bluuebunny/crossref_metadata_2025 huggingface dataset:
S100A8/A9 drives monocytes towards M2-like macrophage differentiation and associates with M2-like macrophages in osteoarthritic synovium
Authors: van Kooten Nienke J T , Blom Arjen B , Teunissen van Manen Iris J , Theeuwes Wessel F , Roth Johannes , Gorris Mark A J , Walgreen Birgitte , Sloetjes Annet W , Helsen Monique M , Vitters Elly L , van Lent Peter L E M , Koëter Sander , van der Kraan Peter M , Vogl Thomas , van den Bosch Martijn H J
Published: January 2024

Objectives

Macrophages are key orchestrators of the osteoarthritis (OA)-associated inflammatory response. Macrophage phenotype is dependent on environmental cues like the inflammatory factor S100A8/A9. Here, we investigated how S100A9 exposure during monocyte-to-macrophage differentiation affects macrophage phenotype and function.

Methods

OA synovium cellular composition was determined using flow cytometry and multiplex immunohistochemistry. Healthy donor monocytes were differentiated towards M1- and M2-like macrophages in the presence of S100A9. Macrophage markers were measured using flow cytometry, and phagocytic activity was determined using pHrodo Red Zymosan A BioParticles. Gene expression was determined using qPCR. Protein secretion was measured using Luminex multianalyte analysis and ELISA.

Results

Macrophages were the dominant leucocyte subpopulation in OA synovium. They mainly presented with an M2-like phenotype, although the majority also expressed M1-like macrophage markers. Long-term exposure to S100A9 during monocyte-to-macrophage differentiation increased M2-like macrophage markers CD163 and CD206 in M1-like and M2-like differentiated cells. In addition, M1-like macrophage markers were increased in M1-like, but decreased in M2-like differentiated macrophages. In agreement with this mixed phenotype, S100A9 stimulation modestly increased expression and secretion of pro-inflammatory markers and catabolic enzymes, but also increased expression and secretion of anti-inflammatory/anabolic markers. In accordance with the upregulation of M2-like macrophage markers, S100A9 increased phagocytic activity. Finally, we indeed observed a strong association between S100A8 and S100A9 expression and the M2-like/M1-like macrophage ratio in end-stage OA synovium.

Conclusion

Chronic S100A8/A9 exposure during monocyte-to-macrophage differentiation favours differentiation towards an M2-like macrophage phenotype. The properties of these cells could help explain the catabolic/anabolic dualism in established OA joints with low-grade inflammation.
Closing the loop without reinventing the wheel: public procurement for innovation promoting a circular economy
Authors: Grimbert Stephanie Francis , Zabala-Iturriagagoitia Jon Mikel
Published: January 2024

This theoretical paper adopts a procedural perspective to identify the challenges associated with the implementation of the full scope of approaches to circular public procurement (CPP). We contend that beyond considering CPP from a substantive standpoint (i.e. the procurement affects outside of the organization), adopting a procedural perspective (i.e. the procurement affects inside an organization) to public procurement can pave the way for reflecting transversally on how CPP can borrow from public procurement for innovation (PPI). Building on the challenges identified in the literature on CPP, we identify that PPI can contribute to consolidating CPP through such mechanisms as market engagement and intermediation, functional specifications, and coordinated unbundling. We provide illustrations for each of the identified procedural contributions of PPI to CPP derived from five cases. We discuss how procurement capabilities and evaluation can act as critical drivers for moving from a substantive to a procedural approach to CPP.
‘The Husband, For Whom She Endures All This’: Dutch Men in Childbirth, 1900–1940
Authors: Huistra Hieke
Published: January 2024

I argue that in the early twentieth-century Netherlands, fathers regularly attended the birth of their children, and that this attendance was generally accepted or even encouraged by doctors. My findings contrast with existing historiography on the Anglo-Saxon countries, where, at the time, fathers were usually not present at births. I explain this difference between the Netherlands and the Anglo-Saxon countries through the ideal of the harmonious family that permeated Dutch society at the time. I show how birth was seen as a family event, in which the father should be emotionally involved. Men had to manage this emotional involvement carefully: they had to display emotions without losing control of these emotions. My findings show that we need to study doctor-led births in order to fully understand the slow rise of hospital births in the Netherlands.
Robotics-Driven Manufacturing of Cartilaginous Microtissues for Skeletal Tissue Engineering Applications
Authors: Decoene Isaak , Nasello Gabriele , Madeiro de Costa Rodrigo Furtado , Nilsson Hall Gabriella , Pastore Angela , Van Hoven Inge , Ribeiro Viseu Samuel , Verfaillie Catherine , Geris Liesbet , Luyten Frank P , Papantoniou Ioannis
Published: January 2024

