and 43.2% were diagnosed prior to age 30 and 50 respectively. Across three institutional LFS cohorts, 32/329 (9.7%) individuals had a pancreatic imaging abnormality, including cysts in 20 (6.1%) and a mass in 4 (1.2%). Whole-body MRI (WBMRI) had the lowest detection rate of pancreatic abnormalities (6%) whereas endoscopic ultrasound (EUS)/MRI Abdomen (MRI Abd) had the highest (50%/20.8%, respectively). Cysts were detected more frequently with EUS/MRI Abd (33.1%/18.1%, respectively) compared to WBMRI (4.3%). Individuals older than age 50 were more likely to have a pancreatic abnormality (35.8% versus 4.7%, P<0.01) or pancreatic cyst (26.4% compared to 2.2%, P<0.001) compared to those younger than age 50.

Conclusions:

PC may occur earlier in LFS compared to the general population. WBMRI identifies pancreatic abnormalities less frequently than other pancreatic cancer screening modalities in LFS. If dedicated PC screening is performed in LFS, screening should likely start prior to age 50 and use either EUS or MRI Abd.
Shaping sustainable paths for HIV/AIDS funding: a review and reminder
Authors: Elendu Chukwuka , Amaechi Dependable C. , Elendu Tochi C. , Amaechi Emmanuel C. , Elendu Ijeoma D. , Akpa Kenneth N. , Oloyede Praise O. , Adegbola Michael O. , Idowu Omoyelemi F.
Published: February 2025

The fight against human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has made significant progress over the past decades, yet sustainable funding remains a critical challenge. Despite advances in medical treatments and prevention methods, the financial resources needed to combat the epidemic consistently face uncertainties and shortfalls. As of 2023, approximately 37.7 million people are living with HIV/AIDS globally, with 1.5 million new infections reported annually. Sub-Saharan Africa remains the hardest-hit region, accounting for 67% of the global HIV burden. This paper examines the current state of HIV/AIDS funding, identifying key gaps and challenges in maintaining adequate financial resources. It highlights the effects of funding fluctuations on treatment accessibility, prevention programs, and research, stressing the urgent need for diversified and innovative financing mechanisms. The paper offers actionable insights into sustainable funding strategies by analyzing successful models such as public-private partnerships and social impact bonds.

This review aims to inform policymakers, stakeholders, and the global community about the financial barriers to HIV/AIDS management and advocate for coordinated efforts to secure stable funding pathways. Ensuring consistent financial support is vital to preserving hard-won progress, expanding access to care, and achieving the ultimate goal of an AIDS-free generation.
Comparing intermittent and daily prednisone in duchenne muscular dystrophy: a systematic review and meta-analysis
Authors: Zulfiqar Eeshal , Hurjkaliani Sonia , Umar Shahood Ahmed , Shahzad Maryam , Ahsan Muneeba , Tahir Quareeha , Nizami Urooj , Rizvi Bariha , Khan Abdullah Abid , Baloch Aniqa , Hussain Syed Shafaat , Rabbani Mehwish , Fatima Marhaba , Larik Muhammad Omar , Hasanain Muhammad , Anjum Muhammad Umair , Bhattarai Pratik
Published: February 2025

Background:

Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by DMD gene mutations, leading to muscle wasting due to dystrophin deficiency. Current treatment with corticosteroids like prednisone shows benefits but lacks clarity on optimal dosing regimens. This systematic review and meta-analysis aim to determine the efficacy and safety of daily versus intermittent prednisone dosing in DMD management.

Methods:

We conducted a systematic search of PubMed, Google Scholar, Embase, and Scopus databases to identify studies comparing daily versus intermittent prednisone in DMD treatment. The study protocol was registered with PROSPERO (CRD42024549050).

Results:

After the systematic search, 6 trials were included in the pooled analysis. Intermittent prednisone was associated with a higher prevalence of cushingoid appearance (RR: 1.72; 95% CI: 1.17 to 2.51; P = 0.005), excessive hair growth (RR: 1.56; 95% CI: 1.08 to 2.24; P = 0.02), and hypertension (RR: 3.42; 95% CI: 1.87 to 6.25; P < 0.0001). In contrast, there were no statistically significant differences between daily versus intermittent prednisone in terms of forced vital capacity (FVC), blood pressure, loss of ambulation, weight changes, weight gain, bone fracture, behavioral changes, and DEXA lumbar spine Z-scores.

Conclusion:

No significant differences in efficacy outcomes regimens were observed. However, intermittent prednisone was associated with a higher prevalence of certain adverse effects, such as cushingoid appearance, excessive hair growth, and hypertension. These findings provide valuable insights for clinicians when choosing treatment strategies and highlight the need for personalized approaches to minimize side effects while maintaining efficacy.
Bone mineral content, growth, and renal health of infants with perinatal exposure to maternal dolutegravir vs efavirenz and tenofovir disoproxil fumarate vs tenofovir alafenamide: the randomized IMPAACT 2010 (VESTED) trial
Authors: Mbengeranwa Tapiwa , Ziemba Lauren , Brummel Sean S , Johnston Ben , Cassim Haseena , Theron Gerhard , Ngqawana Zukiswa , Wabwire Deo , McCarthy Katie , Shepherd John , Lockman Shahin , Chinula Lameck , Stranix-Chibanda Lynda ,   for the IMPAACT 2010/VESTED study team and investigators
Published: February 2025

Background:

The impact on infant bone, growth, and renal health of in utero and breastmilk exposure to contemporary antiretroviral treatment (ART) remains unclear.

