bluuebunny/crossref_metadata_2025 huggingface dataset:
TNFR2 blockade promotes anti-tumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion
Authors: Debesset A. , Pilon C. , Meunier S. , Bonizec O. , Richer W. , Thiolat A. , Houppe C. , Ponzo M. , Magnan J. , Caudana P. , Tosello Boari Jimena , Baulande Sylvain , To N.H. , Salomon B.L. , Piaggio E. , Cascone I. , Cohen J.L.
Published: January 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing TNFα receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in PDAC patients. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing anti-tumoral responses.

Method

To support this hypothesis, we first described TNFR2 expression in a cohort of 24 PDAC patients from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as effect on tumor progression.

Results

PDAC patients exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells but low level in ductal cells. By flow cytometry and single cell RNAseq analysis, we identified two Treg populations in orthotopic mouse models: resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAbs promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice.

Conclusion

Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for PDAC patients.
Constitutive sodium permeability in aC. eleganstwo-pore domain potassium channel
Authors: Andrini O , Ben Soussia I , Tardy P , Walker DS , Peña-Varas C , Ramírez D , Gendrel M , Mercier M , El Mouridi S , Leclercq-Blondel A , González W , Schafer WR , Jospin M , Boulin T
Published: January 2024

Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematodeC. eleganshas one of the largest K2P families, with 47 subunit-coding genes. This remarkable expansion has been accompanied by the evolution of atypical selectivity filter sequences that diverge from the canonical TxGYG motif. Whether and how this sequence variation may impact the function of K2P channels has not been investigated so far. Here we show that the UNC-58 K2P channel is constitutively permeable to sodium ions and that a cysteine residue in its selectivity filter is responsible for this atypical behavior. Indeed, by performingin vivoelectrophysiological recordings and Ca2+imaging experiments, we demonstrate that UNC-58 has a depolarizing effect in muscles and sensory neurons. Consistently,unc-58gain-of-function mutants are hypercontracted, unlike the relaxed phenotype observed in hyperactive mutants of many neuromuscular K2P channels. Finally, by combining molecular dynamics simulations with functional studies inXenopus laevisoocytes, we show that the atypical cysteine residue plays a key role in the unconventional sodium permeability of UNC-58. As predicting the consequences of selectivity filter sequence variationsin silicoremains a major challenge, our study illustrates how functional experiments are essential to determine the contribution of such unusual potassium channels to the electrical profile of excitable cells.

SIGNIFICANCE

Potassium channels play a central role in modulating cellular excitability, particularly of neuronal cells. Their unique structure determines their ability to let ions pass selectively through cell membranes. The impact of pathological or evolutionary variations in this selectivity filter remains difficult to predict. Here, we reveal that UNC-58, a member of the two-pore domain potassium channel family ofC. elegans, exhibits an unusual sodium permeability due to a unique cysteine residue in its selectivity filter. Our findings underscore the importance of functional studies to determine how sequence variation in potassium channel selectivity filters can shape the electrical profiles of excitable cells.
The ecological relevance of flagellar motility in soil bacterial communities
Authors: Ramoneda Josep , Fan Kunkun , Lucas Jane M. , Chu Haiyan , Bissett Andrew , Strickland Michael S. , Fierer Noah
Published: January 2024

Flagellar motility is a key bacterial trait as it allows bacteria to navigate their immediate surroundings. Not all bacteria are capable of flagellar motility, and the distribution of this trait, its ecological associations, and the life history strategies of flagellated taxa remain poorly characterized. We developed and validated a genome-based approach to infer the potential for flagellar motility across 12 bacterial phyla (26,192 genomes in total). The capacity for flagellar motility was associated with a higher prevalence of genes for carbohydrate metabolism and higher maximum potential growth rates, suggesting that flagellar motility is more prevalent in resource-rich environments due to the energetic costs associated with this trait. To test this hypothesis, we focused on soil bacterial communities, where flagellar motility is expected to be particularly important given the heterogeneous nature of the soil environment. We applied a method to infer the prevalence of flagellar motility in whole bacterial communities from metagenomic data, and quantified the prevalence of flagellar motility across 4 independent field studies that each captured putative gradients in soil carbon availability (148 metagenomes). As expected, we observed a positive relationship between the prevalence of bacterial flagellar motility and soil carbon availability in each of these datasets. Given that soil carbon availability is often correlated with other factors that could influence the prevalence of flagellar motility, we validated these observations using metagenomic data acquired from a soil incubation experiment where carbon availability was directly manipulated with glucose amendments, confirming that the prevalence of bacterial flagellar motility is consistently associated with soil carbon availability over other potential confounding factors. Flagellar motility is a fundamental phenotypic trait for bacterial adaptation to soil, defining life history strategies primarily associated with resource availability. More generally, this work highlights the value of combining genomic and metagenomic approaches to expand our understanding of microbial phenotypic traits and reveal their general environmental associations.
In VitroNeutrophil-Bacteria Assay in Whole Blood Microenvironments with Single-Cell Confinement
Authors: Li Chao , Hendrikse Nathan W. , Argall-Knapp Zach , Mai Makenna , Kim Jun Sung
Published: January 2024