Automated technologies are attractive for enhancing the robust manufacturing of tissue-engineered products for clinical translation. In this work, we present an automation strategy using a robotics platform for media changes, and imaging of cartilaginous microtissues cultured in static microwell platforms. We use an automated image analysis pipeline to extract microtissue displacements and morphological features as noninvasive quality attributes. As a result, empty microwells were identified with a 96% accuracy, and dice coefficient of 0.84 for segmentation. Design of experiment are used for the optimization of liquid handling parameters to minimize empty microwells during long-term differentiation protocols. We found no significant effect of aspiration or dispension speeds at and beyond manual speed. Instead, repeated media changes and time in culture were the driving force or microtissue displacements. As the ovine model is the preclinical model of choice for large skeletal defects, we used ovine periosteum-derived cells to form cartilage-intermediate microtissues. Increased expression of COL2A1 confirms chondrogenic differentiation and RUNX2 shows no osteogenic specification. Histological analysis shows an increased secretion of cartilaginous extracellular matrix and glycosaminoglycans in larger microtissues. Furthermore, microtissue-based implants are capable of forming mineralized tissues and bone after 4 weeks of ectopic implantation in nude mice. We demonstrate the development of an integrated bioprocess for culturing and manipulation of cartilaginous microtissues and anticipate the progressive substitution of manual operations with automated solutions for the manufacturing of microtissue-based living implants.
Conserved untranslated regions of multipartite viruses: Natural markers of novel viral genomic components and tags of viral evolution
Authors: Zhang Song , Yang Caixia , Qiu Yuanjian , Liao Ruiling , Xuan Zhiyou , Ren Fang , Dong Yafeng , Xie Xiaoying , Han Yanhong , Wu Di , Ramos-González Pedro Luis , Freitas-Astúa Juliana , Yang Huadong , Zhou Changyong , Cao Mengji
Published: January 2024

Viruses with split genomes are classified as being either segmented or multipartite based on whether their genomic segments occur within a single virion or across different virions. Despite variations in number and sequence during evolution, the genomic segments of many viruses are conserved within the untranslated regions (UTRs). In this study, we present a methodology that combines RNA sequencing with iterative BLASTn of UTRs (https://github.com/qq371260/Iterative-blast-v.1.0) to identify new viral genomic segments. Some novel multipartite-like viruses related to the phylum Kitrinoviricota were annotated using sequencing data from field plant samples and public databases. We identified potentially plant-infecting jingmen-related viruses (order Amarillovirales) and jivi-related viruses (order Martellivirales) with at least six genomic components. The number of RNA molecules associated with a genome of the novel viruses in the families Closteroviridae, Kitaviridae, and Virgaviridae within the order Martellivirales reached five. Several of these viruses seem to represent new taxa at the subgenus, genus, and family levels. The diversity of novel genomic components and the multiple duplication of proteins or protein domains within single or multiple genomic components emphasize the evolutionary roles of genetic recombination (horizontal gene transfer), reassortment, and deletion. The relatively conserved UTRs at the genome level might explain the relationships between monopartite and multipartite viruses, as well as how subviral agents such as defective RNAs and satellite viruses can coexist with their helper viruses.
Multi-Method Investigation of Blood Damage Induced By Blood Pumps in Different Clinical Support Modes
Authors: Li Yuan , Liu Xinyu , Sun Anqiang , Deng Xiaoyan , Chen Zengsheng , Fan Yubo
Published: January 2024

To investigate the effects of blood pumps operated in different modes on nonphysiologic flow patterns, cell and protein function, and the risk of bleeding, thrombosis, and hemolysis, an extracorporeal blood pump (CentriMag) was operated in three clinical modalities including heart failure (HF), venous-venous (V-V) extracorporeal membrane oxygenation (ECMO), and venous-arterial (V-A) ECMO. Computational fluid dynamics (CFD) methods and coupled hemolysis models as well as recently developed bleeding and thrombosis models associated with changes in platelet and von Willebrand factor (vWF) function were used to predict hydraulic performance and hemocompatibility. The V-A ECMO mode had the highest flow losses and shear stress levels, the V-V ECMO mode was intermediate, and the HF mode was the lowest. Different nonphysiologic flow patterns altered cell/protein morphology and function. The V-A ECMO mode resulted in the highest levels of platelet activation, receptor shedding, vWF unfolding, and high molecular weight multimers vWF (HMWM-vWF) degradation, leading to the lowest platelet adhesion and the highest vWF binding capacity, intermediate in the V-V ECMO mode, and opposite in the HF mode. The V-A ECMO mode resulted in the highest risk of bleeding, thrombosis, and hemolysis, with the V-V ECMO mode intermediate and the HF mode lowest. These findings are supported by published experimental or clinical statistics. Further studies found that secondary blood flow passages resulted in the highest risk of blood damage. Nonphysiologic blood flow patterns were strongly associated with cell and protein function changing, blood damage, and complications.
LoopSage: An Energy-Based Monte Carlo approach for the Loop Extrusion Modelling of Chromatin
Authors: Korsak Sevastianos , Plewczynski Dariusz
Published: January 2024