Methods:

643 pregnant women with HIV in nine countries in Africa, Asia and the Americas were randomized to start ART with dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG + FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF between 14-28 weeks’ gestation and continued for 50 weeks postpartum. Pairwise comparisons used two-sample t-tests of mean week 26 infant bone mineral content (BMC) assessed by dual-energy X-ray absorptiometry (DXA) in a subset; mean infant z-scores for length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) at 26 and 50 weeks; and mean infant creatinine and estimated creatinine clearance at birth and 26 weeks.

Results:

577 infants were included in the growth analysis, and 169 in the DXA analysis. Week 26 infant spine BMC was significantly lower in the EFV/FTC/TDF arm (133.5g) compared to the DTG+FTC/TAF (143.4g; mean difference [95% CI]: 0.22 [0.02, 0.42] g) and DTG+FTC/TDF (137.4; mean difference [95%CI]: 0.20 [0.01, 0.40] g) arms. Mean LAZ and WAZ scores through week 50 were also significantly lower in the EFV/FTC/TDF versus DTG arms, but not WLZ. Infant obesity was rare (2-4%) and similar between arms. There was no apparent by-arm difference in infant creatinine or estimated creatinine clearance through week 50 (p-values ≥ 0.18).

Conclusion:

It is reassuring that maternal DTG-based ART during pregnancy and breastfeeding was associated with higher infant spine bone mineral content, better growth, and less stunting than EFV/FTC/TDF.
An Analysis of Delta Apparent Diffusion Coefficient Values for Epithelial Ovarian Cancer Classification and Ki-67 Expression
Authors: Fan Jiao-jiao , Liu Yang , Li Guanxiong , Liu Rui-chao , Xie Ziteng
Published: February 2025

Background:

Ovarian cancer is one of the most common malignant tumors of the female reproductive system, characterized by high malignancy and poor prognosis. Epithelial ovarian cancer (EOC) accounts for 90% to 95% of all cases. This study aims to investigate the diagnostic value of delta apparent diffusion coefficient (dADC) values in distinguishing between type I and type II EOC and to explore its correlation with Ki-67 expression.

Methods:

A retrospective analysis included 95 patients (mean age: 51.6 ± 12.5 y; range: 17 to 73 y) diagnosed with EOC at our hospital from September 2021 to August 2023. Of these, 51 patients had type I EOC (low-grade serous carcinoma, clear cell carcinoma, endometrioid carcinoma, mucinous carcinoma, or borderline tumors), and 44 had type II EOC (high-grade serous carcinoma or high-grade endometrioid carcinoma). Bilateral lesions were observed in 16.8% of patients. Preoperative MRI, including diffusion-weighted imaging (DWI), serum CA125 levels, and postoperative immunohistochemical Ki-67 expression, were analyzed. Tumor staging was based on the 2021 FIGO criteria. Minimum ADC (minADC), maximum ADC (maxADC), and dADC values were calculated from the solid tumor components. Receiver operating characteristic (ROC) curves assessed diagnostic performance, and the correlation between dADC and Ki-67 expression was examined.

Results:

The maxADC and minADC of type II EOC were lower than those of type I, while dADC was higher than type I (P<0.05). ROC curve analysis showed that the efficacy of dADC in distinguishing between type I and type II EOC was higher than that of minADC and maxADC (P<0.05). When the dADC threshold was 0.31×10−3 mm2/s, the area under the curve (AUC) was 0.982, with a sensitivity of 95.3% and specificity of 97.3%. Pearson correlation analysis showed a positive correlation between dADC and Ki-67 expression.

Conclusion:

dADC has a certain value in accurately distinguishing between type I and type II EOC preoperatively, and it can reflect the proliferative activity of tumor cells.
Evaluating Undersampling Schemes and Deep Learning Reconstructions for High-Resolution 3D Double Echo Steady State Knee Imaging at 7 T: A Comparison Between GRAPPA, CAIPIRINHA, and Compressed Sensing
Authors: Marth Thomas , Marth Adrian Alexander , Kajdi Georg Wilhelm , Nickel Marcel Dominik , Paul Dominik , Sutter Reto , Nanz Daniel , von Deuster Constantin
Published: February 2025

Objective

The 3-dimensional (3D) double echo steady state (DESS) magnetic resonance imaging sequence can image knee cartilage with high, isotropic resolution, particularly at high and ultra-high field strengths. Advanced undersampling techniques with high acceleration factors can provide the short acquisition times required for clinical use. However, the optimal undersampling scheme and its limits are unknown.

Materials and Methods

High-resolution isotropic (reconstructed voxel size: 0.3 × 0.3 × 0.3 mm3) 3D DESS images of 40 knees in 20 volunteers were acquired at 7 T with varying undersampling factors (R = 4–30) and schemes (regular: GRAPPA, CAIPIRINHA; incoherent: compressed sensing [CS]), whereas the remaining imaging parameters were kept constant. All imaging data were reconstructed with deep learning (DL) algorithms. Three readers rated image quality on a 4-point Likert scale. Four-fold accelerated GRAPPA was used as reference standard. Incidental cartilage lesions were graded on a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Friedman's analysis of variance characterized rating differences. The interreader agreement was assessed using κ statistics.

