bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief Report: New HIV Diagnoses in PrEP-Experienced and PrEP-Naive Persons in the ICONA Cohort
Authors: Taramasso Lucia , Rossotti Roberto , Tavelli Alessandro , Santoro Maria M. , Mazzotta Valentina , Bandera Alessandra , D'Ettorre Gabriella , Milano Eugenio , Pellicano Giovanni Francesco , Baiguera Chiara , Bruzzesi Elena , D'Arminio Monforte Antonella , Antinori Andrea , Nozza Silvia ,   for the ICONA Foundation Study Group
Published: December 2024

Background:

The best therapeutic management for people with HIV (PWH) who have a history of preexposure prophylaxis (PrEP) is still debated.

Objectives:

The aim of this study was to describe recent HIV infections in PrEP users compared with people never exposed to PrEP.

Methods:

Multicentre retrospective analysis evaluating all recent HIV infections from 2018 to 2021 within the Italian Cohort Naive Antiretrovirals. PWH, PrEP experienced or not, were compared using χ2 test and Wilcoxon rank-sum test for categorical and continuous variables, respectively. A mixed linear model was used to estimate the change of the estimated mean HIV-RNA in the first year after ART initiation, according to PrEP exposure.

Results:

Fifty-one recent HIV diagnoses were identified, 9 in PrEP-experienced people, with an increasing temporal trend over the study period. Clinicians often initiated four-drug ART or NRTI-avoiding regimens in PrEP-experienced individuals, but this approach did not result in better viral decay or faster virologic suppression compared with traditional three-drug regimens. All achieved viral suppression during follow-up, within a median of 5.1 (IQR, 3.2–8.7) months in PWH never exposed to PrEP and 5.2 (IQR 3.2–9.4) months in PrEP-experienced PWH (P = 0.937). M184I/V was the most common mutation in PrEP-experienced individuals (37.5%).

Conclusions:

An increasing number of people newly diagnosed with HIV report previous use of PrEP. All PrEP-experienced PWH in ICONA cohort have achieved rapid virologic suppression, even in cases with the presence of transmitted viral mutations.
Relevance of Prostatic Fluid on the Apparent Diffusion Coefficient
Authors: Skwierawska Dominika , Bickelhaupt Sebastian , Bachl Maximilian , Janka Rolf , Murr Martina , Gloger Felix , Kuder Tristan A. , Zaiss Moritz , Hadler Dominique , Uder Michael , Laun Frederik B.
Published: December 2024

Objectives

Diffusion-weighted imaging (DWI) is pivotal for prostate magnetic resonance imaging. This is rooted in the generally reduced apparent diffusion coefficient (ADC) observed in prostate cancer in comparison to healthy prostate tissue. This difference originates from microstructural tissue composition changes, including a potentially decreased fluid-containing lumen volume. This study explored the nature of the observed ADC contrast in prostate tissue through inversion recovery–prepared DWI examinations that generated varying levels of fluid suppression.

Materials and Methods

This institutional review board–approved, single-center, prospective study was conducted from 2023 to 2024; all participants underwent magnetic resonance imaging including DWI with b-values of 50 and 800 s/mm2 at 16 inversion times (TI; 60–4000 milliseconds). The measured ADC was interpreted with a 2-compartment model (compartments: tissue and fluid). Descriptive statistics were computed for all analyzed parameters.

Results

Twelve healthy male volunteers (45 ± 17 years) and 1 patient with prostate adenocarcinoma (66 years) were evaluated. The ADC map appearance depended heavily on the TI, and we observed a feature-rich ADC(TI) curve. The ADC in the transition zone (TZ) of healthy volunteers increased between TI = 60 milliseconds and approximately 1100 milliseconds, then dropped drastically before increasing again, stabilizing at a very high TI. This effect was greatly reduced in the patient's prostate cancer lesion. The 2-compartment model described this behavior well. After the inversion, tissue magnetization recovers faster, decreasing its signal contribution in absolute terms and resulting in an increase in the ADC. At the tipping point, the total magnetization is zero at b = 0, when the positive tissue magnetization and still-inverted fluid magnetization cancel out. A small diffusion encoding leads to a positive signal, thus generating an infinite ADC. After the tipping point, the fluid magnetization remains negative and thereby reduces the ADC.

Conclusions

Prostate fluid appears to contribute significantly to prostate ADCs. Its contribution could be adjusted by choosing an appropriate inversion recovery preparation, potentially enhancing contrast for prostate cancer lesions.
Surgical Simulation of Kirschner Wiring—Discussion and Review of the Newcastle Surgical Training Centre K-Wiring Course May 2024
Authors: Gundle Leo , Park Eunsoo
Published: December 2024

Simulation training has been growing in popularity, as a means to help supplement the training of surgical residents. The Newcastle Surgical Training Centre K-wiring course, a 1-day course designed for early-years surgical trainees, aims to teach essential skills in K-wire fixation for hand fractures. The course integrates lectures and hands-on practice with both simulated and cadaveric specimens, supported by a high faculty-to-delegate ratio. Despite minor limitations, such as the quality of initial hand simulators and the potential need for more radiographer support, the course provides substantial educational value and practical experience. Overall, authors found the Newcastle Surgical Training Centre K-wiring course to be a well-resourced and effective training opportunity for surgical trainees.
DOES WHOLE BLOOD RESUSCITATION INCREASE RISK FOR VENOUS THROMBOEMBOLISM IN TRAUMA PATIENTS? A COMPARISON OF WHOLE BLOOD VS COMPONENT THERAPY IN 3468 PATIENTS
Authors: Hout Brittany , Van Gent Jan-Michael , Clements Thomas , Rausa Rebecca , Kaminski Carter , Puzio Thaddeus , Rizzo Julie , Cotton Bryan
Published: December 2024

BACKGROUND

Whole blood (WB) resuscitation has been shown to provide mortality benefit. However, the impact of whole blood transfusions on the risk of venous thromboembolism (VTE) remains unclear. We sought to compare the VTE risk in patients resuscitated with WB vs component therapy (COMP).