The connection between the patterns observed in 3C-type experiments and the modeling of polymers remains unresolved. This paper presents a simulation pipeline that generates thermodynamic ensembles of 3D structures for topologically associated domain (TAD) regions by loop extrusion model (LEM). The simulations consist of two main components: a stochastic simulation phase, employing a Monte Carlo approach to simulate the binding positions of cohesins, and a dynamical simulation phase, utilizing these cohesins’ positions to create 3D structures. In this approach, the system’s total energy is the combined result of the Monte Carlo energy and the molecular simulation energy, which are iteratively updated. The structural maintenance of chromosomes (SMC) protein complexes are represented as loop extruders, while the CCCTC-binding factor (CTCF) locations on DNA sequence are modeled as energy minima on the Monte Carlo energy landscape. Finally, the spatial distances between DNA segments from ChIA-PET experiments are compared with the computer simulations, and we observe significant Pearson correlations between predictions and the real data. LoopSage model offers a fresh perspective on chromatin loop dynamics, allowing us to observe phase transition between sparse and condensed states in chromatin.
Time dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets
Authors: Fathi Payam A. , Bales Michelle B. , Ayala Julio E.
Published: January 2024

Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance, yet when this dysregulation occurs is unknown. We assessed the time course of alterations to behaviors promoting weight gain in male and female mice switched to obesogenic 60% or 45% high fat diet (HFD). Switching mice to obesogenic diets promotes transient bouts of hyperphagia during the first 2 weeks followed by persistent caloric hyperphagia. Energy expenditure increases but not sufficiently to offset increased caloric intake, resulting in a sustained net positive energy balance. Hyperphagia is associated with consumption of calorically larger meals (impaired satiation) more frequently (impaired satiety) particularly during the light-cycle. Running wheel exercise delays weight gain in 60% HFD-fed male mice by enhancing satiation and increasing energy expenditure. However, exercise effects on satiation are no longer apparent after 2 weeks, coinciding with weight gain. Thus, exposure to obesogenic diets engages homeostatic regulatory mechanisms for ∼2 weeks that ultimately fail, and consequent weight gain is characterized by impaired satiation and satiety. Insights into the etiology of obesity can be obtained by investigating changes to satiation and satiety mechanisms during the initial ∼2 weeks of HFD exposure.

What is already known about this subject?

Obesity is associated with dysregulated homeostatic mechanisms.

Increased caloric consumption contributes to obesity.

Obese rodents tend to eat larger, more frequent meals.

What are the new findings in your manuscript?

Exposure to obesogenic diets promotes transient attempts to maintain weight homeostasis.

After ∼2 weeks, caloric hyperphagia exceeds increased energy expenditure, promoting weight gain.

This is associated with consumption of larger, more frequent meals.

How might your results change the direction of research or the focus of clinical practice?

Our findings suggest that molecular studies focusing on mechanisms that regulate meal size and frequency, particularly those engaged during the first ∼2 weeks of obesogenic diet feeding that eventually fail, can provide unique insight into the etiology of obesity.
Influence of social and semantic contexts on phonetic encoding in naturalistic conversations
Authors: Abassi Etienne , Zatorre Robert J.
Published: January 2024

Social interactions occupy a significant part of life, and understanding others’ conversations is key to navigating our social world. While the role of semantics in speech comprehension is well-established at the word or sentence level, its influence on larger conversational scales, alongside social context, is less understood. This study examined how semantic and social contexts modulate phonetic encoding during natural conversations using a speech-in-noise paradigm. Participants listened to AI-generated dialogues (two speakers) or monologues (one speaker) in intact or sentence-scrambled order. Each trial contained five sentences, with the fifth embedded in multi-talker babble noise. The same sentence was then repeated without noise, with one word either altered or unchanged. Healthy adults identified whether the sentence matched the in-noise version. Across several online experiments (N=195), both social and semantic contexts showed influences on speech-in-noise processing with improved performance for dialogues over monologues and for intact over sentence-scrambled conversations. These results suggest that both semantic and social factors shape speech comprehension, emphasizing their role in auditory cognition. This raises important questions about predictive and other mechanisms involved in processing complex, multi-sentence conversations, further underscoring the critical role of social interaction in communication.
Synaptotagmin 7 C2 domains induce membrane curvature stress via electrostatic interactions and the wedge mechanism
Authors: Beaven Andrew H. , Bikkumalla Vrishank , Chon Nara L. , Matthews Ariel E. , Lin Hai , Knight Jefferson D. , Sodt Alexander J.
Published: January 2024

0.

Synaptotagmin 7 (Syt-7) is part of the synaptotagmin protein family that regulates exocytotic lipid membrane fusion. Among the family, Syt-7 stands out by its membrane binding strength and stabilization of long-lived membrane fusion pores. Given that Syt-7 vesicles form long-lived fusion pores, we hypothesize that its interactions with the membrane stabilize the specific curvatures, thicknesses, and lipid compositions that support a metastable fusion pore. Using all-atom molecular dynamics simulations and FRET-based assays of Syt-7’s membrane-binding C2 domains (C2A and C2B), we found that Syt-7 C2 domains sequester anionic lipids, are sensitive to cholesterol, thin membranes, and generate lipid membrane curvature by two competing, but related mechanisms. First, Syt-7 forms strong electrostatic contacts with the membrane, generating negative curvature stress. Second, Syt-7’s calcium binding loops embed in the membrane surface, acting as a wedge to thin the membrane and induce positive curvature stress. These curvature mechanisms are linked by the protein insertion depth as well as the resulting protein tilt. Simplified quantitative models of the curvature-generating mechanisms link simulation observables to their membrane-reshaping effectiveness.
CutaneousLeishmania mexicanaInfections in the United States: Defining Strains Through Endemic Human Pediatric Cases in Northern Texas
Authors: Nepal Binita , McCormick-Baw Clare , Patel Karisma , Firmani Sarah , Wetzel Dawn M.
Published: January 2024