Results

The quality of 16-fold accelerated CS images was not rated significantly different from that of 4-fold accelerated GRAPPA and 8-fold accelerated CAIPIRINHA images, whereas the corresponding data were acquired 4.5 and 2 times faster (01:12 min:s) than in 4-fold accelerated GRAPPA (5:22 min:s) and 8-fold accelerated CAIPIRINHA (2:22 min:s) acquisitions, respectively. Interreader agreement for incidental cartilage lesions was almost perfect for 4-fold accelerated GRAPPA (κ = 0.91), 8-fold accelerated CAIPIRINHA (κ = 0.86), and 8- to 16-fold accelerated CS (κ = 0.91).

Conclusions

Our results suggest significant advantages of incoherent versus regular undersampling patterns for high-resolution 3D DESS cartilage imaging with high acceleration factors. The combination of CS undersampling with DL reconstruction enables fast, isotropic, high-resolution acquisitions without apparent impairment of image quality. Since DESS specific absorption rate values tend to be moderate, CS DESS with DL reconstruction promises potential for high-resolution assessment of cartilage morphology and other musculoskeletal anatomies at 7 T.
Urbanicity and anxiety disorders: current evidence and quo vadis?
Authors: Chew Qian Hui , Sim Kai Samuel , Shi Yao Eric , Sim Kang
Published: February 2025

Purpose of review

There are few studies investigating the effects of urbanization on various anxiety-related conditions in specific population subgroups. This review aims to examine the effects of urbanization through the lens of population subgroups as well as anxiety disorder subtypes.

Recent findings

There was more consistent evidence suggesting that those of a younger age group and from disadvantaged backgrounds (such as lower socioeconomic status, refugee status) may be more vulnerable to posttraumatic stress disorder (PTSD). When we examined the relationship between urbanization and anxiety disorder subtype, the results were largely mixed, with some evidence for the positive association between urbanization and PTSD. Many of the recent studies had been conducted in the context of the recent coronavirus disease 2019 (COVID-19) pandemic.

The association between urbanicity and anxiety-related disorders in the various subgroups can be influenced by socio-demographic factors. Interventions and policies that aim to ameliorate the effects of urbanicity would need to identify vulnerable individuals early based on social or environmental factors. Given that the short and long-term psychological sequelae of the recent COVID-19 pandemic are still being evaluated, the inter-relationships between urbanization, external factors and specific anxiety disorders await further delineation.
Crystalline lens dislocation as a presenting sign of Streptococcus pyogenes invasive infections
Authors: Liberman Paulina , Light Jacob G , Dharssi Shazia , Howard Tracy , Lu Jen , Simner Patricia J. , Carroll Karen C. , Ho Cheng-Ying
Published: February 2025

Introduction
To describe two cases of crystalline lens dislocation as a presenting feature of invasive group A Streptococcus (GAS) infection and its management.
Case presentation
We report on a 58-year-old female and a 36-year-old male who presented in 2024 with acute vision loss and severe ocular and systemic symptoms. Both patients were found to have lens dislocation and were diagnosed with invasive GAS infection. The 58-year-old female had a complicated clinical course leading to enucleation, while the 36-year-old male responded favorably to early and aggressive treatment with systemic and intravitreal antibiotics. The responsible GAS strains were sequence type (ST) 28 and ST433, respectively.
Conclusion
These cases highlight the importance of recognizing crystalline lens dislocation as a potential sign of ocular GAS infection. Two specific strain types of GAS associated with these findings, ST28 and ST433, are reported. In patients with GAS sepsis presenting with corneal edema and zonular loss, clinicians should immediately initiate treatment, including intravitreal antibiotic injections and systemic therapy. Prompt and aggressive management can be crucial in preserving ocular structures.
A novel Enrichment-free, Low-volume filtration and Rapid lysis method (ELR) in combination with real-time PCR for detection of Shiga toxin-producing Escherichia coli (STEC) in water
Authors: Alfahl Zina , O’Connor Louise , Morris Dearbháile , Smith Terry J. , O'Dwyer Jean , Hynds Paul D. , Cormican Martin , Burke Liam P.
Published: February 2025

Consequences of Shiga toxin-producing Escherichia coli (STEC) infection can range in severity from asymptomatic infection to haemolytic uraemic syndrome (HUS), renal failure, and death. Groundwater-derived drinking water is an important route for STEC transmission. Detection of STEC in water is crucial for timely response and public health interventions, however currently used culture-based methods are time-consuming and laborious. Therefore, there is a need for rapid methods that maintain high sensitivity and specificity. We describe a novel sensitive, enrichment-free water filtration method using a convenient sample volume (100 mL) to detect DNA markers of STEC serogroups and virulence factors within 6 hours. Quantitative real-time Polymerase Chain Reaction (qPCR) was used to detect and quantify the most common STEC infection-associated serogroups globally, O157 and O26. Real-time PCR was used to detect genetic determinants of STEC virulence (stx1,stx2 and eae genes) and specific marker genes for the clinically relevant serogroups O111, O103, O145 and O104. Results showed that the novel method can detect as low as 5 CFU/mL of STEC in water. The limit of detection for O157 and O26 qPCR assays was 2 and 6 copies, respectively. Groundwater and surface water samples (n=28) were collected and processed using the novel method. STEC O157 and O26 serogroups were detected in 23/28 (82.1%) samples (mean 5.2x104 copies/reaction) and 19/28 (67.9%) samples (mean 7.83x104 copies/reaction), respectively. Shiga toxin genes stx1 or stx2 were detected in 15/28 (53.6%) and 9/28 (32.1%) samples, respectively. Virulence factor intimin gene eae was detected in 24/28 (85.7%) samples. STEC serogroups O111, O103, O145 and O104 were detected in 15/28 (53.6%), 10/28 (35.7%), 11/28 (39.3%) and 15/28 (53.6%) samples, respectively. This novel method reproducibly detects low copies of STEC in low volume fresh water and has the potential to be used for detection and quantification of waterborne bacterial pathogens.
Description of Flavobacterium fructosi sp. nov., Flavobacterium xylosi sp. nov. and Flavobacterium zhouii sp. nov., three new members of the genus Flavobacterium
Authors: Han Dou , Yang Lei-Lei , Xin Yu-Hua , Liu Qing
Published: February 2025