Blood is a common medium through which invasive bacterial infections disseminate in the human body.In vitroneutrophil-bacteria assays allow flexible mechanistic studies and screening of interventional strategies. In standard neutrophil-bacteria assays, both the immune cells and microorganisms are typically interrogated in an exogenous, homogeneous, bulk fluid environment (e.g., culture media or bacterial broth in microtiter plates), lacking the relevant physicochemical factors in the heterogenous blood-tissue microenvironment (e.g., capillary bed) with single-cell confinement. Here we present anin vitroneutrophil-bacteria assay by leveraging an open microfluidic model known as “μ-Blood” that supports sub-microliter liquid microchannels with single-cell confinement. In this study we compare the exogenous and endogenous fluids including neutrophils in RPMI (standard suspension cell culture media) and whole blood in response toStaphylococcus aureus(S. aureus, a gram-positive, non-motile bacterium) in phosphate buffered saline (PBS), Mueller Hinton Broth (MHB), and human serum. Our results reveal a significant disparity between the exogenous and endogenous fluid microenvironments in the growth kinetics of bacteria, the spontaneous generation of capillary (i.e., Marangoni) flow, and the outcome of neutrophil intervention on the spreading bacteria.
Accounting for Twins and Other Multiple Births in Perinatal Studies Conducted Using Healthcare Administration Data
Authors: Brown Jeremy P , Yland J Jennifer J , Williams Paige L , Huybrechts Krista F , Hernández-Díaz Sonia
Published: January 2024

The analysis of perinatal studies is complicated by twins and other multiple births even when they are not the exposure, outcome, or a confounder of interest. Common approaches to handling multiples in studies of infant outcomes include restriction to singletons, counting outcomes at the pregnancy-level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and, typically, accounting for clustering of outcomes by using generalised estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different causal questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example. Furthermore, we provide guidance on the handling of multiples in perinatal studies when using healthcare administration data.
Safety and efficacy of management for intraprocedural rupture during endovascular treatment for intracranial aneurysms
Authors: Hirai Sakyo , Hanazawa Ryoichi , Yoshimura Masataka , Shigeta Keigo , Sato Yohei , Taira Naoki , Kawano Yoshihisa , Karakama Jun , Obata Yoshiki , Hara Mutsuya , Yamada Kenji , Ishii Yosuke , Sawada Kana , Imae Shogo , Wakabayashi Hikaru , Sagawa Hirotaka , Fujita Kyohei , Fujii Shoko , Takahashi Satoru , Hirakawa Akihiro , Nemoto Shigeru , Sumita Kazutaka
Published: January 2024

Background

Although intraprocedural rupture (IPR) is rare, it is a devastating complication of endovascular treatment (EVT) for intracranial aneurysms. Very few studies have been conducted on IPR, and the safety and efficacy of management techniques of IPR have not been investigated.

Methods

Patients who underwent IPR during EVT between 2013 and 2022 were enrolled from the multicenter observational registry. Focusing on the management of IPR, we examined its safety and efficacy using imaging markers, including increased hemorrhage and ischemic lesions evaluated using postoperative computed tomography and diffusion-weighted imaging, respectively.

Results

Of the 3269 EVT for intracranial aneurysms, 74 patients who underwent IPR (2.26%) were analyzed. Fifty-five patients (3.36%) experienced IPR in 1636 EVT cases for ruptured aneurysms. The multivariate analysis revealed that increased hemorrhage was significantly associated with poor outcomes (odds ratio [OR], 6.67 [95% confidence interval (CI), 1.07–41.44], p=0.042), whereas ischemic lesions were not. Regarding management techniques of IPR, antihypertensive medication use was significantly associated with increased hemorrhage (OR, 13.17 [95% CI, 2.26–76.69], p=0.004). Heparin reversal was an independent factor for ischemic lesions (OR, 4.81 [95% CI, 1.09–21.14], p=0.038).

Conclusions

Even though the setting of IPR may be miscellaneous, and optimal management varies depending on individual cases, heparin reversal might be associated with ischemic complications rather than being useful for controlling bleeding in IPR during EVT for ruptured aneurysms.
Zebrafish eye development and function is affected by crude oil exposure – line of evidence from underlying molecular effects to behavioral consequences
Authors: Mueller Leonie K. , Johann Sarah , Denecke Bernd , Abdallah Ali T. , Hecker Markus , Hollert Henner , Seiler Thomas-Benjamin
Published: January 2024