Over a six-month span, three patients under five years old with cutaneous leishmaniasis presented to the Pediatric Infectious Diseases Clinic at the University of Texas Southwestern Medical Center/Children’s Health Dallas. None had traveled outside of the United States (US); all had confirmedL. mexicanainfections by PCR. We provide case descriptions and images to increase the awareness of this disease among US physicians and scientists. Two patients responded to fluconazole, but one required topical paromomycin. Combining these cases with guidelines and our literature review, we suggest that: 1) higher doses (ten-twelve mg/kg/day) of fluconazole should be considered in young children to maximize likelihood and rapidity of response and 2) patients should transition to alternate agents if they do not respond to high-dose fluconazole within six weeks. Furthermore, and of particular interest to the broad microbiology community, we used samples from these cases as a proof-of-concept to propose a mechanism to strain-type US-endemicL. mexicana.For our analysis, we sequenced three housekeeping genes and the internal transcribed sequence 2 of the ribosomal RNA gene. We identified genetic changes that not only allow us to distinguish US-basedL. mexicanastrains from strains found in other areas of the Americas, but also establish polymorphisms that differ between US isolates. These techniques will allow documentation of genetic changes in this parasite as its range expands. Hence, our cases of cutaneous leishmaniasis provide significant evolutionary, treatment and public health implications as climate change increases exposure to formerly tropical diseases in previously non-endemic areas.

IMPORTANCE

Leishmaniasis is a parasitic disease that typically affects tropical regions worldwide. However, the vector that carriesLeishmaniais spreading northward into the United States (US). Within a six-month period, three young cutaneous leishmaniasis patients were seen at the Pediatric Infectious Diseases Clinic at The University of Texas Southwestern/Children’s Health Dallas. None had traveled outside of north Texas. We document their presentations, treatments, and outcomes and compare their management to clinical practice guidelines for leishmaniasis. We also analyzed the sequences of three critical genes inLeishmania mexicanaisolated from these patients. We found changes that not only distinguish US-based strains from strains found elsewhere, but also differ between US isolates. Monitoring these sequences will allow tracking of genetic changes in parasites over time. Our findings have significant US public health implications as people are increasingly likely to be exposed to what were once tropical diseases.
Epidemiology and burden of respiratory syncytial virus in Italian adults: A systematic review and meta-analysis
Authors: Domnich Alexander , Calabrò Giovanna Elisa
Published: January 2024

Objective

Respiratory syncytial virus (RSV) is a common respiratory pathogen not only in children, but also in adults. Country-specific data on the epidemiology and burden of disease are essential for policy decisions. In view of a recent authorization of adult RSV vaccines, we aimed to comprehensively collect and assess evidence on the epidemiology and burden of RSV in Italian adults.

Methods

A systematic literature review was conducted according to the available guidelines. Random-effects proportional meta-analysis was performed to obtain pooled estimates and the observed heterogeneity was investigated by using both subgroup and meta-regression analyses.

Results

A total of 35 studies were identified. RSV seasonal attack rates ranged from 0.8 ‰ in community-dwelling older adults to 10.9% in hematological outpatients. On average, 4.5% (95% CI: 3.2–5.9%) of respiratory samples tested positive for RSV. This positivity prevalence was higher in older adults (4.4%; 95% CI: 2.8– 6.3%) than in working-age adults (3.5%; 95% CI: 2.5–4.6%) and in outpatient (4.9%; 95% CI: 3.1–7.0%) than inpatient (2.9%; 95% CI: 1.5–4.8%) settings. Study location and sample size were also significant predictors of RSV detection frequency. The pooled estimate of in-hospital mortality was as high as 7.2% (95% CI: 4.7– 10.3%). However, other important indicators of the diseases burden, such as complication and hospitalization rates, are missing.

Conclusion

RSV poses a measurable burden on Italian adults, especially those of older age and with some co-morbidities. Policy makers should give priority to health technology assessment of the novel RSV vaccines.
Alzheimer’s Disease biological PET staging using plasma p217+tau
Authors: Feizpour Azadeh , Doré Vincent , Krishnadas Natasha , Bourgeat Pierrick , Doecke James D. , Saad Ziad S. , Triana-Baltzer Gallen , Laws Simon M. , Shishegar Rosita , Huang Kun , Fowler Christopher , Ward Larry , Masters Colin L. , Fripp Jurgen , Kolb Hartmuth C. , Villemagne Victor L. , Rowe Christopher C.
Published: January 2024

Background

Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s Disease (AD) neuropathology. However, questions remain regarding their capacity to inform AD biological PET stages at group level and maintain the same precision at individual patient level.