Three novel strains, designated LB3P45T, LS2P90T and ZS1P70T, were isolated from glaciers located on the Tibetan Plateau, PR China. These strains were Gram-stain-negative, aerobic, rod-shaped and yellow or orange coloured. Phylogenetic analysis based on the 16S rRNA gene and genomic sequences indicated that they belong to the genus Flavobacterium. The 16S rRNA gene sequence similarity among the three strains ranged from 97.4 to 98.6%. Strain LB3P45T showed 98.9% and 98.7% similarity to Flavobacterium urumqiense CGMCC 1.9230T and Flavobacterium xinjiangense JCM 11314T, respectively. Strain LS2P90T displayed 99.0% and 98.7% similarity to F. xinjiangense JCM 11314T and F. urumqiense CGMCC 1.9230T. Strain ZS1P70T had the highest sequence similarity with F. xinjiangense JCM 11314T (98.0%) and F. urumqiense CGMCC 1.9230T (97.8%). The average nucleotide identity and digital DNA–DNA hybridization values between these strains and their closest relatives were lower than 93.0% and 47.9%, respectively. All three strains contained summed feature 3 (comprising C16:1
ω7c and/or C16:1
ω6c) as the major fatty acids. Based on phenotypic characteristics, phylogenetic analysis and genotypic data, the three novel species are proposed: Flavobacterium fructosi sp. nov. (LB3P45T=CGMCC 1.11439T=NBRC 114819T), Flavobacterium xylosi sp. nov. (LS2P90T=CGMCC 1.11685T=NBRC 114823T) and Flavobacterium zhouii sp. nov. (ZS1P70T=CGMCC 1.24124T=NBRC 114829T).
Muscle Activation of Upper Body in Different-Angle Suspension Push-Ups: An Analysis of Angle-Specific Muscle Engagement
Authors: Lin Yu-Chin , Lin Kuei-Fu , Chen Chu , Chan Shih-Hsuan , Lee Po-Chun , Hsu Chih-Hsiang , Chiang Tsung-Lin
Published: February 2025

The aim of this study was to understand the effect on upper body muscle activation of bodily angle during push-ups performed with TRX suspension training. Nineteen men (age: 21.1 ± 1.2 years; height: 174.1 ± 4.9 cm; weight: 70.7 ± 7.2 kg) with resistance training experience participated in this study. The participants were required to perform five push-ups on a stable surface and with TRX at five angles (+30°, +15°, 0°, −15°, and −30°, where 0° indicates that the shoulder joints were at the same height as the ankle joints when the arms were extended). The recovery period between the sets at each angle was 3–5 minutes. Stable-surface and TRX push-ups were separated by at least 48 hours. During push-ups, electromyography (EMG) data from the pectoralis major (PM), anterior deltoids (AD), triceps brachii (TRI), upper trapezius (UT), and serratus anterior (SA) were recorded. Muscle activation was indicated by the percentage of maximum voluntary isometric contraction (%MVIC). The %MVIC of each muscle group was then categorized. Repeated-measured two-way analysis of variance was used to determine differences in the muscle group activation between the push-up surface types and five angles. Statistical significance was set at p < .05. The activation of the PM, AD, and TRI during TRX push-ups was categorized as medium to extremely high. Compared with that for stable-surface push-ups, the activation of the PM during TRX push-ups was significantly higher (p < .05). Furthermore, +30°, +15°, and 0° push-ups produced greater PM activation than push-ups at lower angles (p < .05). Both TRX and stable-surface push-ups resulted in greater anterior deltoids, TRI, UT, and SA activation during −30° push-ups. This study indicates the appropriate push-up practices for different muscle groups, as determined by quantifying the muscle activation.
Prebiotic xylo-oligosaccharides for alleviation of hepatic steatosis: Results from a four-month dietary intervention and determinants of response
Authors: Hintikka Jukka E , Permi Perttu , Lehtonen Marko , Lensu Sanna , Driuchina Anastasiia , Jormanainen Mika , Laukkanen Jari , Bayal Nitin , Erawijantari Pande P. , O’Connell Thomas M , Lahti Leo , Pekkala Satu
Published: February 2025

A common complexity from increasing rates of overweight is metabolic dysfunction associated steatotic liver disease (MASLD) which can develop into more severe conditions such as fibrosis or hepatocellular carcinoma. The gut and its microbial flora interact with the liver through the gut-liver axis and supporting healthy composition and metabolism of the microbiota can benefit metabolic health. We have previously shown in animals that a xylo-oligosaccharide (XOS) prebiotic can drive beneficial gut flora and ameliorate hepatic steatosis- our current objective is to validate these results in humans. Forty-two adults (mean age 53.7, mean BMI 33.5) ingested a prebiotic dose of XOS daily for four months. Liver fat was quantified with MRI and body composition was measured. Standard clinical measurements and untargeted metabolomes were analyzed from serum. Microbiota composition, metagenome and metabolites were analyzed from fecal samples. A subgroup analysis was conducted between non-steatotic individuals, non-responders, and responders. The XOS supplementation caused decreases in detrimental amino acid degradation products (AADPs) isovalerate, isobutyrate, and phenylacetate in the gut while serum metabolome remained stable. A decrease in liver fat during the prebiotic was accompanied by a decrease in visceral fat. In a prediction analysis, this response was driven by higher initial ratio ofBacteroidestoFaecalibacterium, higher fecal AADPs, and higher serum amino acids. Non-responders had metabolomic signatures of advanced steatosis, possibly impeding effects from XOS. In overweight individuals with early hepatic steatosis, XOS may correct fermentation imbalances in the gut and decrease production of harmful metabolites, which may benefit hepatic health.