Crude oil can affect the normal eye development and swimming behavior of fish embryos. In this study 0-4 hours post fertilization (hpf) zebrafish (Danio rerio) embryos were exposed to low, sublethal concentrations of water-accommodated fractions (WAF) of a naphthenic North Sea crude oil alone and in combination with a third-generation chemical dispersant. Effects on eye development and function at the transcript, histological, morphological, and behavioral level were assessed relative to untreated control specimen at 119 hpf. Exposed embryos swam significantly less during the dark phases of the light/dark transition test. Eye size of zebrafish embryos was significantly smaller in groups exposed to crude oil WAFs. Zebrafish retina histology revealed that, among other structural alterations, the outer nuclear layer, containing photoreceptor cells relevant for normal visual functioning, was significantly thinner in exposed embryos. Transcriptome analysis revealed that several genes involved in eye development and function (opsins and crystallins) were dysregulated upon oil exposure. The molecular effects on gene expression and eye histology results form a novel line of evidence that explains the observed effects of crude oil on the swimming activity of exposed fish embryos. The present study is in line with recent findings highlighting the importance of ocular toxicity in developing embryos exposed to petroleum samples at environmentally relevant and non-lethal concentrations without visible malformations. The study suggests that oculotoxicity should be considered as a major toxicity pathway alongside to the well-established cardiotoxicity.
AutScore– An integrative scoring approach for prioritization of ultra-rare autism spectrum disorder candidate variants from whole exome sequencing data
Authors: Shil Apurba , Arava Noa , Levi Noam , Levine Liron , Golan Hava , Meiri Gal , Michaelovski Analya , Tsadaka Yair , Aran Adi , Menashe Idan
Published: January 2024

Background

Discerning clinically relevant ASD candidate variants from whole-exome sequencing (WES) data is complex, time-consuming, and labor-intensive. To this end, we developedAutScore, an integrative prioritization algorithm of ASD candidate variants from WES data, and assessed its performance to detect clinically relevant variants.

Methods

We studied WES data from 581 ASD probands, and their parents registered in the Azrieli National Center database for Autism and Neurodevelopment Research. We focused on rare allele frequency <1%), high-quality proband-specific variants affecting genes associated with ASD or other neurodevelopmental disorders (NDDs). We assigned a score (i.e.,AutScore) to each such variant based on their pathogenicity, clinical relevance, gene-disease association, and inheritance patterns. Finally, we compared theAutScoreperformance with the rating of clinical experts and the NDD variants prioritization algorithm,AutoCasC.

Results

Overall, 1161 ultra-rare variants distributed in 687 genes in 441 ASD probands were evaluated byAutScorewith scores ranging from -4 to 25, with a mean ± SD of 5.89 ± 4.18.AutScorecut-off of ≥ 12 outperformsAutoCasCin detecting clinically relevant ASD variants, with a detection accuracy rate of 72.3% and an overall diagnostic yield of 11.9%. Sixteen variants withAutScoreof ≥ 12 were distributed in fifteen novel ASD genes.

Conclusion

AutScoreis an effective automated ranking system for ASD candidate variants that could be implemented in ASD clinical genetics pipelines.
An International, Cross-Sectional Survey of Psychiatry Researchers and Clinicians: Perceptions of Complementary, Alternative, and Integrative Medicine
Authors: Ng Jeremy Y. , Kochhar Jassimar , Cramer Holger
Published: January 2024

Background

Psychiatry is a branch of medicine that focuses on mental, behavioural and emotional well-being. Complementary, alternative, and integrative medicine has been an increasingly popular choice for patients with psychiatric disorders, therefore our study aimed to explore the perceptions of psychiatry researchers and clinicians on the use of CAIM.

Methods

We conducted an online, anonymous, cross-sectional survey for researchers and clinicians who have published their work in psychiatry medical journals that are indexed in MEDLINE. 42,667 researchers and clinicians were sent the link to the survey after extraction of their email addresses from their respective publications. Respondents were asked numerous multiple-choice questions regarding their perceptions on various CAIM therapies, followed by an open-ended question where they could include any additional thoughts.

Results

The survey was completed by 987 respondents, with a majority identifying as a researcher (n=447, 46.51%), or as both a researcher and a clinician (n=368, 38.29%) within the field of psychiatry. Most respondents (n=629, 78.04%) perceived mind-body therapies such as meditation, biofeedback, hypnosis, and yoga to be the most promising CAIM therapy for the prevention, treatment, and management of psychiatric diseases. Many participants said that they agree (n=285, 38.14%) that most CAIM therapies in general are safe, however, many disagree that CAIM therapies are effective (n=245, 32.93%). Respondents indicated that there is value to conducting research on CAIM therapies (n=356, 47.91%), and that there should be more funding allocated to researching these therapies (n=265, 35.71%). Respondents are also in agreement that clinicians should receive training on CAIM therapies through formal education (n=295, 39.76%) or supplementary education (n=380, 51.28%).

Conclusions

The findings from this study showed that there is great interest and potential in researching CAIM within the field of psychiatry. This information can be used as a basis for further research and to develop tailored educational resources for researchers and clinicians in psychiatry.
Immunogenicity and vaccine-serotype carriage prevalence after full or fractional doses of Pneumococcal Conjugate Vaccines in Kenyan infants: an individually randomised, controlled, non-inferiority trial
Authors: Gallagher Katherine E. , Lucinde Ruth , Bottomley Christian , Kaniu Mary , Suaad Badaud , Mutahi Mary , Mwalekwa Laura , Ragab Sarah , Twi-Yeboah Louise , Berkley James A. , Hamaluba Mainga , Karani Angela , Shangala Jimmy , Otiende Mark , Gardiner Elizabeth , Mugo Daisy , Smith Peter G. , Tabu Collins , Were Fred , Goldblatt David , Scott FMedSci J. Anthony G.
Published: January 2024

Background

Pneumococcal conjugate vaccines (PCVs) are the most expensive component of the routine immunisation schedule in Gavi-supported countries. As countries transition out of Gavi support, PCV programmes are at risk. We assessed whether immunogenicity was non-inferior after fractional doses of PCV10 (GlaxoSmithKline plc.) or PCV13 (Pfizer Inc.), when compared to full doses, and analysed vaccine serotype (VT) carriage prevalence.

