bluuebunny/crossref_metadata_2025 huggingface dataset:
The Doctrine of Equivalents at the Unified Patent Court: A Comparative Analysis of the Main EPC Jurisdictions and a Shot at Harmonization
Authors: Borgogni Daniel
Published: January 2025

The purpose of this analysis is to offer insights on how the recently established Unified Patent Court (‘UPC’) – particularly the Court of Appeal in Luxembourg – might apply the Doctrine of Equivalents (‘DoE’). The answer to this question will affect, in a concrete manner, the scope of protection of most patents (with the exception of national patents) litigated in countries subject to the UPC and greatly influence members of the broader EPC, with evident practical consequences. Specifically, the following work seeks to address this query by looking in turn at the policy considerations underlying the DoE, at the legal framework binding the UPC, and at the jurisprudence on the DoE of the main EPC countries (in order: Germany, UK, France, The Netherlands and Italy). Finally, drawing from the above findings, a number of informed assumptions are made, setting out what is most likely to be expected from the UPC.
Efficacy and safety of antiviral therapies for the treatment of persistent COVID-19 in immunocompromised patients since the Omicron surge: a systematic review
Authors: Hirsch Caroline , Kreuzberger Nina , Skoetz Nicole , Monsef Ina , Kluge Stefan , Spinner Christoph D , Malin Jakob J
Published: January 2025

Background

Persistent COVID-19 (pCOVID-19) in immunocompromised patients is characterized by unspecific symptoms and pulmonary infiltrates due to ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication. Treatment options remain unclear, leading to different approaches, including combination therapy and extended durations. The purpose of this study was to assess the efficacy and safety of antiviral therapies for pCOVID-19 in immunocompromised patients since the Omicron surge.

Methods

We searched MEDLINE and Scopus from 1 January 2022 to 6 August 2024 for cohort studies and case series on nirmatrelvir/ritonavir, remdesivir, ensitrelvir and molnupiravir. Evidence certainty was rated using Grading of Recommendations Assessment, Development, and Evaluation for outcomes including viral clearance, recurrence/relapse, mortality, adverse events (AEs) and symptom resolution.

Results

Thirteen studies involving 127 cases were included. Evidence certainty was very low. In combination therapy with at least two direct antiviral agents, viral clearance was 79%, with a 16% recurrence rate. All-cause mortality was 9%, and mortality was 6% while SARS-CoV-2 positive. In 47 cases, AEs were reported in 11%. Symptom resolution ranged from 3 to 6 days in two studies. In combination therapy with one direct antiviral agent and passive immunization, viral clearance was 89%, with an 11% recurrence rate and no deaths. In four documented cases, no AEs were observed. In monotherapy, viral clearance was 100%, with a 15% recurrence rate. One death, unrelated to SARS-CoV-2, occurred. In 12 documented cases, no AEs were observed.

Conclusions

Based on very low certainty evidence, combining one direct antiviral with passive immunization resulted in high rates of viral clearance and few recurrences. AEs occurred in cases treated with at least two direct antivirals. Controlled studies are needed.
Influence of Saccharomyces cerevisiae CNCM I-1077 on the fecal pH, markers of gut permeability, fecal microbiota, and markers of systemic inflammation in sedentary horses fed a high-starch diet
Authors: Carter M M , Leatherwood J L , Paris B L , Moore G E , George J M , Martinez R E , Karges K , Cox J R , Arnold C E , Glass K G , Bradbery A N , Rodiles A , Wickersham T A
Published: January 2025