Method

Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay,18F-NAV4694 Aβ PET (A) and18F-MK6240 tau PET (T) data. Biological PET stages were defined based on the draft NIA-AA Revised Criteria (July 2023): Initial (A+T-), Early (A+TMTL+), Intermediate (A+TMOD+), and Advanced (A+THIGH+). We used thresholds for A+ of 25 Centiloid and for THIGHof 80 Centaur (2.68 SUVRtemporo-parietal). Adding an A-T- stage for comparison, we assessed the performance of p217+tau in discriminating between these stages at the group level using Receiver Operating Characteristic (ROC) analysis and at the individual level using logistic regression.

Results

Plasma p217+tau concentrations increased across the stages, with significant differences between them, except for the Initial and Early stages. Screening for Advanced (vs. lower stages), combined Intermediate/Advanced (vs. lower stages), or all stages (vs. A-T-), p217+tau showed good group-level discriminations (AUC 0.91, 0.92 and 0.92; CI only: AUC 0.83, 0.89, 0.93, respectively). At the individual level, the likelihood of PET stagevs. p217+tau level showed good discrimination of A-T- vs any A+ stage and of combined Intermediate/Advanced disease stage vs lower stages in the CI.

Conclusion

In addition to accurately screening for A+ individuals, plasma p217+tau shows promise for separating persons with either Intermediate or Advanced stage AD from those at a lower stage, providing prognostic information and informing better selection for trials and disease modifying therapies.
Psychosocial distress and health status as risk factors for ten-year major adverse cardiac events and mortality in patients with non-obstructive coronary artery disease
Authors: Mommersteeg Paula M.C. , Lodder Paul , Aarnoudse Wilbert , Magro Michael , Widdershoven Jos W.
Published: January 2024

Background

Patients with non-obstructive coronary artery disease (NOCAD) experience psychological distress and are at risk for major adverse cardiac events with mortality (MACE). We examined the risk of psychosocial distress, including Type D personality, depressive symptoms, anxiety, positive mood, hostility, and health status fatigue and disease specific and generic quality of life for MACE in patients with NOCAD.

Methods

In the Tweesteden mild stenosis (TWIST) study, 546 patients with NOCAD were followed for 10 years to examine the occurrence of cardiac mortality, a major cardiac event, or non-cardiac mortality in the absence of a cardiac event. Cox proportional hazard models were used to examine the impact of psychosocial distress and health status on the occurrence of MACE while adjusting for age, sex, disease severity, and lifestyle covariates. Sex differences and interactions were explored.

Results

In total 19% of the patients (mean age baseline = 61, SD 9 years; 52% women) experienced MACE, with an annualized event rate (AER) of 20 events per 1,000 person-years, and a lower risk for women compared to men. Positive mood (HR 0.97, 95%CI 0.95-1.00), fatigue (HR 1.03, 95%CI 1.00-1.06), and physical limitation (HR 0.99, 95%CI 0.98-1.00) were associated with MACE in adjusted models. No significant interactions between sex and psychosocial factors were present. Depressive symptoms were predictive of MACE, but no longer after adjustment. Neither Type D personality, anxiety, hostility, mental health status, or angina frequency and stability were significantly associated with MACE.

Conclusions

In patients with NOCAD fatigue, low positive mood, and a lower physical limitation score were associated with MACE, without marked sex differences. Type D personality, psychosocial factors, and health status were not predictive of adverse outcomes. Reducing psychosocial distress is a valid intervention goal by itself, though it is less likely to affect MACE in patients with NOCAD.
Characteristics, temporal trends, and outcomes of intravenous thrombolysis in stroke patients aged > 80 years in China
Authors: Li Chang-sheng , Jiang Ying-yu , Gu Hong-Qiu , Wang Meng , Chen Zi-mo , Yang Xin , Zhou Qi , Meng Xia , Wang Chun-juan , Li Zi-xiao
Published: January 2024

Background/Purpose

No large cohort study has examined intravenous thrombolysis (IVT) in Chinese patients aged > 80 years.We aim to evaluate temporal trends in alteplase use, clinical characteristics, and outcomes in acute ischemic stroke (AIS) patients over 80 years of age in China.

Methods

Data were collected from The China Stroke Center Alliance program, which is a nationwide, multicenter, prospective registry at 1751 hospitals in 31 provinces, between January 1, 2018, and December 14, 2022.The primary outcome was a modified Rankin scale score (mRS) of 0-2 at discharge, and the secondary study outcomes were an mRS score 0-1 and independent ambulation at discharge. The safety outcomes included in-hospital mortality and symptomatic intracranial hemorrhage(sICH).