Methods

2100 healthy infants were enrolled and randomised into seven equal-sized trial arms. Doses were delivered in the 2p+1 schedule (6, 14 weeks and 9-12 months) in six trial arms: A) Full dose PCV13, B) 40%-PCV13, C) 20%-PCV13, D) Full dose PCV10, E) 40%-PCV10, F) 20%-PCV10. Participants in the seventh trial arm received full dose PCV10 at 6, 10 and 14 weeks. Immunogenicity was assessed 4-weeks post-prime and 4-weeks post-boost. Carriage was assessed at 9 and 18 months of age.

Results

In the per-protocol analysis, 40%-PCV13 met the non-inferiority criteria for 12/13 serotypes post-prime and 13/13 serotypes post-boost. 20%-PCV13 met the criteria for 9/13 serotypes post-prime and 10/13 serotypes post-boost. 40%-PCV10 met the criteria for 8/10 serotypes post-prime and 6/10 serotypes post-boost. 20%-PCV10 met the criteria for 7/10 serotypes post-prime and 1/10 serotype post-boost.

Conclusions

A 3-dose schedule of 40%-PCV13 met the non-inferiority criteria at both timepoints and could be implemented by using 4-dose UNICEF vials as 10-dose vials. A 3-dose schedule of 40%-PCV13 would cost UNICEF 3.30 USD and represents the most affordable, effective PCV schedule option currently available for countries transitioning out of Gavi-support.ClinicalTrials.govID:NCT03489018.
Validity and reproducibility of a culturally tailored dietary screening tool for hypertension risk in Nigerian healthcare
Authors: Batubo Nimisoere P. , Auma Carolyn I. , Moore J. Bernadette , Zulyniak Michael A.
Published: January 2024

Food frequency questionnaires (FFQ) are commonly used tools in dietary assessment but require validation. This study aimed to assess the relative validity and reproducibility of a culturally tailored FFQ for estimating food intake among Nigerian adults in clinical settings. The FFQ was administered to 58 patients at the Rivers State University Teaching Hospital, Nigeria, on two occasions, two weeks apart. Three repeat non-consecutive 24-hour dietary recalls (24DR) were also conducted as a reference method to evaluate the validity of the FFQ. Spearman’s rank correlations, Wilcoxon signed-rank tests, cross-classification agreement, intraclass correlation coefficients (ICC), and Bland-Altman analysis were performed in R to evaluate the relative validity and reproducibility. The trial was registered withClinicalTrials.gov:NCT05973760. The correlation coefficient (rs) between the FFQ and 24DR ranged from 0.20 for ‘fats and oils’ to 0.78 for vegetables, with an averagersof 0.60 (p<0.05). The Wilcoxon signed-rank tests indicated no significant differences in the 19 food groups queried (p>0.05), except for fats and oils (p<0.05). The exact agreement between FFQ and 24DR for classifying individuals into quartiles ranged from 17% for salt to 88% for processed meats and alcoholic drinks, with 90% of individuals classified into the same or neighbouring quartile. Additionally, the Bland-Altman analysis demonstrated acceptable agreement, with > 96% of observations within the acceptable limits of agreement for all food groups. For reproducibility, the ICC ranged from 0.31 for stew to 0.98 for fruit, with an average ICC of 0.77 between the FFQs delivered two weeks apart. These data demonstrate good agreement between our culturally tailored FFQ and 24DR, and moreover, robust reproducibility for quantifying intakes of food groups associated with hypertension in Nigeria. This confirms that this novel FFQ is a valid and reliable tool for assessing the intake of key food groups among Nigerian adults.
Modelling the Impact of Obesity Reduction on the Prevalence of Hypertension in India: A Discrete-Event Microsimulation Approach
Authors: Mustafa Akif
Published: January 2024

Obesity is one of the most significant risk factors of non-communicable diseases, disability, and premature death. Due to its profound impact on health, researchers have started classifying it as a disease rather than a mere abnormality. India, following the global trend, is experiencing a surge in obesity prevalence, posing a critical research question about the potential impact of obesity reduction on NCD incidence and related disorders. This study employs discrete-event dynamic microsimulation modelling to investigate how changes in BMI distribution in early years of life can influence the prevalence of hypertension, one of the most prevalent diseases in India. The microsimulation modelling approach enables the simulation of individual-level real-life behaviors and interactions within a given population. The model simulated the lives of 100,000 individuals aged 20 over the next 50 years till age 70. Baseline characteristics, prevalence rates, and transition probabilities were derived from diverse data sources, including Census 2011, the National Family Health Survey - V (NFHS-5), and the Longitudinal Aging Study in India (LASI, 2017-18). The study explores the impact of two scenarios on hypertension prevalence: (i) a one-unit reduction in mean BMI level at baseline, and (ii) a one-unit reduction in the standard deviation of BMI distribution at baseline. Results indicate that a one-unit reduction in mean BMI level at baseline could lead to a 5% reduction in hypertension prevalence at age 70, while a one-unit reduction in the standard deviation of BMI distribution at baseline could result in a 7.5% reduction. These findings underscore the importance of targeting children and adolescents with elevated BMI values to mitigate the later-life prevalence of hypertension. Additionally, the study highlights the significance of promoting the use of microsimulation modelling in health research in the Indian context.
N-terminal signals in the SNX-BAR paralogs Vps5 and Vin1 guide coat complex formation
Authors: Shortill Shawn P. , Frier Mia S. , Davey Michael , Conibear Elizabeth
Published: January 2024