Thirty mature Quarter Horse geldings were used in a completely randomized 32-d study to test the hypotheses that supplemental live Saccharomyces cerevisiae CNCM I-1077 improves apparent digestion, stabilizes the fecal pH, reduces gut permeability, maintains microbial communities, and decreases inflammation in horses fed a high-starch diet. Horses were stratified by body weight, age, and body condition score (BCS) to one of two treatments: concentrate formulated with 2g starch • kg BW-1 • meal-1 (CON; n=15) or the same concentrate top-dressed with 25g/d Saccharomyces cerevisiae CNCM I-1077 (SC; n=15; 8×108 CFU). Horses were fed individually in stalls every 12h. Between meals, horses were housed in dry lots with ad libitum access to water and Coastal bermudagrass hay. On d0 and 32, BW and BCS were recorded, and blood was collected before feeding and 2, 8, 16, and 24 h postmeal on d32 to analyze serum D-lactate. Fecal samples were collected on d0, 16, and 32 at 8, 16, and 24h post-meal for fecal pH and starch content. Intake and fecal production were recorded over 4-d to measure digestibility on d28-31. Whole blood total bacterial counts and 16S fecal microbiota rRNA sequencing were performed at d0, 16, and 32. Results revealed an increased ∆BW in SC horses compared with CON horses (P=0.03), with no change in BCS (P=0.97). D-lactate tended to be greater in SC horses on d32 at 16 and 24h post-meal compared with CON horses (P=0.10). Concentrations of TNFα and LogCCL2 decreased from d0 to d 32 regardless of dietary supplementation (P≤0.02). Fold change of percent reads from d0 in whole blood bacterial 16S rRNA did not differ between groups. Fecal starch was undetectable, and there were no differences in intake or apparent digestibility. Fecal pH tended (P=0.07) to be lower in CON at 0h on d32 (6.03 ± 0.06) than d16 (6.14 ± 0.06). Additionally, pH tended (P=0.09) to be lower in CON (6.03 ± 0.06) than SC (6.16 ± 0.06) at 0h on d32. Supplementation of Saccharomyces cerevisiae CNCM I-1077 maintained Bacteroidales and reduced acidosis-like bacteria like Streptococcus and potential pathogens like Enterobacteriaceae, Stenotrophomonas, and Rhodococcus at d16 (P<0.05). Further, supplementation increased fibrolytic bacteria at d32, such as Ruminococcus, Fibrobacter, and Succinivibrio (P<0.05). These results indicate Saccharomyces cerevisiae CNCM I-1077 increases BW and promotes a more diverse microbiome when hoses are fed ad libitum hay and a high-starch concentrate.
Bladder wash: a proof of concept as an alternative specimen for postmortem toxicology
Authors: Rodda Luke N , Candela Kylie E , Hart Amy P , Moffatt Ellen G , Farley Megan C , Sue Pearring , Scott Karen S
Published: January 2025

In postmortem forensic investigation cases where the bladder is voided or dehydrated prior to autopsy, it is possible to wash the bladder with saline to collect the “bladder wash” and any residual urine for toxicological analysis. While not conventional, this study aims to determine the use of bladder washes as alternative specimens in postmortem forensic toxicology. Comprehensive drug and alcohol analysis was performed on blood, urine, vitreous humor, and bladder wash samples. Control studies consisted of matched bladder wash and urine samples for comparison. Authentic applicability studies were performed on bladder wash samples in cases where only blood or no urine samples were available. Bladder wash testing via the routine urine methodology was shown to have the appropriate sensitivity and specificity to serve as an alternative specimen. Specificity of the applicability studies was further improved when comparisons were corrected by evaluating individual analytes jointly with their related parent drug or metabolites. Individual and corrected sensitivity and specificity rates of above 99% were typically observed in both comparisons against urine and blood paired samples. Following drug analysis of 31 cases in which only a bladder wash was available, 57 detections from 23 different analytes were detected that otherwise would not have been obtained. This study demonstrates that standardized collection of the easily accessible bladder wash for postmortem toxicological analysis serves forensic toxicologists and pathologists with invaluable information where urine or other biological specimens are not available.
The Newport Manual: The new kid on the block on the laws of naval warfare
Authors: Fink Martin
Published: January 2025

The Newport Manual on the law of Naval Warfare, prepared by a group of naval law experts, is a new publication that helps navigate what the law is in naval warfare. This is helpful because this area of the laws of armed conflict has always been in an ever-existent state of crisis. The Newport Manual touches on a number of topical issues, discusses subjects that have not been dealt with in the form of an expert manual, and contains a critical view towards the San Remo Manual on the International law Applicable to Armed Conflicts at Sea. This article discusses the background and aim of the Newport Manual, compares the main differences between the Newport Manual and the San Remo Manual, and highlights four other noteworthy issues in the Newport Manual.
Similar phylogeographic history in a fig species and its obligate pollinators forms parallel genetic structure
Authors: Liu Min , Huang Man-Juan , Kjellberg Finn , Chen Yan , Zhang Jian , Zhao Rui , Ding Yuan-Yuan , Yang Yang , Deng Jun-Yin , Jiang Kai , Li Yuan-Yuan , Tong Xin , Luo Tong , Wang Rong , Chen Xiao-Yong
Published: January 2025

Closely related and co-distributed species usually share a common phylogeographic history, but it is still largely unclear whether ecologically interacting species can respond synchronously to historical climate changes. Here, we focused on a fig-pollinator mutualism comprising Ficus pumila var. pumila and its obligate pollinators (morphospecies Wiebesia pumilae), and collected samples across most of their distribution ranges. We employed both cytoplasmic DNA sequences and nuclear microsatellite loci to reveal the species composition within the pollinator and to test whether the two mutualists exhibited similar postglacial phylogeographic patterns. In the three cryptic pollinator species observed here, two dominant cryptic species were parapatric, covering the north and the south of the plant’s distribution range, respectively. Similar current spatial genetic structure was detected in the two dominant cryptic pollinator species and the plant, with an eastern and a western genetic cluster. Moreover, for these three species, evidence for postglacial expansion was found, and their potential refugia at the last glacial maximum were located in the east and the west of their distribution ranges. These results suggest their synchronous responses to historical climate changes. Our study therefore shows congruent phylogeographic patterns between obligate mutualists and highlight the role of biogeographic factors in shaping the current biodiversity across trophic levels.
Constructing merger trees of density peaks using phase-space watershed segmentation algorithm
Authors: Geda Robel , Teyssier Romain
Published: January 2025