METHODS

Trauma patients aged 18 and older, admitted to two Level 1 trauma centers between 2016 and 2021, who received at least one unit of emergency-release blood products were identified. Clinical and transfusion data were collected. Patients that received any WB during resuscitation were compared to those who received only COMP therapy. The primary outcome was VTE incidence, defined as deep vein thrombosis and/or pulmonary embolism.

RESULTS

3468 patients met inclusion criteria (WB: 1775, COMP: 1693). WB patients were more likely to be male (82 vs. 68%), receive tranexamic acid (21 vs. 16%), and had higher Injury Severity Score (ISS, 26 vs. 19; all p < 0.001). WB patients exhibited less hospital-free days (11 vs. 15), ICU-free days (23 vs. 25), and 30-day survival (74 vs. 84; all p < 0.001). The WB group had lower VTE incidence (6 vs. 10%; p < 0.001). Logistic regression revealed WB was protective against VTE (OR 0.70, 95% CI 0.54-091, p = 0.009), while RBC transfusions and TXA exposure increased VTE risk.

DISCUSSION

Using WB as part of resuscitation was associated with a 30% reduction in VTE, while TXA and RBC transfusion increased VTE risk. Further research is needed to evaluate VTE risk with empiric use of TXA in the setting of early WB transfusion capability.
The Impact of Cholecystectomy on the Metabolic Profile of Patients Previously Submitted to Bariatric Surgery
Authors: Ferraz Álvaro A. B. , Vianna Cassio F. M. , Henriques Deborah F. , Gorgulho Gustavo C. F. , Santa-Cruz Fernando , Siqueira Luciana T. , Kreimer Flávio
Published: December 2024

Purpose:

To evaluate the influence of late cholecystectomy following bariatric surgery on the postoperative evolution of weight loss and biochemical, metabolic, and micronutrient parameters.

Methods:

A retrospective study that assessed 86 patients who underwent cholecystectomy after at least 18 months of bariatric surgery. The analyzed variables included demographic data, comorbidities, weight loss, and biochemical, metabolic, and micronutrient parameters.

Results:

Among the analyzed patients, 20 underwent gastric bypass (GB) and 66 underwent sleeve gastrectomy (SG). The GB group comprised 55% of women, with a mean age of 54.4 years and a mean preoperative body mass index (BMI) of 29.2 kg/m2. The mean time elapsed between GB and cholecystectomy was 118.3±43.9 months. The sample of SG comprised 83.3% of women, with a mean age of 41.1 years and a mean preoperative BMI of 28.7 kg/m2. The mean time elapsed between SG and cholecystectomy was 26.1±17.5 months. Both SG and GB groups showed a reduction in the mean BMI, but it was not statistically significant after cholecystectomy. In the metabolic, biochemical, and micronutrient evaluation, there was no statistically significant difference, except in the GB group, where an increase in vitamin D was observed after cholecystectomy with statistical significance.

Conclusion:

Cholecystectomy does not negatively impact the clinical and anthropometric evolution of patients previously submitted to bariatric surgery.
Distinct Patterns of Socioemotional Dysfunction Relate to Aggressive Versus Nonaggressive Rule-breaking Antisocial Behaviors in Behavioral Variant Frontotemporal Dementia
Authors: Lee Jayden J. , Keener Lindsey C. , Phan Tony X. , Reeder Jerica E. , Wang Siyi , Considine Ciaran M. , Darby R. Ryan
Published: December 2024

Background:

Antisocial behaviors occur in up to 91% of individuals with behavioral variant frontotemporal dementia (bvFTD). Prior work has shown that antisocial behaviors can be differentiated into aggressive and nonaggressive rule-breaking behavioral subtypes. Socioemotional dysfunction is common in bvFTD and unique compared to other types of dementia.

Objective:

To determine whether socioemotional dysfunction relates to general antisocial behaviors in individuals with bvFTD, or whether different types of socioemotional dysfunction relate to aggressive versus rule-breaking behaviors.

Methods:

Informants for 28 participants with bvFTD and 21 participants with Alzheimer disease (AD) completed the Social Behavior Questionnaire (SBQ) and the Interpersonal Reactivity Index (IRI). The SBQ measures the presence and severity of 26 antisocial behaviors, including subscales for aggressive behaviors (SBQ-AGG) and nonaggressive rule-breaking behaviors (SBQ-RB). The IRI measures cognitive and emotional empathy capabilities, including subscales for Empathic Concern (IRI-EC) and Perspective-taking (IRI-PT).

Results:

As expected, participants with bvFTD had higher scores on the SBQ in total than participants with AD, as well as on the SBQ-AGG and SBQ-RB separately. Participants with bvFTD had lower scores on the IRI-EC and IRI-PT than participants with AD (P < 0.0001 for all measures). Lower scores on the IRI-PT correlated with higher scores on the SBQ-AGG—but not with higher scores on the SBQ-RB—across the combined group of participants (P = 0.007), and within participants in the bvFTD group (P = 0.01) specifically, after controlling for covariates of age, sex, dementia severity, and IRI-EC scores. Lower scores on the IRI-EC correlated with higher scores on the SBQ-AGG—but not with higher scores on the SBQ-RB—across the combined group of participants (P = 0.02) after controlling for covariates of age, sex, dementia severity, and IRI-PT scores.