Endosomal coat complexes assemble by incorporating membrane-binding subunits such as those of the sorting nexin (SNX) family. TheS. cerevisiaeSNX-BAR paralogs Vin1 and Vps5 are respective subunits of the endosomal VINE and retromer complexes that arose from a fungal whole genome duplication. Interactions mediated by the Vin1 and Vps5 BAR domains are required for protein complex assembly and membrane association. However, a degree of promiscuity is predicted for yeast BAR-BAR pairings, suggesting that another mechanism guides the formation of specific endosomal coat complexes. Previous work by our group and others has implicated the unstructured N-terminal domains of Vin1 and Vps5 in complex assembly. Here, we map N-terminal signals in both SNX-BAR paralogs that contribute to the formation and function of two distinct endosomal coatsin vivo. Whereas Vin1 leverages a polybasic region and adjacent hydrophobic motif to bind Vrl1 and form VINE, the N-terminus of Vps5 interacts with the retromer subunit Vps29 at two separate sites. We show that one of these Vps5 motifs binds to a conserved hydrophobic pocket in Vps29 that is shared with other accessory proteins and targeted by a bacterial virulence factor in humans. Lastly, we examined the sole isoform of Vps5 from the milk yeastK. lactisand found that ancestral yeasts may have used a nested N-terminal signal to form both VINE and retromer. Our results suggest that the specific assembly of Vps5-family SNX-BAR coats depends on inputs from unique N-terminal sequence features in addition to BAR domain coupling, expanding our understanding of endosomal coat assembly mechanisms.
Automatic, web-based typing ofClostridioides difficileribotypes using MALDI-TOF MS
Authors: Blázquez-Sánchez Mario , Guerrero-López Alejandro , Candela Ana , Belenguer-Llorens Albert , Moreno José Miguel , Sevilla-Salcedo Carlos , Sánchez-Cueto María , Arroyo Manuel J. , Gutiérrez-Pareja Mark , Gómez-Verdejo Vanessa , Olmos Pablo M. , Mancera Luis , Muñoz Patricia , Marín Mercedes , Alcalá Luis , Rodríguez-Temporal David , Rodríguez-Sánchez Belén ,   the AutoCdiff Study Group, Martínez Mariela , Verdú Cristina , Soliveri Juan , Cuadros Juan , Pérez Felipe , Nieto Alberto , Ruiz Luís Moisés , Simón María , López Joan , Cuevas Óscar , Ezpeleta Carmen , Illescas Soledad
Published: January 2024

Clostridioides difficileis a major cause of hospital-acquired diarrhea, posing significant clinical challenges due to its high morbi-mortality rates and its involvement in nosocomial outbreaks. Detecting its toxigenic ribotypes rapidly and accurately is crucial for effective outbreak control. This study aimed to create a rapid diagnostic methodology based on MALDI-TOF MS and Machine Learning algorithms to differentiate toxigenicC. difficileRTs.

MALDI-TOF spectra were acquired from 379 clinical isolates sourcing from 10 Spanish hospitals and analysed using Clover MSDAS, a specific software for MALDI-TOF spectra analysis, considered as the state-of-the-art tool for this purpose, and AutoCdiff, anad hocsoftware developed in this study.

Seven biomarker peaks were found to differentiate epidemic RT027 and RT181 strains from other RTs (2463, 3353, 4933, 4993, 6187, 6651 and 6710m/z). Two peaks (2463 and 4993m/z) were specifically found in RT027 isolates while combinations of the other 5 peaks allowed the differentiation of RT181 from other ribotypes. Automatic classification tools developed in Clover MSDAS and AutoCdiff using the specific peaks and the entire protein spectra, respectively, showed up to 100% balanced accuracy. Both methods allowed correct ribotype assignment for isolates sourcing from real-time outbreaks.

The developed models, available from Clover MSDAS and the AutoCdiff website -https://bacteria.id-offerresearchers a valuable tool for quickC. difficileribotype determination based on MALDI-TOF spectra analysis. Although further validation of the models is still required, they represent rapid and cost-effective methods for standardizedC. difficileribotype assignment.
Dissociable neural signals for reward and emotion prediction errors
Authors: Heffner Joseph , Frömer Romy , Nassar Matthew R. , FeldmanHall Oriel
Published: January 2024

Reinforcement learning models focus on reward prediction errors (PEs) as the driver of behavior. However, recent evidence indicates that deviations from emotion expectations, termed affective PEs, play a crucial role in shaping behavior. Whether there is neural separability between emotion and reward signals remains unknown. We employ electroencephalography during social learning to investigate the neural signatures of reward and affective PEs. Behavioral results reveal that while affective PEs predict choices when little is known about how a partner will behave, reward PEs become more predictive overtime as uncertainty about a partner’s behavior diminishes. This functional dissociation is mirrored neurally by engagement of distinct event-related potentials. The FRN indexes reward PEs while the P3b tracks affective PEs. Only the P3b predicts subsequent choices, highlighting the mechanistic influence of affective PEs during social learning. These findings present evidence for a neurobiologically viable emotion learning signal that is distinguishable—behaviorally and neurally—from reward.