Results

Of 212,814 patients eligible for thrombolysis, 30,902 patients were aged > 80 years; among them, 8,673 patients (median [IQR] age, 84 [82-87] years) were treated with alteplase, 52.7% of whom were female (n=4570). The usage rate of alteplase in elderly patients increased from 22.1% in 2018 to 35.7% in 2022, while the rate among younger patients increased from 30.5% in 2018 to 43.3% in 2022. Patients treated with alteplase had better short-term functional outcomes, including mRS scores 0-2 (adjusted OR [aOR] 1.13, 95% CI 1.08-1.19, p<0.001), mRS scores 0-1 (aOR 1.14, 95% CI 1.09-1.20, p<0.001), and independent ambulation at discharge (aOR 1.27, 95% CI 1.19-1.39, p<0.001). Furthermore, there was no increased risk of in-hospital mortality (aOR 0.92, 95% CI 0.79-1.08, p=0.31). However, alteplase was associated with a higher risk of sICH (aOR 2.85, 95% CI 2.48-3.27, p<0.001).

Conclusions

Elderly patients receiving IVT with alteplase had better short-term functional outcomes without an increased risk of in-hospital mortality; however, elderly patients are at higher risk of developing symptomatic intracranial hemorrhage.
Functional trajectory following pediatric stroke: a cohort study of acute inpatient rehabilitation outcomes
Authors: Wu Jennifer , Godfrey Deena S. , Orme Patricia , Wishart Brian D.
Published: January 2024

Background

Stroke in childhood is a significant cause of morbidity and mortality. Neurologic impairments due to childhood stroke are associated with long-term disability and decreased quality of life. However, there are limited studies examining functional outcomes of childhood stroke. The goal of this study was to characterize functional outcomes of children and adolescents admitted to acute inpatient rehabilitation following stroke.

Methods

A retrospective cross-sectional study of 100 patients aged 0 to 21 years admitted to a pediatric acute inpatient rehabilitation program following new diagnosis of stroke in childhood. The primary outcome measures were Functional Independence Measure in Children (WeeFIM) score at admission and discharge. Secondary outcome measures included change in WeeFIM score and IRF Efficiency score.

Results

The 56 male/43female/1 transgender patients were 10.4±6.1 years old with ischemic (n=53), hemorrhagic (n=41), and hemorrhagic converted ischemic (n=6) strokes. At admission, the group demonstrated moderate-to-severe functional impairments (WeeFIM total score=47.9±26.3 points). Inpatient rehabilitation length of stay was 34.1±28.6 days and at inpatient rehabilitation discharge, WeeFIM total score improved to 73.2±31.5 points, representing a group IRF Efficiency score of 1.42±1.5 points/day. Group effects were also found for medical management of agitation, stroke prophylaxis, and stimulant therapy.

Conclusions

Acute inpatient rehabilitation demonstrates statistically and clinically significant functional improvements following pediatric stroke as measured on the WeeFIM scale. Additional studies are needed to examine group effects found from medical management in the inpatient rehabilitation setting.
The impact of kinship composition on social structure
Authors: Pereira André S. , Pavez-Fox Melissa A. , Hart Jordan D. A. , Negron-Del Valle Josué E. , Phillips Daniel , Casanova Catarina , De Moor Delphine , Brent Lauren J. N.
Published: January 2024

The relatedness between group members is a potential driver of variation in social structure. Relatedness predicts biases in partner choice and formation of strong relationships among group members. As such, groups that differ in their percentage of non-kin dyads, i.e., in their kinship composition, should therefore differ in the structure of their social networks. Yet the relationship between kinship composition and social structure remains unclear. Here, we used long-term social and pedigree data from a population of rhesus macaques to investigate the relationship between kinship composition and the connectivity, cohesion, potential for transmission and social differentiation of the social networks of adult female macaques. We found no evidence that the social structure of groups composed of greater proportion of unrelated females differ from that of groups with a lower proportion of non-kin. To investigate this unexpected finding, we built agent-based models parameterised with the empirical data to further explore (1) the expected relationship between kinship composition and social structure and (2) why we did not find such a relationship in the empirical data. Agent-based models showed that kinship composition can influence social structure in populations similar to the one studied, but that this effect may only be detectable with a sample size even larger than ours (19 group-years) and with greater variance in kinship composition (proportion of non-kin varied between 0.830-0.922 in the empirical data). The relationship between kinship composition and social structure might be more apparent when comparing data from species that differ strongly in their social organisation, translating into marked differences in kinship composition. This further emphasises the importance of reporting existing and future kinship composition data to deepen our understanding of the evolution of sociality and highlights the potential of agent-based models to better understand empirical results.
Comparative analysis of multiplexed in situ gene expression profiling technologies
Authors: Hartman Austin , Satija Rahul
Published: January 2024

The burgeoning interest in in situ multiplexed gene expression profiling technologies has opened new avenues for understanding cellular behavior and interactions. In this study, we present a comparative benchmark analysis of six in situ gene expression profiling methods, including both commercially available and academically developed methods, using publicly accessible mouse brain datasets. We find that standard sensitivity metrics, such as the number of unique molecules detected per cell, are not directly comparable across datasets due to substantial differences in the incidence of off-target molecular artifacts impacting specificity. To address these challenges, we explored various potential sources of molecular artifacts, developed novel metrics to control for them, and utilized these metrics to evaluate and compare different in situ technologies. Finally, we demonstrate how molecular false positives can seriously confound spatially-aware differential expression analysis, requiring caution in the interpretation of downstream results. Our analysis provides guidance for the selection, processing, and interpretation of in situ spatial technologies.
Synaptic Theory of Working Memory for Serial Order
Authors: Mongillo Gianluigi , Tsodyks Misha
Published: January 2024