Conclusion:

Our results suggest that socioemotional dysfunction relates to antisocial behaviors in individuals with bvFTD, but that the mechanisms leading to aggressive and rule-breaking behaviors are differentiable, providing meaningful implications for distinct approaches to treatment and prevention.
Estimation of tsunami direction and horizontal velocity field from tsunami magnetic field
Authors: Lin Zhiheng
Published: December 2024

During tsunamis, the interaction between moving seawater and the Earth’s magnetic field generates a magnetic field detectable by electromagnetic sensors located on land or on the seafloor. In this study, we introduce new methods for estimating tsunami propagation direction and horizontal velocity fields using tsunami magnetic field data. We derive a transfer function that establishes a relationship between the tsunami magnetic field and the velocity field, emphasizing the alignment between the horizontal magnetic field and the tsunami’s propagation direction. This transfer function was validated with data from the 2009 Samoa and 2010 Chile tsunamis. Our findings show that tsunami horizontal velocities and directions can be accurately determined from these magnetic fields. This advancement enables the use of tsunami magnetic fields to provide comprehensive data for tsunami warning systems and to improve the inversion of tsunami seismic sources.

This article is part of the theme issue ‘Magnetometric remote sensing of Earth and planetary oceans’.
The primate gut microbiota contributes to interspecific differences in host metabolism
Authors: Mallott Elizabeth K. , Kuthyar Sahana , Lee Won , Reiman Derek , Jiang Hongmei , Chitta Sriram , Waters E. Alexandria , Layden Brian T. , Sumagin Ronen , Manzanares Laura D. , Yang Guan-Yu , Sardaro Maria Luisa Savo , Gray Stanton , Williams Lawrence E. , Dai Yang , Curley James P. , Haney Chad R. , Liechty Emma R. , Kuzawa Christopher W. , Amato Katherine R.
Published: December 2024

Because large brains are energetically expensive, they are associated with metabolic traits that facilitate energy availability across vertebrates. However, the biological underpinnings driving these traits are not known. Given its role in regulating host metabolism in disease studies, we hypothesized that the gut microbiome contributes to variation in normal cross-vertebrate species differences in metabolism, including those associated with the brain’s energetic requirements. By inoculating germ-free mice with the gut microbiota (GM) of three primate species – two with relatively larger brains and one with a smaller brain – we demonstrated that the GM of larger-brained primates shifts host metabolism towards energy use and production, while that of smaller-brained primates stimulates energy storage in adipose tissues. Our findings establish a causal role of the GM in normal cross-host species differences in metabolism associated with relative brain size and suggest that the GM may have been an important facilitator of metabolic changes during human evolution that supported encephalization.
A novel RyR2-selective stabilizer prevents stress-induced ventricular tachycardia without compromising cardiac function
Authors: Kurebayashi Nagomi , Kodama Masami , Murayama Takashi , Konishi Masato , Sugihara Masami , Inoue Hana , Ishida Ryosuke , Ishii Koichiro , Mori Shuichi , Endo Yukari , Zeng Xi , Inoue Yukiko U. , Inoue Takayoshi , Noguchi Satoru , Nishio Hajime , Yokoyama Utako , Kurokawa Junko , Kagechika Hiroyuki , Sakurai Takashi
Published: December 2024

Aims

Excessive activation of the type 2 ryanodine receptor (RyR2) causes lethal arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Stabilization of RyR2 in the closed state is expected to prevent the occurrence of these arrhythmias, but there are no clinically available antiarrhythmic drugs that are exclusively RyR2-specific. In this study, we investigated the antiarrhythmic effect of a high-affinity and selective RyR2 modulator, Ryanozole, using CPVT mouse models harboring mutant RyR2s.

Methods and Results

In vitroeffects of Ryanozole were assessed by ER Ca2+-based assay using RyR2-expressing HEK293 cells and [3H]Ryanodine binding assay. To evaluatein situandin vivoeffects of Ryanozole, we used two lines of mice, RyR2-R420W and -K4750Q, with different arrhythmia severity. Intracellular Ca2+signals were monitored with Cal520 in isolated ventricular cardiomyocytes. Antiarrhythmic effects of Ryanozole and three typical antiarrhythmic drugs were evaluated by electrocardiography (ECG) in anesthetized R420W and K4750Q mice challenged with catecholamine and in conscious K4750Q mice that showed activity-dependent arrhythmias. Cardiac function was assessed by echocardiography before and after drug administration. Ryanozole suppressed wild type and mutant RyR2s with 15−40 nM IC50. [3H]Ryanodine binding showed that the inhibition was more potent at low [Ca2+]cytthan at high [Ca2+]cyt. In isolated cardiomyocytes, Ryanozole suppressed isoproterenol-induced Ca2+waves and sparks without affecting action potential-evoked Ca2+transients. Ryanozole effectively suppressed adrenaline-induced arrhythmias and terminated activity-dependent arrhythmias. Unlike conventional antiarrhythmic drugs, Ryanozole did neither affect ECG parameters nor impair cardiac contractility.

Conclusions

This study demonstrated that selective suppression of RyR2 alone is sufficient to prevent arrhythmias in CPVT without compromising cardiac function.