Significance

For nearly a century, scientists have asked how humans learn about their worlds. Learning models borrowed from computer science—namely, reinforcement learning—provide an elegant and simple framework that showcases how reward prediction errors are used to update one’s knowledge about the environment. However, a fundamental question persists: what exactly is ‘reward’? This gap in knowledge is problematic, especially when we consider the multiplicity of social contexts where external rewards must be contextualized to gain value and meaning. We leverage electroencephalography to interrogate the role of emotion prediction errors—violations of emotional expectations—during learning. We observe distinct neural signals for reward and emotion prediction errors, suggesting that emotions may act as a bridge between external rewards and subjective value.
Operational performance of crystal collimation with 6.37
Z
TeV Pb ion beams at the LHC
Authors: D’Andrea M. , Aberle O. , Bruce R. , Butcher M. , Di Castro M. , Cai R. , Lamas I. , Masi A. , Mirarchi D. , Redaelli S. , Rossi R. , Scandale W.
Published: January 2024

The concept of crystal collimation relies on the use of bent crystals to coherently deflect positively charged particles with suitable impact conditions by trapping them in the potential well generated by adjacent crystalline planes. The resulting deflection is much higher than what can be achieved by multiple scattering on amorphous materials. For this reason, this technique has been explored in the past decades for applications to particle accelerators. In particular, a full test stand was installed in the betatron collimation insertion of the Large Hadron Collider (LHC) to explore applications to hadron beam collimation. This setup was extensively studied in Run 2 (2015–2018), as a way to improve the cleaning performance of the machine in particular with Pb ion beams, in view of the more challenging parameters envisaged for the High Luminosity upgrade (HL-LHC). This paper reports the results of measurements performed with Pb ion beams, demonstrating the capability of crystal collimation to improve the cleaning performance at the LHC. These results supported the integration of this advanced technology in the baseline upgrade program for HL-LHC.

Published by the American Physical Society
2024
Neutrino phenomenology in a model with generalized
CP
symmetry within type-I seesaw framework
Authors: Tapender  , Kumar Sanjeev , Verma Surender
Published: January 2024

We investigate the consequences of generalized CP (GCP) symmetry within the context of the two Higgs doublet model (2HDM), specifically focusing on the lepton sector. Utilizing the type-I seesaw framework, we study an intriguing connection between the Dirac Yukawa couplings originating from both Higgs fields, leading to a reduction in the number of independent Yukawa couplings and simplifying the scalar and Yukawa sectors when compared to the general 2HDM. The constraints coming from CP symmetry of class three (CP3) results in two right-handed neutrinos having equal masses and leads to a diagonal right-handed Majorana neutrino mass matrix. Notably, CP symmetry experiences a soft breaking due to the phase associated with the vacuum expectation value of the second Higgs doublet. The model aligns well with observed charged lepton masses and neutrino oscillation data, explaining both masses and mixing angles, and yields distinct predictions for normal and inverted neutrino mass hierarchies. It features a novel interplay between atmospheric mixing angle θ23 and neutrino mass hierarchy: The angle θ23 is below maximal for the normal hierarchy and above maximal for inverted hierarchy. Another interesting feature of the model is inherent CP violation for the inverted hierarchy.

Published by the American Physical Society
2024
Winos from natural SUSY at the high luminosity LHC
Authors: Baer Howard , Barger Vernon , Tata Xerxes , Zhang Kairui
Published: January 2024

In natural supersymmetric models defined by no worse than a part in thirty electroweak fine-tuning, winos and binos are generically expected to be much heavier than Higgsinos. Moreover, the splitting between the Higgsinos is expected to be small, so that the visible decay products of the heavier Higgsinos are soft, rendering the Higgsinos quasi-invisible at the LHC. Within the natural supersymmetry (SUSY) framework, heavy electroweak gauginos decay to W, Z or h bosons plus Higgsinos in the ratio ∼2∶1∶1, respectively. This is in sharp contrast to models with a binolike lightest superpartner and very heavy Higgsinos, where the charged (neutral) wino essentially always decays to a W (h) boson and an invisible bino. Wino pair production at the LHC, in natural SUSY, thus leads to VV, Vh and hh+ET final states (V=W, Z) where, for TeV scale winos, the vector bosons and h daughters are considerably boosted. We identify eight different channels arising from the leptonic and hadronic decays of the vector bosons and the decay h→bb¯, each of which offers an avenue for wino discovery at the high luminosity LHC (HL-LHC). By combining the signal in all eight channels we find, assuming s=14  TeV and an integrated luminosity of 3000  fb−1, that the discovery reach for winos extends to m(wino)∼1.1  TeV, while the 95% CL exclusion range extends to a wino mass of almost 1.4 TeV. We also identify “Higgsino specific channels” which could serve to provide 3σ evidence that winos lighter than 1.2 TeV decay to light Higgsinos rather than to a binolike lightest supersymmetric particle, should a wino signal appear at the HL-LHC.