IMPORTANCE

Pre- and probiotics are emerging, yet unknown, avenues of treatment for metabolism-associated steatotic liver disease. In overweight humans, a xylo-oligosaccharide (XOS) prebiotic induced shifts in gut bacteria and their metabolites. High proteolytic activity in the gut was predictive of hepatic response to XOS, which may serve the development of personalized treatment of fatty liver.
gyōza: a Snakemake workflow for modular analysis of deep-mutational scanning data
Authors: Durand Romain , Pageau Alicia , Landry Christian R.
Published: February 2025

Deep-mutational scanning (DMS) is a powerful technique that allows screening large libraries of mutants at high throughput. It has been used in many applications, including to estimate the fitness impact of all single mutants of entire proteins, to catalog drug resistance mutations and even to predict protein structure. Here, we present gyōza, a Snakemake-based workflow to analyze DMS data. gyōza requires little programming knowledge and comes with comprehensive documentation to help the user go from raw sequencing data to functional impact scores. Complete with quality control and an automatically generated HTML report, this new pipeline should facilitate the analysis of any DMS experiment. gyōza is freely available on GitHub (https://github.com/durr1602/gyoza).
Breaking Free from Tobacco: Insights from Chipangali’s Small-Scale Farmers on Embracing Alternative Crops in Zambia
Authors: Mataliro Mercy , Mutalange Martha , Ngambi Wingston Felix , Zyambo Cosmas
Published: February 2025

Abstract

Tobacco is an important cash crop for farmers across the globe but has substantial health and environmental risks, thus the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) emphases the need for countries to promote alternative crop farming. This study seeks to understand the success of the alternative crop promotion program among tobacco small-scale farmers and government officials in Chipangali district, Zambia. The study analyzed data from qualitative key-informant interviews (KIIs) with government officials and extension officers (n = 5) and focus group discussions (FGDs) with farmers (n = 6). The FGDs and KIIs were audio recorded, transcribed, and then translated into English. An inductive thematic analysis was conducted to identify challenges and lessons learned from alternative crop farming program provided by participants. We highlight important factors linked to the success of the alternative crop promotion program, challenges and lessons learned. The results highlight several factors, including access to farming inputs, market dynamics, government support and farmers’ perceptions of tobacco farming associated with success of the program. Challenges identified included high faming input costs, market uncertainties, limited support, and dependency on tobacco companies. The alternative crop promotion program provided valuable lessons to farmers. However, majority of farmers felt the program was not inclusive and such initiative in future should accommodate all farmers to be successful. Additionally, provision of farming inputs and improvement of supply chain for the promoted crops could motivate tobacco farmers to transition to alternative crop cultivation. Furthermore, addressing environmental challenges such as water scarcity and unpredictable weather patterns through adaptive measures like drought-resistant crops and irrigation systems, could contribute to the success of the program. This study highlights the concerns and lessons that tobacco farmers raised which could be incorporated in the implementation of alternative crop promotion program in Chipangali.
Single-cell omics-based characterization of human basophils reveals two transcriptionally distinct populations
Authors: Papavasileiou Sofia , Mo Jiezhen , Boey Daryl , Wu Chenyan , Tronstad Magnus , Olsen Remi-André , Bachmann Jörg A. , Low Jing Hui , Ong Jocelyn , Blom Lars Heede , Andiappan Anand Kumar , Nilsson Gunnar , Dahlin Joakim S.
Published: February 2025

Background

Basophils are implicated in various diseases including allergies, but a comprehensive characterization of human basophils has yet to be performed at the single-cell level.

Objective

We aimed to generate a single-cell omics-based resource of circulating human basophils, to be made accessible to the research community. We also sought to investigate basophil heterogeneity at the transcriptional and surface epitope levels.

Methods

Circulating basophils were analyzed using short- and long-read single-cell RNA-sequencing in combination with large-scale immunoprofiling of more than 100 cell surface markers.

Results

We used a cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) based cell barcoding system to accurately track side scatterlowlineage−CCR3+FcεRI+basophils through the single-cell omics analysis. The approach allowed for accurate transcriptional profiling of basophils among low-density peripheral blood leukocytes. The generation of an additional dataset with only basophils revealed two transcriptionally distinct populations. Single-cell transcriptomic analysis of samples from additional donors was performed and coupled with a large-scale immunoprofiling screen, producing a third CITE-seq dataset containing basophils. The analysis verified the existence of the two transcriptionally distinct populations and revealed that these populations have similar immunophenotypes with regard to the investigated surface markers. Long-read single-cell RNA-sequencing analysis provided further insights into the gene expression dynamics of the circulating basophils and confirmed the transcriptionally defined basophil states.