Translational perspective

Ryanozole is superior to conventional drugs in that it has potent antiarrhythmic effects without adverse effects such as cardiac contractile dysfunction and conduction delay. Ryanozole is a promising novel therapeutic candidate for the prevention and treatment of arrhythmias.
HyperMPNN – A general strategy to design thermostable proteins learned from hyperthermophiles
Authors: Ertelt Moritz , Schlegel Phillip , Beining Max , Kaysser Leonard , Meiler Jens , Schoeder Clara T.
Published: December 2024

Stability is a key factor to enable the use of recombinant proteins in therapeutic or biotechnological applications. Deep learning protein design approaches like ProteinMPNN have shown strong performance both in creating novel proteins or stabilizing existing ones. However, it is unlikely that the stability of the designs will significantly exceed that of the natural proteins in the training set, which are biophysically only marginally stable. Therefore, we collected predicted protein structures from hyperthermophiles, which differ substantially in their amino acid composition from mesophiles. Notably, ProteinMPNN fails to recover their unique amino acid composition. Here we show that a retrained network on predicted proteins from hyperthermophiles, termed HyperMPNN, not only recovers this unique amino acid composition but can also be applied to proteins from non-hyperthermophiles. Using this novel approach on a protein nanoparticle with a melting temperature of 65°C resulted in designs remaining stable at 95°C. In conclusion, we created a new way to design highly thermostable proteins through self-supervised learning on data from hyperthermophiles.
Thrifty wide-context models of B cell receptor somatic hypermutation
Authors: Sung Kevin , Johnson Mackenzie M. , Dumm Will , Simon Noah , Haddox Hugh , Fukuyama Julia , Matsen Frederick A
Published: December 2024

Somatic hypermutation (SHM) is the diversity-generating process in antibody affinity maturation. Probabilistic models of SHM are needed for analyzing rare mutations, for understanding the selective forces guiding affinity maturation, and for understanding the underlying biochemical process. High throughput data offers the potential to develop and fit models of SHM on relevant data sets. In this paper we model SHM using modern frameworks. We are motivated by recent work suggesting the importance of a wider context for SHM, however, assigning an independent rate to each k-mer leads to an exponential proliferation of parameters. Thus, using convolutions on 3-mer embeddings, we develop “thrifty” models of SHM that have fewer free parameters than a 5-mer model and yet have a significantly wider context. These offer a slight performance improvement over a 5-mer model. We also find that a per-site effect is not necessary to explain SHM patterns given nucleotide context. Also, the two current methods for fitting an SHM model — on out-of-frame sequence data and on synonymous mutations — produce significantly different results, and augmenting out-of-frame data with synonymous mutations does not aid out-of-sample performance.
MultiPopPred: A Trans-Ethnic Disease Risk Prediction Method, and its Application to the South Asian Population
Authors: Kamal Ritwiz , Narayanan Manikandan
Published: December 2024

Genome-wide association studies (GWAS) aimed at estimating the disease risk of genetic factors have long been focusing on homogeneous Caucasian populations, at the expense of other understudied non-Caucasian populations. Therefore, active efforts are underway to understand the differences and commonalities in exhibited disease risk across different populations or ethnicities. There is, consequently, a pressing need for computational methods that efficiently exploit these population specific vs. shared aspects of the genotype-phenotype relation. We propose MultiPopPred, a novel trans-ethnic polygenic risk score (PRS) estimation method, that taps into the shared genetic risk across populations and transfers information learned from multiple well-studied auxiliary populations to a less-studied target population. MultiPopPred employs a specially designed Nesterov-smoothed penalized shrinkage model and a L-BFGS optimization routine. We present three variants of MultiPopPred based on the availability of individual-level vs. summary-level data and the weightage of each auxiliary population. Extensive comparative analyses performed on simulated genotype-phenotype data reveal that MultiPopPred improves PRS prediction in the South Asian population by 65% on settings with low target sample sizes and by 21% overall across all simulation settings, when compared to state-of-the-art trans-ethnic PRS estimation methods. This performance trend is promising and encourages application and further assessment of MultiPopPred under other simulation and real-world settings.
Implementation of aClostridium luticellariigenome-scale model for upgrading syngas fermentations
Authors: Scott William T. , Rockx Siemen , Mariën Quinten , Regueira López Alberte , Candry Pieter , Ganigué Ramon , Koehorst Jasper J. , Schaap Peter J.
Published: December 2024

Syngas fermentation is a powerful platform for converting waste streams into sustainable carboxylic acid precursors for value-added biochemicals. Steel mills produce significant syngas, yet industrial microbial syngas valorization remains unrealized. The most promising syngas-converting biocat-alysts consist ofClostridiaspecies, such asClostridium kluyveri, Clostridium autoethanogenum, andClostridium ljungdahlii. Clostridium luticellarii, a recently discovered species, shares close phylogenetic ties with these organisms. Preliminary metabolic studies suggest its potential for syngas acetogenesis as well as chain elongation. In this study, we createiSJ444, a constraint-based metabolic model ofC. luticellariiusingiHN637of a close relativeC. ljungdahliias a starting point. Model predictions support hypothesized methanol and syngas pathways from the metabolic characterization studies; however, the use of propionate could not be accurately predicted. Thermodynamic Flux Analysis (TFA) reveals thatC. luticellariimaintains stable energy dissipation across most reactions when exposed to varying pH, with significant increases observed in reactions associated with the Wood-Ljungdahl pathway (WLP), such as the HACD1 reaction, at higher pH (6.5), suggesting an adaptive role in energy management under neutral conditions. Flux sampling simulations exploring metabolic flux distributions show thatC. luticellariimight fit into syngas fermenting platforms. In both cases, high hydrogen-to-carbon source ratios result in better production of (iso)butyrate and caproate. We present a minimal genome-scale metabolic model ofC. luticellariias a foundation for further exploration and optimization. Although our predictions of its metabolic behavior await experimental validation, they underscore the potential ofC. luticellariito enhance syngas fermentation platforms.