Abstract

People effortlessly remember short, but otherwise arbitrary, sequences of familiar stimuli over a brief period of time. This deceptively mundane ability is core for purposeful behavior and cognition. Surprisingly, however, it remains largely unexplained. Here, we propose that both the stimuli and their order of occurrence are encoded by transient synaptic enhancement over multiple time scales. To substantiate this proposal, we extend our previously-proposed synaptic theory of Working Memory (WM) to include synaptic augmentation besides short-term depression and facilitation, consistently with experimental observations. Like facilitation, augmentation builds up with repetitive activation but persists for much longer. We find that the long time scales associated with augmentation naturally lead to the emergence of a “primacy gradient” in the synaptic efficacies that can be used to reconstruct the order of presentation at recall. The novel theory accounts for prominent features of the behavior of humans recalling lists of items, makes testable predictions and, intriguingly, suggests that WM capacity limitations result from a failure in retrieving, rather than storing, information. Taken together, our results advance the understanding of the neuronal mechanisms underpinning the encoding of serial order and offer novel insights into the origin of WM capacity.
Targeting thePlasmodium falciparumUCHL3 ubiquitin hydrolase using chemically constrained peptides
Authors: King Harry R. , Bycroft Mark , Nguyen Thanh-Binh , Kelly Geoff , Vinogradov Alexander A. , Rowling Pamela J. E. , Stott Katherine , Ascher David B. , Suga Hiroaki , Itzhaki Laura S. , Artavanis-Tsakonas Katerina
Published: January 2024

The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, includingPlasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disruptP. falciparumgrowth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within thePlasmodiumubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of anti-malarial therapeutics.
Distinct alterations in white matter properties and organization related to maternal treatment initiation in neonates exposed to HIV but uninfected
Authors: Magondo Ndivhuwo , Meintjes Ernesta M. , Warton Fleur L. , Little Francesca , van der Kouwe Andre J.W. , Laughton Barbara , Jankiewicz Marcin , Holmes Martha J.
Published: January 2024

HIV exposed-uninfected (HEU) infants and children are at risk of developmental delays as compared to uninfected unexposed (HUU) populations. The effects of exposure toin uteroHIV and ART regimens on the HEU the developing brain are not well understood.

In a cohort of 2-week-old newborns, we used diffusion tensor imaging (DTI) tractography and graph theory to examine the influence of HIV and ART exposurein uteroon neonate white matter integrity and organisation. The cohort included HEU infants born to mothers who started ART before conception (HEUpre) and after conception (HEUpost), as well as HUU infants from the same community. We investigated HIV exposure and ART duration group differences in DTI metrics (fractional anisotropy (FA) and mean diffusivity (MD)) and graph measures across white matter.

We found increased MD in white matter connections involving the thalamus and limbic system in the HEUpregroup compared to HUU. We further identified reduced nodal efficiency in the basal ganglia. Within the HEUpostgroup, we observed reduced FA in cortical-subcortical and cerebellar connections as well as decreased transitivity in the hindbrain area compared to HUU.

Overall, our analysis demonstrated distinct alterations in white matter integrity related to the timing of maternal ART initiation that influence regional brain network properties.
Activity-dependent expression ofFezf2regulates inhibitory synapse formation in pyramidal cells
Authors: Kroon Tim , Sanalidou Stella , Maeso Patricia , Garces Teresa , Yang Han , Rico Beatriz
Published: January 2024

The function of the cerebral cortex relies on the precise integration of diverse neuronal populations during development, which is regulated by dynamic fine-tuning mechanisms maintaining the balance between excitation and inhibition. For instance, the development of excitatory pyramidal cells is simultaneously and precisely counterbalanced by the formation of inhibitory synapses during the maturation of neuronal circuits. Although this process relies on neuronal activity, different types of pyramidal cells likely respond to changes in activity through the expression of cell-specific genes. However, the molecular programs underlying the activity-dependent recruitment of inhibition by distinct types of pyramidal cells in the neocortex are unknown. Here, we combined neuronal activity manipulation with ribosome-associated mRNA profiling of layer 5 (L5) extra-telencephalic (ET) cells to address this question in mice. We unveiled a novel function for the selector geneFezf2as an activity-dependent transcription factor controlling the parvalbumin inputs onto L5 ET neurons. One of the downstream effectors of FEZF2 shaping the formation of inhibitory synapses onto L5 ET pyramidal cells is the cell-surface molecule cadherin 22. Our study identifies activity-dependent factors regulating the cell type-specific assembly of inhibitory synapses onto pyramidal cells.
Node centrality in MEG resting-state networks co-varies with neurotransmitter receptor and transporter density
Authors: Siebenhühner Felix , Palva J. Matias , Palva Satu
Published: January 2024

Neuronal oscillations are central mechanisms in the regulation of neuronal processing and communication (Deco et al., 2011; Fries, 2015; S. Palva & Palva, 2012; Siegel et al., 2012; Singer, 1999), but the relationship between the emergent inter-areal synchronization of oscillations and their underlying synaptic and neuromodulatory mechanisms - the dynome - has remained poorly understood (Kopell et al., 2014).