Conclusions

The single-cell omics analysis revealed two transcriptionally distinct basophil populations. Our single-cell omics resource constitutes a reference for charting human basophils at the cellular and molecular levels in health and disease.

Capsule summary

Short- and long-read single-cell RNA-sequencing coupled with large-scale immunoprofiling characterize human basophils in peripheral blood and reveal two transcriptionally distinct populations.
Identification of novelcis-acting elements, E-box and ISRE, regulating IFNγ-IRF1 axis-mediated NLRC5 expression
Authors: Yoo Ji-Seung , Kasuga Yusuke , Vijayan Saptha , Yousuf Suhail , Kobayashi Koichi S.
Published: February 2025

NLRC5 and CIITA are the primary transcriptional regulators of MHC class I and MHC class II, respectively, and play essential roles in adaptive immunity. While the regulatory mechanisms of CIITA have been extensively characterized, the transcriptional control of NLRC5 remains incompletely understood. In this study, we identified two novel conservedcis-regulatory elements within the NLRC5 promoter, an E-box and an ISRE. Furthermore, we revealed IRF1 as a novel transcriptional regulator of NLRC5, binding directly to the ISRE within the NLRC5 promoter. Using the newly identified NLRC5 ISRE, we established a screening platform to identify modulators of the IFNγ-IRF1-NLRC5 axis. This system corroborated the inhibitory effects of known viral antagonists and led to the identification of novel SARS-CoV-2 viral factors that suppress IFNγ- mediated IRF1 nuclear translocation, thereby inhibiting the MHC class I pathway. By elucidating the previously unproven molecular mechanism underlying IFNγ-mediated NLRC5 regulation, our study provides critical insights into viral immune evasion strategies and the modulation of antigen presentation. These findings may facilitate the development of MHC class I-targeted therapeutics by modulating the IRF1-NLRC5 axis.
Single-molecule observation of multi-scale dynamic heterogeneity in the molecular bearing of the bacterial flagellum
Authors: Rieu Martin , Nord Ashley , Courbet Alexis , El Sayyed Hafez , Berry Richard Michael
Published: February 2025

The bacterial flagellar motor (BFM) is a protein-based rotary machine that drives bacterial motility. It comprises a stator anchored to the cell wall and a rotor in the cytoplasmic membrane, linked via the flagellar rod to the extracellular hook and filament. We describe high-speed polarization microscopy of gold nanorods attached to the hook, allowing unprecedented continuous recording of single BFMs with a few degrees resolution at 250 kHz for tens of minutes. The angular distribution of actively rotating motors exhibited multiple periodicities that are consistent with structure of the bearing between the rod and LP-ring. We observed passive diffusional rotation of this bearing, revealing complex dynamics at odds with the expected classical Ornstein-Uhlenbeck process in a smooth potential. Resolved transitions between the main 26-fold bearing states exhibited highly non-Poissonian kinetics spanning four orders of magnitude in timescale. Using the average transition times, we estimated the interaction barrier in the bearing to be close to 13 kBT, suggesting that the previously estimated torque generated by a single stator unit is just sufficient to overcome this barrier. At sub-millisecond timescales we observed anomalous ultra-slow diffusion typically associated with multi-scale disordered systems, despite the ordered crystalline atomic structure of the bearing revealed by cryo-Electron Microscopy. Over longer periods, we observed dynamic shifts in the preferred angular positions, indicating that the motor's potential energy landscape evolves over time. We speculate that these newly discovered rich dynamics may be a universal feature of protein machines.
Electrostatics facilitate mid-air host attachment in parasitic jumping nematodes
Authors: Ran Ranjiangshang , Burton Justin C. , Ortega-Jimenez Victor M.
Published: February 2025

Jumping can be hazardous for entomopathogenic nematodes (EPNs) as those that fail to attach to an insect host face death by predation or starvation. Recently, it has been shown that electrostatic charges on large insects can prompt a close-range detachment of free-living nematodes, which are non-parasitic and unable to jump. However, it remains unclear if static electricity can influence aerial interactions between parasitic jumping worms and their insect hosts. Here we analyze and model the trajectories of jumping EPNs in still air as they approach fruit flies with varying electrostatic charge. We discover that the nematodes’ attachment to the host is facilitated by an electrical potential of a few hundred volts, a magnitude commonly found in flying insects. A model combining electrostatics, aerodynamics, and Bayesian inference indicates that the electrostatic charge on jumping nematodes is ~ 0.1 pC, which aligns with theoretical predictions for electrostatic induction. Drag coefficients based on host-nematode interactions in the presence of horizontal wind show differences at both low and high jumping velocities. Numerical simulations show that intermediate wind speeds (~ 0.2 m/s) can further increase the likelihood of host attachment, as wind-driven aerial drifting allows the worms to reach hosts at greater distances. Our results suggest that submillimeter parasites that become airborne may exploit the electric charge carried by their host to facilitate attachment and thus enhance survival. The use of quantitative physical models provides valuable insights into understanding complex airborne infectious diseases mediated by natural environmental forces.