Highlights

iSJ444modelsC. luticellariimetabolism for syngas fermentation and chain elongation.

Thermodynamic flux analysis (TFA) reveals adaptive energy balancing in pathways.

Simulations highlightC. luticellariias a producer of value-added biochemicals like butyrate, isobutyrate, and caproate

Metabolic insights fromiSJ444suggest efficient syngas conversion using varied substrates for industrial use.
TheMUC5Bpromoter variant results in proteomic changes in the non-fibrotic lung
Authors: Herrera Jeremy A. , Maslanka Mark , Blumhagen Rachel Z. , Blomberg Rachel , Lwin Nyan Ye , Brancato Janna , Cool Carlyne D. , Huber Jonathan P. , Kurche Jonathan S. , Magin Chelsea M. , Hansen Kirk C. , Yang Ivana V. , Schwartz David A.
Published: December 2024

The gain-of-functionMUC5Bpromoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF lung specimens have not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry (LCM-MS), we investigated the proteomic profiles of airway and alveolar epithelium in non-fibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the presence of theMUC5Bpromoter variant. Through qualitative and quantitative analyses, as well as pathway analysis and immunohistological validation, we have identified a distinct MUC5B-associated protein profile. Notably, the non-fibrotic control alveoli exhibited substantial MUC5B-associated protein changes, with an increase of IL-3 signaling. Additionally, we found that the epithelial cells overlying IPF fibroblastic foci cluster closely to alveolar epithelia and express proteins associated with cellular stress pathways. In conclusion, our findings suggest that theMUC5Bpromoter variant leads to protein changes in alveolar and airway epithelium that appears to be associated with the initiation and progression of lung fibrosis.
Structural basis of broad protection against influenza virus by a human antibody targeting the neuraminidase active site via a recurring motif in CDR H3
Authors: Jo Gyunghee , Yamayoshi Seiya , Ma Krystal M. , Swanson Olivia , Torres Jonathan L. , Ferguson James A. , Fernandez-Quintero Monica L. , Huang Jiachen , Copps Jeffrey , Rodriguez Alesandra J. , Steichen Jon M. , Kawaoka Yoshihiro , Han Julianna , Ward Andrew B.
Published: December 2024

Influenza viruses evolve rapidly, driving seasonal epidemics and posing global pandemic threats. While neuraminidase (NA) has emerged as a vaccine target, shared molecular features of NA antibody responses are still not well understood. Here, we describe cryo-electron microscopy structures of the broadly protective human antibody DA03E17, which was previously identified from an H1N1-infected donor, in complex with NA from A/H1N1, A/H3N2, and B/Victoria-lineage viruses. DA03E17 targets the highly conserved NA active site using its long CDR H3, which features a DR (Asp-Arg) motif that engages catalytic residues and mimics sialic acid interactions. We further demonstrate that this motif is conserved among several NA active site-targeting antibodies, indicating a common receptor mimicry strategy. We also identified potential antibody precursors containing this DR motif in all donors of a healthy human donor BCR database, highlighting the prevalence of this motif and its potential as vaccine targeting. Our findings reveal shared molecular features in NA active site-targeting antibodies, offering insights for NA-based universal influenza vaccine design.
Temporal dynamics of fluorescence and photoacoustic signals of a Cetuximab-IRDye800 conjugate in EGFR-overexpressing tumors
Authors: Saad Mohammad A. , Allen Derek , Sweeney Allison , Xavierselvan Marvin , Mallidi Srivalleesha , Hasan Tayyaba
Published: December 2024

Molecular fluorescence-guided surgery has shown promise for tumor margin delineation but is limited by its depth profiling capability. Interestingly, most fluorophores, either clinically approved or in clinical trials, can also be used as photoacoustic contrast agents, yet their use is limited due to the low light fluence permitted for clinical use and the limited sensitivity of current photoacoustic imaging systems. There is therefore an urgent unmet need to establish methods for enhancing contrast in molecular targeted PA imaging which could potentially complement and overcome limitations in molecular fluorescence guided therapies. In this study, we compare the photoacoustic (PA) and fluorescence imaging capabilities of a cetuximab-IRDye800 conjugate in a subcutaneous tumor xenograft model. We demonstrate that while the fluorescence signal increases steadily over time after administration of cetuximab-IRDye800, PA signal peaks early (∼2 fold higher at 6-hour as compared to pre-injection controls) and then decreases (∼1.3 fold higher at 24-hour as compared to pre-injection controls). This pattern aligns with previous findings using other antibody-conjugated PA contrast agents. Mechanistically, we demonstrate that the formation of H-aggregates upon antibody conjugation enhances PA contrast of the IRDye800. The disruption of these H-aggregates, as the antibody-dye conjugate is degraded post receptor-mediated endocytosis, decreases PA signal intensity. The timeframe of maximum PA signal and decrease thereafter is consistent with the time frame of receptor-mediated endocytosis of cetuximab-IRDye800. Our data suggests that tumor cell surface binding results in peak PA signal while lysosomal localization and degradation results in a significant drop in PA signal. Our study sheds light on the distinct temporal dynamics of PA and fluorescence signals of Cetuximab-IRDye800 conjugate and we propose that optimizing IRDye800 conjugation to antibodies can further enhance PA signal intensity when timed to precisely to capture IRDye800 in an H-aggregate form.
A multi-level formalism to capture the characteristics of hybrid phenotypes in Epithelial-Mesenchymal Plasticity
Authors: Hari Kishore , Tripathi Shubham , Anand Vaibhav , Jolly Mohit Kumar , Levine Herbert
Published: December 2024