Structure identification in cosmological simulations plays an important role in analysing simulation outputs. The definition of these structures directly impacts the inferred properties derived from these simulations. This paper proposes a more straightforward definition and model of structure by focusing on density peaks rather than haloes and clumps. It introduces a new watershed algorithm that uses phase-space analysis to identify structures, especially in complex environments where traditional methods may struggle due to spatially overlapping structures. Additionally, a merger tree code is introduced to track density peaks across time-steps, making use of the boosted potential for identifying the most bound particles for each peak.
Occupation and 11-year lung function decline in the HUNT Study
Authors: Aarhus L , Skare Ø , Nordby K-C , Gulsvik A , Vikjord S , Hedman L , Langhammer A
Published: January 2025

Background

The association between occupational titles and lung function has mostly been examined through cross-sectional studies. Preventive measures are expected to mitigate adverse effects; hence, updated estimates are necessary.

Aims

To study change in lung function measured by spirometry across occupations.

Methods

This population-based prospective cohort study comprised 5618 working adult participants of the Trøndelag Health Study (HUNT3, 2005–07), Norway. Among these, 3800 individuals (43% men, mean age 42 years, range 20–55) also attended HUNT4 (2017–19). We analysed longitudinal decline in forced expiratory volume in 1 second (FEV1) z-score during the 11-year follow-up by occupation (white-collar workers as reference category), in mixed models, adjusting for age, sex and smoking. We assessed the prevalence of self-reported respiratory symptoms and disease in the working population in HUNT4 (n = 32 124) and HUNT3 (n = 32 070).

Results

Compared with white-collar workers, agricultural workers and ‘drivers and mobile plant operators’, had larger declines in FEV1z-score during follow-up. In sex-stratified analyses, men defined as agricultural workers and ‘drivers and mobile plant operators’ had larger declines than white-collar workers. Among women, who were underrepresented in many blue-collar jobs, workers classified as ‘machine operators and assemblers’ experienced greater declines. In the working population in HUNT4, the prevalence of respiratory symptoms in connection with work was 8%, and lower among white-collar workers (6%) than blue-collar workers (14%).

Conclusions

Although certain workers in Norway remain at risk for occupational lung function decline, there were modest differences between occupations. The findings encourage continuous efforts to implement preventive measures in high-risk jobs.
Association Between Positive Airway Pressure Therapy and Healthcare Costs Among Older Adults with Comorbid Obstructive Sleep Apnea and Common Chronic Conditions: An Actuarial Analysis
Authors: Wickwire Emerson M , Fernandez Chris R , Huynh Nhan , Watson Nathaniel F , Duncan Ian
Published: January 2025

Study objectives

To determine the association between adherence to positive airway pressure and healthcare costs among a national sample of older adults with comorbid OSA and common chronic conditions

Methods

Our data source was a random sample of Medicare administrative claims for years 2016-2019. Inclusion criteria included age >65 years and new diagnosis of OSA. Exclusion criteria included evidence of prior OSA treatment during the 12 months prior to the index date, active cancer, or end-stage renal disease. OSA was defined using physician-assigned diagnostic codes. Common chronic conditions included chronic obstructive pulmonary disease, congestive heart failure, depression, hypertension, type 2 diabetes mellitus, obesity, and stroke. Based on Medicare policy, individuals were classified as adherers, non-adherers, or non-initiators. Risk adjustment was based on the CMS-HCC approach developed by the Centers for Medicaid and Medicare Service specifically to estimate anticipated costs. To examine the impact of PAP adherence on costs, we employed a weighted DID regression framework to account for baseline variations in health status and other confounding factors.

Results

Participants included 28,220 Medicare beneficiaries with comorbid OSA. Of these, 45% were adherent to PAP, 10% were non-adherent, and 44% did not initiate PAP. Relative to non-initiators, beneficiaries who initiated PAP displayed $195 reduced per-member per-month costs over 24 months. This finding remained consistent across all seven medical and psychiatric subgroups, as well as among individuals with multimorbidity.