Significance Statement

Entomopathogenic nematodes (EPNs) are submillimeter parasites renowned for their explosive aerial jumping, allowing them to reach distant insect hosts. They serve as important model organisms and natural biopesticides. Our work reveals that these tiny organisms can be electrostatically attracted to charged hosts, such as fruit flies, increasing the likelihood of infection. Experiments show that host attachment is significantly enhanced by electrostatic forces generated by naturally occurring electric fields from flying insect hosts. Our computational model confirms that the static charge of EPNs agrees with theoretical predictions from electrostatic induction. We propose that electrostatics play a crucial role in enhancing the survival of these jumping parasites and provide a framework for modeling environmental forces in aerial parasite-host interactions.
Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma
Authors: Wheelan Justin , Spigelman Melissa , Cirinelli Angelo , Reilly James , Molina Carlos A.
Published: February 2025

Melanoma, the most lethal form of skin cancer, is commonly associated by mutations in the BRAF gene, particularly BRAFV600E, which drives tumor proliferation via ERK1/2 signaling cascade. While BRAF inhibitors initially demonstrate efficacy, therapeutic resistance remains a significant challenge. Emerging evidence implicates the cAMP signaling pathway, particularly the cAMP response element-binding protein (CREB) and its repressor, Inducible cAMP Early Repressor (ICER), in melanoma progression and drug resistance. ICER, a transcriptional repressor regulated via Ras/MAPK-mediated phosphorylation and ubiquitination, is degraded in melanoma, undermining its tumor-suppressive role. In abrafV600E;p53(loss of function) transgenic zebrafish (Danio rerio) model, we investigated the role of a ubiquitin-resistant ICER mutant (S35-41A-ICER) in tumor progression. Transgenic fish expressing S35-41A-ICER exhibited extended survival and reduced tumor invasiveness compared to wild-type ICER. RNA sequencing revealed dysregulation of CREB/CREM targets and compensatory pathways, including Rap1 and PI3K/AKT signaling, as well as candidate gene targets of ICER regulation, including the Protein Kinase A catalytic subunitprkacaa. Our findings suggest that a ubiquitin resistant ICER mitigates melanoma progression and represses oncogenic pathways in abrafV600Emelanoma context.

Summary Statement

This study shows that ubiquitin-resistant ICER mutant suppresses melanoma progression, prolongs survival inbrafV600Ezebrafish, revealing its potential as a tumor suppressor and therapeutic target in melanoma resistance.
Risk of Alopecia Areata with Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss
Authors: Sodhi Mohit , Rezaeianzadeh Ramin , Kezouh Abbas , Frey Connor , Etminan Mahyar
Published: February 2025

GLP-1 (glucagon-like peptide-1) agonists including semaglutide and liraglutide are possibly the most prescribed medications in the world. Many recent studies have quantified their adverse events with a focus on gastrointestinal adverse events. However, no large epidemiologic study has investigated the risk of hair loss with these medications. We conducted a retrospective cohort study using a large health claims database to investigate this risk. Using a random sample of 16 million patients, we identified new users of semaglutide or liraglutide and an active comparator bupropion-naltrexone. We excluded those with a diagnosis of diabetes or use of antihyperglycemics prior to cohort entry. Cohort members were followed from the first date of a study drug prescription to the diagnosis of alopecia areata. We adjusted for age, sex, geographic location, depression, steroid use, hypothyroidism, polycystic ovary syndrome, and anemia. Our cohort included 926 semaglutide users, 17,898 liraglutide users, and 1,348 users of bupropion-naltrexone. We found that compared to bupropion-naltrexone, the crude hazard ratio and adjusted hazard ratio for alopecia areata for semaglutide or liraglutide use was 1.73 (95% confidence interval: 1.00-3.01) and 2.09 (95% confidence interval: 1.20-3.65) respectively. Our results demonstrate an increased risk of alopecia areata with GLP-1 agonists. Future studies are required to ascertain the association between GLP-1 agonists and alopecia areata.
Regulatory genomic circuitry of brain age by integrative functional genomic analyses
Authors: Zhao Xingzhong , Yang Anyi , Ding Jing , Yang Yucheng T. , Zhao Xing-Ming
Published: February 2025

Brain age gap (BAG) is a valuable biomarker for evaluating brain healthy status and detecting age-associated cognitive degeneration. However, the genetic architecture of BAG and the underlying mechanisms are poorly understood. Here, we estimate brain age from magnetic resonance imaging with improved accuracy using our proposed adversarial convolution network (ACN), followed by applying the ACN model to an elder cohort from UK Biobank. The genetic heritability of BAG is significantly enriched in the regulatory regions and implicated in glial cells. We prioritize a set of BAG-associated genes, and further characterize their expression patterns across brain cell types and regions. Two BAG-associated genes,RUNX2andKLF3, are found as associated with epigenetic clock and diverse aging-related biological pathways. Finally, two BAG-associated hub transcription factors,KLF3andSOX10, are identified as regulators of pleiotropic risk genes from diverse brain disorders. Altogether, we improve the estimation of BAG, and identify BAG-associated genes and regulatory networks that are implicated in brain disorders.
RNA Transcripts Serve as a Template for Double-Strand Break Repair in Human Cells
Authors: Jalan Manisha , Brambati Alessandra , Shah Hina , McDermott Niamh , Patel Juber , Zhu Yingjie , Doymaz Ahmet , Wu Julius , Anderson Kyrie S , Gazzo Andrea , Pareja Fresia , Yamaguchi Takafumi N , Vougiouklakis Theodore , Ahmed-Seghir Sana , Steinberg Philippa , Neiman-Golden Anna , Azeroglu Benura , Gomez-Aguilar Joan , da Silva Edaise M , Hussain Suleman , Higginson Daniel , Boutros Paul C , Riaz Nadeem , Reis-Filho Jorge S , Powell Simon N , Sfeir Agnel
Published: February 2025