Epithelial-mesenchymal plasticity (EMP) is a cell-fate switching program that enables cells to adopt a spectrum of phenotypes ranging from epithelial (E) to mesenchymal (M) and hybrid E/M states. Hybrid E/M phenotypes are considered optimal for cancer metastasis due to their association with metastatic initiation and traits such as stemness, drug resistance, and collective migration. Boolean models of gene regulatory networks (GRNs) underlying EMP have provided valuable insights into the dynamics of E and M phenotypes. However, these models fail to capture hybrid phenotypes effectively, as Boolean frameworks allow only binary gene expression, while hybrid E/M cells exhibit partial expression of both E and M genes. To address this limitation, we modified a threshold-based Boolean formalism to incorporate intermediate gene expression levels. The resulting multilevel model reveals new hybrid steady states with partial expression of both E and M genes, expanding the phenotypic landscape beyond that captured by traditional Boolean models. These hybrid states exhibit lower frustration and higher abundance, indicating enhanced stability. By resolving degeneracy in the dynamics, we further demonstrate that hybrid states identified by the multilevel model are more stable. These findings suggest that adding minimal complexity to Boolean models can uncover previously hidden qualitative features of phenotypic landscapes governed by GRNs.
Integration of spatial multiplexed protein imaging and transcriptomics in the human kidney tracks the regenerative potential timeline of proximal tubules
Authors: Asghari Mahla , Sabo Angela R. , Barwinska Daria , Ferreira Ricardo Melo , Ferkowicz Michael , Bowen William S. , Cheng Ying-Hua , Gisch Debora L. , Gulbronson Connor , Phillips Carrie L , Kelly Katherine J. , Sutton Timothy A. , Williams James C , Vazquez Miguel , O’Toole John , Palevsky Paul , Rosas Sylvia E. , Waikar Sushrut S. , Kiryluk Krzysztof , Parikh Chirag , Hodgins Jeff , Sarder Pinaki , De Boer Ian H. , Himmelfarb Jonathan , Kretzler Matthias ,   Kidney Precision Medicine Project, Jain Sanjay , Eadon Michael T. , Winfree Seth , El-Achkar Tarek M. , Dagher Pierre C
Published: December 2024

The organizational principles of nephronal segments are based on longstanding anatomical and physiological attributes that are closely linked to the homeostatic functions of the kidney. Novel molecular approaches have recently uncovered layers of deeper signatures and states in tubular cells that arise at various timepoints on the spectrum between health and disease. For example, a dedifferentiated state of proximal tubular cells with mesenchymal stemness markers is frequently seen after injury. The persistence of such a state is associated with failed repair. Here, we introduce a novel analytical pipeline applied to highly multiplexed spatial protein imaging to characterize proximal tubular subpopulations and neighborhoods in reference and disease human kidney tissue. The results were validated and extended through integration with spatial and single cell transcriptomics. We demonstrate that, in reference tissue, a large proportion of S1 and S2 proximal tubular epithelial cells express THY1, a mesenchymal stromal and stem cell marker that regulates differentiation. Kidney disease is associated with loss of THY1 and transition towards expression of PROM1, another stem cell marker shown recently to be linked to failed repair. We demonstrate that the trajectory of proximal tubular cells to THY1 expression is clearly distinct from that of PROM1, and that a state with PROM1 expression is associated with niches of inflammation. Our data support a model in which the interplay between THY1 and PROM1 expression in proximal tubules associates with their regenerative potential and marks the timeline of disease progression.
Epigenetic Regulation of Inflammatory NF-κB Target Genes by IFN-γ via IRF1
Authors: Mishra Bikash , Wingert Claire , Bachu Mahesh , Ivashkiv Lionel B.
Published: December 2024

The regulation of inflammatory gene expression involves complex interactions between transcription factors (TFs), signaling pathways and epigenetic chromatin-mediated mechanisms. This study investigated mechanisms by which by IFN-γ-mediated priming augments TLR-induced expression of NF-κB target genes in primary human monocytes. IFN-γ priming enhanced the expression of signature inflammatory genes such asIL6,TNF,IL1B, andCXCL10when monocytes were exposed to various TLR agonists. RNA-seq analysis identified genes synergistically activated by IFN-γ and LPS, which were enriched in inflammatory pathways. Similar synergistic activation was observed with the TLR1/2 agonist PAM3CYS, suggesting a shared regulatory mechanism. ATAC-seq analysis revealed that TLR ligands induce IRF1 TF activity independently of IFN-γ. JAK1/2 inhibitor (iJAK) treatment reduced IRF1 expression and protein levels, especially in IFN-γ-treated monocytes, but not in LPS-stimulated monocytes, suggesting LPS-induced IRF1 may compensate for loss of IFN-γ-induced IRF1. We applied CRISPR-Cas9 to knock out IRF1 in primary human monocytes and found loss of IRF1 abrogates synergistic activation of key inflammatory genes, suggesting a pivotal role for IRF1. This genetic data was corroborated by IRF1 CUT&RUN data showing resistance of IRF1 binding to JAK inhibition under (IFN-γ + LPS) costimulated conditions, and co-occupancy of IRF1 binding sites by NF-κB. This study enhances our understanding of inflammatory gene regulation, highlighting IRF1 as a key player and a potential therapeutic target for inflammatory diseases.
Cell type-SpecificIn VivoProteomes with a Multi-copy Mutant Methionyl t-RNA Synthetase Mouse Line
Authors: Alvarez-Pardo Rodrigo , tom Dieck Susanne , Desch Kristina , Nassim Assir Belquis , Olmedo Salinas Cristina , Sivakumar Riya S. , Langer Julian D. , Alvarez-Castelao Beatriz , Schuman Erin M.
Published: December 2024