While oscillations are largely generated by fast synaptic neurotransmission among pyramidal cells and interneurons (Traub et al., 2004), these microcircuits are subject to slower neuromodulation in a frequency- and region-specific manner (Batista-Brito et al., 2018; Roopun et al., 2010). While the efferent connections, receptor densities, and neurotransmitter reuptake regulation of neuromodulatory systems are highly heterogeneous across the cortical mantle (Avery & Krichmar, 2017; Deco et al., 2017; Hansen et al., 2022), it has remained unresolved how this variability shapes inter-areal connectivity of neuronal oscillations.

Here, we used source-reconstructed human magnetoencephalography (MEG) data to assess how the centrality of brain areas (nodes) in large-scale networks of phase synchrony and amplitude correlations covaries with neurotransmitter receptor and transporter densities. Node centrality strongly covaried with receptor and transporter densities in a coupling- and frequency-specific manner both at the level of individual receptors and transporters and that of principal components.

In delta, theta, and gamma frequencies, node centrality in phase-synchronization networks covaried positively, and in high-alpha and beta bands negatively, with dopaminergic, GABA, NMDA, muscarinic, and most serotonergic receptor densities. In amplitude-correlation networks, node centrality in delta and gamma bands covaried positively, and in theta to beta bands negatively, with most receptor and transporter densities. These results establish the contribution of neurotransmitter receptor and transporter densities for shaping connectivity of neuronal oscillations in the human brain and demonstrate a link between coupling of neuronal oscillations with the underlying biological details.
Neural variability compresses with increasing belief precision during Bayesian inference
Authors: Skowron Alexander , Kosciessa Julian Q. , Lorenz Robert , Hertwig Ralph , van den Bos Wouter , Garrett Douglas D.
Published: January 2024

To make optimal decisions, intelligent agents must learn latent environmental states from discrete observations. Bayesian frameworks argue that integration of evidence over time allows us to refine our state belief by reducing uncertainty about alternate possibilities. How is this increasing belief precision during learning reflected in the brain? We propose that moment-to-moment neural variability should scale with the degree of reduction of uncertainty during learning. In a sample of 47 healthy adults, we found that BOLD signal variability (SDBOLD, as measured with functional MRI) indeed compressed with successive exposure to decision-related evidence. Crucially, more accurate participants expressed greater SDBOLDcompression primarily in Default Mode Network regions, possibly reflecting the increasing precision of their latent state belief during more efficient learning. Further, computational modeling of behavior suggested that more accurate subjects held a more unbiased (flatter) prior belief over possible states that allowed for larger uncertainty reduction during learning, which was directly reflected in SDBOLDchanges. Our results provide first evidence that moment-to-moment neural variability compresses with increasing belief precision during effective learning, proposing a flexible mechanism for how we come to learn the probabilistic nature of the world around us.
The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19
Authors: Martin-Castaño Benita , Diez-Echave Patricia , García-García Jorge , Hidalgo-García Laura , Ruiz-Malagon Antonio Jesús , Molina-Tijeras José Alberto , Rodríguez-Sojo Maria Jesús , Redruello Anaïs , Martínez-Zaldívar Margarita , Mota Emilio , Cobo Fernando , Alvarez-Estevez Marta , García Federico , Morales-García Concepción , Merlos Silvia , García-Flores Paula , Colmenero-Ruiz Manuel , Hernandez-Quero José , Nuñez María , Rodríguez-Cabezas Maria Elena , Carazo Ángel , Martín Javier , Morón Rocío , Rodríguez-Nogales Alba , Gálvez Julio
Published: January 2024

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that displays great variability in clinical phenotype. Many factors have been described to be correlated with its severity, and microbiota could play a key role in the infection, progression, and outcome of the disease. SARS-CoV-2 infection has been associated with nasopharyngeal and gut dysbiosis and higher abundance of opportunistic pathogens. To identify new prognostic markers for the disease, a multicenter prospective observational cohort study was carried out in COVID-19 patients divided into three cohorts based on symptomatology: mild (n=24), moderate (n=51), and severe/critical (n=31). Faecal and nasopharyngeal samples were taken, and the microbiota was analyzed. Linear discriminant analysis identifiedM. salivarium,P. dentalis, andH. parainfluenzaeas biomarkers of severe COVID-19 in nasopharyngeal microbiota, whileP. biviaandP. timonensiswere defined in faecal microbiota. Additionally, a connection between faecal and nasopharyngeal microbiota was identified, with a significant ratio betweenP. timonensis(faeces) andP. dentalisandM. salivarium(nasopharyngeal) abundances found in critically ill patients. This ratio could serve as a novel prognostic tool for identifying severe COVID-19 cases.