Published by the American Physical Society
2024
Cross-correlation of the thermal Sunyaev-Zel’dovich and CMB lensing signals in
Planck
PR4 data with robust CIB decontamination
Authors: McCarthy Fiona , Hill J. Colin
Published: January 2024

We use the full-mission PR4 data to measure the CMB lensing convergence (κ)–thermal Sunyaev-Zel’dovich (tSZ, y) cross-correlation signal, Cℓyκ. This is only the second measurement to date of this signal, following Hill and Spergel []. We perform the measurement using foreground-cleaned tSZ maps built from the PR4 frequency maps via a tailored needlet internal linear combination (NILC) code in our companion paper [F. McCarthy and J. C. Hill, companion paper, .], in combination with the PR4 κ maps and various systematic-mitigated PR3 κ maps. A serious systematic is the residual cosmic infrared background (CIB) signal in the tSZ map, as the high CIB—κ cross-correlation can significantly bias the inferred tSZ—κ cross-correlation. We mitigate this contamination by deprojecting the CIB in our NILC algorithm, using a moment deprojection approach to avoid leakage due to incorrect modeling of the CIB frequency dependence. We validate this method on mm-wave sky simulations. We fit a theoretical halo model to our measurement, finding a best-fit amplitude of A=0.82±0.21 (for the highest signal-to-noise PR4 κ map) or A=0.56±0.24 (for a PR3 κ map built from a tSZ-deprojected CMB map), indicating that the data are consistent with our fiducial model within ≈1−2σ. Although our error bars are similar to those of the previous measurement [J. C. Hill and D. N. Spergel, ], our method is significantly more robust to CIB contamination. Our moment-deprojection approach lays the foundation for future measurements of this signal with higher signal-to-noise κ and y maps from ground-based telescopes, which will precisely probe the astrophysics of the intracluster medium of galaxy groups and clusters in the intermediate-mass (M∼1013–1014h−1M⊙), high-z (z≲1.5, c.f. z≲0.8 for the tSZ auto-power signal) regime, as well as CIB-decontaminated measurements of tSZ cross-correlations with other large-scale structure probes.

Published by the American Physical Society
2024
Energy loss of a fast moving parton in Gribov-Zwanziger plasma
Authors: Debnath Manas , Ghosh Ritesh , Jamal Mohammad Yousuf , Kurian Manu , Prakash Jai
Published: January 2024

The Gribov-Zwanziger prescription applied within Yang-Mills theory is demonstrated to be an efficient method for refining the theory’s infrared dynamics. We study the collisional energy loss experienced by a high-energetic test parton as it traverses through the Grivov plasma at finite temperature. To achieve this, we employ a semiclassical approach that considers the parton’s energy loss while accounting for the backreaction induced by the polarization effects due to its motion in the medium. The polarization tensor of the medium is estimated within a nonperturbative resummation considering the Gribov-Zwanziger approach. The modification of the gluon and ghost loops due to the presence of the Gribov parameter plays a vital role in our estimation. We observe that the nonperturbative interactions have a sizable effect on the parton energy loss. Further, we discuss the implications of our findings in the context of relativistic heavy-ion collisions.

Published by the American Physical Society
2024
Precision unification and the scale of supersymmetry
Authors: Bhattiprolu Prudhvi N. , Wells James D.
Published: January 2024

In this paper, we study the implications of precise gauge coupling unification on supersymmetric particle masses. We argue that precise unification favors the superpartner masses that are in the range of several TeV and well beyond. We demonstrate this in the minimal supersymmetric theory with a common sparticle mass threshold, and two simple high-scale scenarios; minimal supergravity and minimal anomaly-mediated supersymmetry. We also identify candidate models with a Higgsino or a wino dark matter candidate. Finally, the analysis shows unambiguously that unless one takes foggy naturalness notions too seriously, the lack of direct superpartner discoveries at the LHC has not diminished the viability of supersymmetric unified theories in general nor even precision unification in particular.

Published by the American Physical Society
2024
Morphological Entanglement in Living Systems
Authors: Day Thomas C. , Zamani-Dahaj S. Alireza , Bozdag G. Ozan , Burnetti Anthony J. , Bingham Emma P. , Conlin Peter L. , Ratcliff William C. , Yunker Peter J.
Published: January 2024