The functional diversity of cells is driven by the different proteins they express. While improvements in protein labeling techniques have allowed for the measurement of proteomes with increased sensitivity, measuring cell type-specific proteomesin vivoremains challenging. One of the most useful pipelines is bioorthogonal non-canonical amino acid tagging (BONCAT) with the MetRS* system, consisting of a transgenic mouse line expressing a mutant methionyl-tRNA synthetase (MetRS*) controlled by Cre recombinase expression. This system allows for cell type-specific labeling of proteins with a non-canonical amino acid (azidonorleucine, ANL), which can be subsequently conjugated to affinity or fluorescent tags using click chemistry. Click-modified proteins can then be visualized, purified and identified. The reduction in sample complexity allows for the detection of small changes in protein composition. Here we describe a multicopy MetRS* mouse line (3xMetRS* mouse line), which exhibits markedly enhanced ANL protein labeling, boosting the sensitivity and temporal resolution of the system and eliminating the need for working under methionine depletion conditions. Cell type-specificin vivolabeling is possible even in heterozygous animals, thus offering an enormous advantage for crossing the line into mutation and disease-specific backgrounds. Using the 3xMetRS* line we identified thein vivoproteome of a sparse cell population - the dopaminergic neurons of the olfactory bulb and furthermore determined newly synthesized proteins after short labeling durations following a single intraperitoneal ANL injection.
Birth weight discordance, gene expression, and DNA methylation: A review of epigenetic twin studies
Authors: Wadji Dany Laure , Nemoda Zsofia , Martin-Soelch Chantal , Wicky Chantal
Published: December 2024

Background

Birth weight is considered as an important indicator of environmental conditions during prenatal development. Molecular mechanisms, including epigenetic modifications play an important role in the body’s adaptation to ever changing environmental conditions. As twin design can be used to identify the role of environmental contributions while controlling for genetic variations, numerous monozygotic twin studies have shown how adverse prenatal environment can lead to birth weight discordance (BWD).

Objective

An overview of the literature about epigenetic modifications associated with BWD in twins.

Method

We searched PubMed and Ovid MEDLINE(R) databases and included 34 papers that studied associations between BWD and DNA (hydroxy)methylation or gene expression in easily accessible samples of twin pregnancies or peripheral tissues of twins later in life.

Results

Researchers and clinicians still lack consensus on BWD thresholds, which vary between 15-30% depending on the type of placentation and gestational age. The gene expression twin studies measured mostly metabolism-related candidate genes in placental tissues. Only small-scale twin studies measured BWD associated gene expression patterns on genome-wide level using neonatal cells. Most DNA methylation twin studies used epigenome-level analyses, but the analysed tissue and age of sampling varied widely (blood from adults, saliva samples from children, placenta at delivery). Importantly, a handful of growth-related genes (e.g.,IGF2,LEPROT, ADRB3,GLUT3) were associated with BWD.

Conclusion

Transcriptional changes of genes coding for placental glucose transporters and hypoxia-induced proteins possibly reflect compensatory processes in twin pregnancies. Epigenetic regulation of growth-related genes in the offspring offer a relevant mechanism to counterbalance adverse prenatal environment.

Graphical abstract

Graphical abstract/Figure 1.

(Created inhttps://BioRender.com)

Although monozygotic twins have almost the same DNA sequence (see double stranded DNA helix in the middle), there are many molecular regulatory processes differentially affected by certainin uteroenvironmental factors (such as unequal blood supply). Therefore, in a proportion of twin pregnancies, the intrauterine growth of the developing embryos is uneven, resulting in substantial birth weight difference. The underlying epigenetic alterations, such as DNA methylation changes can be long-lasting, measurable after birth and may serve as biomarkers reflecting risk for later health problems. An important technical feature is that the DNA molecule is quite stable and the methyl groups are attached covalently (shown as Me), hence methylation analyses are wide-spread in medical studies.
Inflammatory signature and restriction of adaptive immunity are associated with unfavorable outcomes on immune checkpoint blockade in patients with advanced head and neck squamous cell carcinoma
Authors: Paschold Lisa , Schultheiss Christoph , Schmidt-Barbo Paul , Klinghammer Konrad , Hahn Dennis , Tometten Mareike , Schafhausen Philippe , Blaurock Markus , Brandt Anna , Westgaard Ingunn , Kowoll Simone , Stein Alexander , Hinke Axel , Binder Mascha
Published: December 2024

Background

In most patients with relapsed or metastatic head and neck squamous cell carcinoma (rmHNSCC), immunotherapy with PD-1 targeting antibodies does not yield durable responses. PD-L1 tissue expression - the most commonly assessed marker for checkpoint inhibiting antibodies - is an insufficient predictor of treatment outcome.