Double-strand breaks (DSBs) are toxic lesions that lead to genome instability. While canonical DSB repair pathways typically operate independently of RNA, emerging evidence suggests that RNA:DNA hybrids and transcripts near damaged sites can influence repair outcomes. However, a direct role for transcript RNA as a template during DSB repair in human cells is yet to be established. In this study, we designed fluorescent- and sequencing-based assays, which demonstrated that RNA-containing oligonucleotides and messenger RNA serve as templates to promote DSB repair. We conducted a CRISPR/Cas9-based genetic screen to identify factors that promote RNA-templated DSB repair (RT-DSBR), and of the candidate polymerases, we identified DNA polymerase-zeta (Polζ) as the potential reverse transcriptase that facilitates RT-DSBR. Furthermore, by analyzing sequencing data from cancer genomes, we identified the presence of whole intron deletions, a unique genomic scar reflective of RT-DSBR activity generated when spliced mRNA serves as the repair template. These findings highlight RT-DSBR as an alternative pathway for repairing DSBs in transcribed genes, with potential mutagenic consequences.
Nonstandard coding of deceased-donor kidney out-of-sequence allocation leads to underrecognition of allocation deviations
Authors: Tucker Emma G. , Yu Miko E. , Adler Joel T. , Cron David C. , Sahni Prateek V. , Schold Jesse D. , Mohan Sumit , Husain Syed Ali
Published: February 2025

Out-of-sequence (OOS) allocation, the process by which organ procurement organizations (OPOs) can deviate from standard rank lists of potential recipients to expeditiously allocate deceased-donor kidneys, is rising in the U.S. We aimed to determine whether current OPO reporting practices obscure the extent of OOS allocation. Using match-run data for all U.S. deceased-donor kidney transplants from 2021-2023, we defined “miscoded” OOS (mOOS) allocation transplants as those with use of the 799 or 898 OPO- initiated refusal codes (“other, specify”) with free text responses clearly indicating OOS allocation, and compared these to “explicit” OOS (eOOS) allocation, wherein OOS transplants are appropriately coded using refusal codes 861-863. We found that the prevalence of mOOS allocation increased from 2021 (122 transplants) to 2023 (430 transplants) and accounted for 12% of all OOS transplants by 2023. Organs allocated via mOOS had a lower median KDPI than those allocated via eOOS (51% vs 55%, p <0.01). While an increasing number of OPOs used mOOS throughout the study period, the practice remained concentrated overall, with 5 “outlier” OPOs performing 66% of mOOS allocations in 2023. These findings highlight the need for stricter oversight of organ allocation and underscore the responsibility of the OPTN to ensure proper data reporting.
Impact of Patient Positioning on Hemodynamic Assessment: A Comparison of Supine and Upright Right Heart Catheterization in Pulmonary Hypertension and HFpEF
Authors: Chowdhury Mohammed A. , Squires Johanna , Systrom David M. , Waxman Aaron B.
Published: February 2025

Background

Right heart catheterization (RHC) is the gold standard for the objective diagnosis of heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH). Typically performed in the supine position, RHC may not accurately reflect the hemodynamic changes that occur during upright activity. The effect of patient positioning on RHC measurements, especially in distinguishing between precapillary and postcapillary PH, has been underexplored. This study aims to compare hemodynamic measurements between supine and upright RHC and assess how patient positioning influences the diagnosis of PH.

Methods

We performed a retrospective observational study of patients who underwent both supine and upright RHC during invasive cardiopulmonary exercise testing (iCPET) at Brigham and Women’s Hospital between January 2015 and January 2024. Hemodynamic parameters were measured and compared between both positions.

Results

Compared to upright RHC, supine RHC showed consistently higher mean PAP (21 ± 8.5 mmHg vs. 16 ± 8 mmHg) and PCWP (12 ± 4.7 mmHg vs. 6.4 ± 4.9 mmHg). Supine RHC diagnosed significantly more cases of HFpEF (21.8% vs. 5.7%) and isolated postcapillary PH (10.9% vs. %), primarily due to overestimation of PCWP. Upright RHC had a higher specificity for detecting elevated PCWP (>15 mmHg) in patients with elevated NT-proBNP (92.8% vs. 74.3%), iCPET diagnosed exercise HFpEF (95.29% vs 80.92%), PCWP/CO>2 (98.27% vs 84.61%) and demonstrated stronger association with PCWP/CO>2 (OR 9.11, 95% CI 5-16) compared to supine RHC. The differences in mPAP and PCWP measurement between supine and upright RHC persisted regardless of sex, age, BMI, or severity of chronic lung disease.

Conclusions

Hemodynamic discrepancies between supine and upright RHC exist which can significantly affect the diagnosis of PH and HFpEF. Upright RHC provides more physiologically relevant data, potentially enhancing diagnostic accuracy and should be considered in the evaluation of patients with PH.

Clinical Perspective

What is new?

This study highlights significant differences in hemodynamic measurements of mean pulmonary artery pressure and pulmonary capillary wedge pressure between supine and upright RHC.

The difference in supine and upright hemodynamics persists despite age, sex, BMI, FEV1 or smoking.

Compared to upright RHC, supine RHC results in overestimation of PCWP resulting in misclassification of PH.

What are the clinical implications?

Utilizing upright RHC may enhance the accuracy of diagnosing PH and HFpEF, leading to better-targeted therapies and management strategies for patients.

Improved diagnostic precision could reduce unnecessary treatments and hospitalizations associated with misdiagnosed heart failure and pulmonary hypertension.