Many organisms exhibit branching morphologies that twist around each other and become entangled. Entanglement occurs when different objects interlock with each other, creating complex and often irreversible configurations. This physical phenomenon is well studied in nonliving materials, such as granular matter, polymers, and wires, where it has been shown that entanglement is highly sensitive to the geometry of the component parts. However, entanglement is not yet well understood in living systems, despite its presence in many organisms. In fact, recent work has shown that entanglement can evolve rapidly and play a crucial role in the evolution of tough, macroscopic multicellular groups. Here, through a combination of experiments, simulations, and numerical analyses, we show that growth generically facilitates entanglement for a broad range of geometries. We find that experimentally grown entangled branches can be difficult or even impossible to disassemble through translation and rotation of rigid components, suggesting that there are many configurations of branches that growth can access that agitation cannot. We use simulations to show that branching trees readily grow into entangled configurations. In contrast to nongrowing entangled materials, these trees entangle for a broad range of branch geometries. We, thus, propose that entanglement via growth is largely insensitive to the geometry of branched trees but, instead, depends sensitively on timescales, ultimately achieving an entangled state once sufficient growth has occurred. We test this hypothesis in experiments with snowflake yeast, a model system of undifferentiated, branched multicellularity, showing that lengthening the time of growth leads to entanglement and that entanglement via growth can occur for a wide range of geometries. Taken together, our work demonstrates that entanglement is more readily achieved in living systems than in their nonliving counterparts, providing a widely accessible and powerful mechanism for the evolution of novel biological material properties.

Published by the American Physical Society
2024
Modelling dynamical 3D electron diffraction intensities. I. A scattering cluster algorithm
Authors: Mendis Budhika
Published: January 2024

Three-dimensional electron diffraction (3D-ED) is a powerful technique for crystallographic characterization of nanometre-sized crystals that are too small for X-ray diffraction. For accurate crystal structure refinement, however, it is important that the Bragg diffracted intensities are treated dynamically. Bloch wave simulations are often used in 3D-ED, but can be computationally expensive for large unit cell crystals due to the large number of diffracted beams. Proposed here is an alternative method, the `scattering cluster algorithm' (SCA), that replaces the eigen-decomposition operation in Bloch waves with a simpler matrix multiplication. The underlying principle of SCA is that the intensity of a given Bragg reflection is largely determined by intensity transfer (i.e. `scattering') from a cluster of neighbouring diffracted beams. However, the penalty for using matrix multiplication is that the sample must be divided into a series of thin slices and the diffracted beams calculated iteratively, similar to the multislice approach. Therefore, SCA is more suitable for thin specimens. The accuracy and speed of SCA are demonstrated on tri-isopropyl silane (TIPS) pentacene and rubrene, two exemplar organic materials with large unit cells.
The longer, the farther? The internationalization of Chinese firms
Authors: Ma Hanyang , Zou Jingjie , Zou Hailiang
Published: January 2024

Purpose

This study aims to explore the internationalization of multinational enterprises (MNEs) from China and aims to examine the relationship between Chinese MNEs’ duration of internationalization and export intensity, and the contingent roles of the home country government.

Design/methodology/approach

By extending the springboard theory with institutional and cost-benefit analyses, the authors elaborate a two-phase framework of internationalization to explain how Chinese MNEs develop their international business under the influences of the home country government. Furthermore, the authors apply the Heckman two-stage method based on a panel data set of 19,994 firm-year observations of Chinese listed firms in 2008–2018 to test the hypotheses.

Findings

The research findings demonstrate an inverted U-shape relationship between the duration of internationalization and the export intensity of MNEs from China. The export intensity of MNEs from China increases during the initial phase of internationalization, and decreases during the subsequent. A further study reveals that the inverted U-shape of Chinese non-SOEs is steeper than that of SOEs, and this moderating effect is more salient after the Belt and Road Initiative. These results highlight the influence of the home government through state ownership and policies on the inverted U-shaped relationship.

Originality/value

This study helps to refine the understanding of Chinese MNEs’ global expansion by addressing time as an explicit dimension and revealing the mechanism of state ownership and the home country governmental policy in the dynamic internationalization process.
From the emancipated to the emancipator: an integrative perspective on women social entrepreneurs’ emancipation experiences
Authors: Shang Liang
Published: January 2024

Purpose

Social entrepreneurship has been recently viewed as an emancipatory process that promotes freedom and autonomy for social entrepreneurs and those they serve. However, the mechanisms of how emancipation is enacted remain relatively underexplored. By using an integrative lens, this paper aims to explore the emancipation experiences of women social entrepreneurs and unpack the processes through which they extend their self-emancipation to facilitate the empowerment of others.

Design/methodology/approach

This study adopted a qualitative multiple-case study approach. Semistructured interviews were conducted with eight women social entrepreneurs from various industries in Hong Kong to understand and examine their experiences of “emancipation from” and “emancipation to” in social entrepreneurship.

Findings

This study identified a three-phase emancipatory journey of women social entrepreneurs. Specifically, the findings revealed that their emancipation experiences started with self-awareness of constraints in their surroundings, primarily due to stereotyped social norms and institutional barriers. This phase is followed by embracing social entrepreneurship as a coping strategy for navigating the perceived constraints and exploring new possibilities with increased agency. Ultimately, this transformation extends beyond their individual growth into broader social impacts as women social entrepreneurs use their newfound agency to effect meaningful social changes.

Originality/value

This study enriches the “entrepreneuring as emancipation” perspective by embracing an integrative lens that allows us to delve into the complex layers of emancipation experiences of women social entrepreneurs. Notably, this study differentiates various conceptions of emancipation, presenting a dual role of women social entrepreneurs as both the emancipated and the emancipator. By situating the study in Hong Kong, where women often face gendered expectations that shape their career choices and development, this study offers a nuanced and contextual understanding of the unique challenges and opportunities women social entrepreneurs encounter in their environment.