Methods

We evaluated various blood and tissue-based biomarkers in the context of immune checkpoint blockade-based treatment to find suitable response biomarkers in a clinical trial cohort of patients with rmHNSCC.

Results

The PD-L1 expression level in tumor or tumor microenvironment was not associated with treatment benefit. In contrast, inflammation-related markers such as IL-6, high peripheral neutrophils and high levels of cell-free DNA, as well as markers related to adaptive immune dysfunction such as altered T cell dynamics and secretion of immune checkpoint molecules, were associated with poor clinical outcomes. Patients lacking these high-risk markers performed remarkably well on inhibition of immune checkpoints with pembrolizumab.

Conclusions

Biomarker-guided patient selection for pembrolizumab monotherapy or novel combinatorial approaches - potentially including anti-inflammatory agents – for patients with immune-impaired, inflammatory profiles may be the next step in personalizing immunotherapy for these hard-to-treat patients.
Investigating Nutritional Interventions for Managing Irritable-Bowel Syndrome: A Bibliometric Analysis
Authors: Mal Madho , Arshad Faraz , Iftikhar Sadaf , Tummala Nayanika , Waqas Saad Ahmed , Kamal Usama Hussain , Noor Rizwana , Afridi Muhammad Khalid , Ali Abraish
Published: December 2024

Background

The bibliometric analysis provides a structured approach for providers and researchers to access clinically relevant information to improve patient care.

Methods

We used SCOPUS as our database and made a list of the top 50 most-cited articles from 2002 to 2022. Variables analyzed included citation count, annual citations, publication year, journal with impact factor, author details, country, institution, and funding.

Results

Citations for 50 articles varied from 67 to 919, with a median of 129 and an IQR of 210. Most of the articles (n = 34) were published between 2013 and 2018. The number of authors per article ranged from 3 to 18. Munir J.G. coauthored the most significant number of articles (n = 7). The top countries of origin for the articles were the UK (n = 15), the USA (n = 10), and Australia (n = 7). The dietary interventions discussed in our list included low FODMAP (n = 27), probiotics (n = 6), GFD (n = 4), an Ig4 exclusion diet (n = 3), and other interventions (n = 10). Female authors were the first authors in 30 articles and senior authors in 19 articles, compared to their male counterparts.

Conclusions

An analysis of the top 50 cited articles on nutritional interventions in IBS highlights interest and impact trends, aiding policymakers in funding decisions. The predominance of a low-FODMAP diet underscores the focus on efficacy, potentially guiding standardized dietary guidelines.
Antimicrobial resistance of bacteria isolates among patients with chronic wound infections in Tanga Regional Referral Hospital, Tanzania
Authors: Dawer Aleena , Msengi Victor , Mtui Theresia B. , Sarakikya Sarah , Suleiman Rashid , Lusingu John P. A.
Published: December 2024

Background

Bacterial wound infections are the second leading cause of mortality globally, with approximately 50% of contaminated wounds evolving into chronic infections. In Tanzania, this challenge is exacerbated by the over prescription of antibiotics and the emergence of drug-resistant bacteria, compounded by inadequate hospital hygiene and sanitation practices. This study investigated chronic wound infections in Tanga, Tanzania, focusing on antibiotic susceptibility patterns.

Methods

A cross-sectional, mixed-methods study was conducted at the Tanga Regional Referral Hospital (TRRH) from July 2023 to December 2023. Pus and Culture Sensitivity tests were performed on samples from 89 chronic wound patients to identify bacterial isolates and assess antibiotic susceptibility. Data was analyzed using STATA, Excel, and Python.

Results

Of 89 patients, 82 (92.1%) had positive bacterial isolates in wound cultures, predominantly withStaphylococcus aureus,24 (29.3%). Surgical-site infections (SSI) were the most prevalent diagnosis, followed by diabetic foot ulcers and septic wounds. Antibiotic resistance analysis revealed a marked trend in multi-drug resistance (MDR), notably against amoxicillin, while meropenem was identified as the most effective antibiotic.

Conclusion

The elevated rate of MDR at TRRH, particularly against commonly used antibiotics, emphasizes the need for improved antibiotic stewardship and healthcare worker education. It necessitates increased health awareness about effective wound management and the development of robust healthcare strategies to combat the escalating challenge of MDR.
NuMA mechanically reinforces the spindle independently of its partner dynein
Authors: Cho Nathan H. , Aslan Merve , Yildiz Ahmet , Dumont Sophie
Published: December 2024

Both motor and non-motor proteins organize microtubules to build the spindle and maintain it against opposing forces. NuMA, a long microtubule binding protein, is essential to spindle structure and function. NuMA recruits the motor dynein to spindle microtubule minus-ends to actively cluster them, but whether NuMA performs other spindle roles remains unknown. Here, we show that NuMA acts independently of dynein to passively reinforce the mammalian spindle. NuMA that cannot bind dynein is sufficient to protect spindle poles against fracture under external force. In contrast, NuMA with a shorter coiled-coil or disrupted self-interactions cannot protect spindle poles, and NuMA turnover differences cannot explain mechanical differences.In vitro, NuMA’s C-terminus self-interacts and bundles microtubules without dynein, dependent on residues essential to pole protectionin vivo. Together, this suggests that NuMA reinforces spindle poles by crosslinking microtubules, using its long coiled-coiled and self-interactions to reach multiple, far-reaching pole microtubules. We propose that NuMA acts as a mechanical “multitasker” targeting contractile motor activity and separately crosslinking microtubules, both functions synergizing to drive spindle mechanical robustness.