Conclusions

In this national analysis of Medicare beneficiaries with common chronic conditions, PAP adherence was associated with reduced costs over 24 months.
Clinical, Pathologic, and Molecular spectrum of Angioinmmunoblastic T-cell Lymphoma Cutaneous Lesions
Authors: Díaz de la Pinta Francisco Javier , Pérez-Guillermo Cuevas M. Ángeles , Manso Rebeca , Torre Castro Juan , Astilleros Blanco de Cordova Laura , Saus Carles , Morillo Giles Daniel , Requena Caballero Luis , Rodríguez Pinilla Socorro María
Published: January 2025

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive malignancy that frequently presents with extranodal involvement. Cutaneous tropism is clinically and histopathologically variable, which may pose a diagnostic challenge. We conducted a retrospective analysis of 40 samples of 20 cases of cutaneous AITL, focusing on the clinicopathologic and molecular correlations between skin and lymph node (LN) samples. In all cases, cutaneous involvement was concurrent with or followed the diagnosis of nodal AITL, with no cases preceding systemic involvement. Clinically, cutaneous AITL presented in 2 main forms: an evanescent rash and persistent lesions, with histopathology revealing diverse infiltration patterns, including perivascular, nodular, granulomatous, panniculitic, vasculitis, and epidermotropic. Clinical presentation and histologic patterns tend to correlate. Histopathologically, plasma cells were present in 15/22 skin samples, 5 of them being kappa-light restricted but polytypic in corresponding LNs. Epstein-Barr virus+ B cells were present in 10 cutaneous lesions and were already present in corresponding LNs. Molecular studies found correlations in all but one case between LN and skin, particularly in the presence of RHOA and TET2 mutations, which were identified in 8 of 12 cases. Molecular analysis was also informative in 4 cases with low levels of infiltration. The study also highlighted unique cases with distinct clinical and histopathologic patterns coexisting in the same patient over time. One case exhibited simultaneous granulomatous and epidermotropic patterns in different skin lesions. Four cases of cutaneous B-cell lymphomas associated with AITL were identified. Our study underscores the importance of integrating clinical, histopathologic, and molecular data to accurately diagnose cutaneous AITL.
Severity of Impaired Oxygenation and Conservative Oxygenation Targets in Mechanically Ventilated Children: A Post Hoc Subgroup Analysis of the Oxy-PICU Trial of Conservative Oxygenation
Authors: Ray Samiran , Wiegand Martin , Gould Doug W. , Harrison David A. , Mouncey Paul R. , Peters Mark J. ,   on behalf of the Oxy-PICU Investigators of the United Kingdom Paediatric Critical Care Society Study Group
Published: January 2025

Objectives:

A conservative oxygenation strategy is recommended in adult and pediatric guidelines for the management of acute respiratory distress syndrome to reduce iatrogenic lung damage. In the recently reported Oxy-PICU trial, targeting peripheral oxygen saturations (Spo
2) between 88% and 92% was associated with a shorter duration of organ support and greater survival, compared with Spo
2 greater than 94%, in mechanically ventilated children following unplanned admission to PICU. We investigated whether this benefit was greater in those who had severely impaired oxygenation at randomization.

Design:

Post hoc analysis of a pragmatic, open-label, multicenter randomized controlled trial.

Setting:

Fifteen PICUs across England and Scotland.

Patients:

Children between 38 weeks old corrected gestational age and 15 years accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange.

Interventions:

A mixed-effects ordinal regression model was used to explore the effect of severity of lung injury, dichotomized to an oxygen saturation index (OSI) less than 12 or greater than or equal to 12 at randomization, the trial group allocation, age, and Pediatric Index of Mortality-3 on the composite ordinal outcome measure of duration of organ support at day 30 and mortality, with death being the worst outcome. An interaction term was included to specifically understand the effect of trial arm allocation on those with and OSI less than 12 and OSI greater than or equal to 12.

Measurements and Main Results:

Data were available for 1775 of 1986 eligible children. Two hundred twelve of 1775 children had an OSI greater than or equal to 12 at randomization. The trial primary outcome did not vary significantly according to OSI category. Both children with OSI less than 12 (odds ratio [OR], 0.85; 95% CI, 0.71–1.01) and OSI greater than or equal to 12 (OR, 0.95; 95% CI, 0.49–1.84) benefited from conservative arm allocation, with relative benefit greater for those with an OSI less than 12.

Conclusions:

These data do not provide evidence that a conservative oxygenation strategy should be limited to mechanically ventilated children with severely impaired oxygenation.
Desulfovibrio falkowii sp. nov., Porphyromonas miyakawae sp. nov., Mediterraneibacter flintii sp. nov. and Owariibacterium komagatae gen. nov., sp. nov., isolated from human faeces
Authors: Hamaguchi Tomonari , Ohara Misuzu , Hisatomi Atsushi , Sekiguchi Kyohei , Takeda Jun-ichi , Ueyama Jun , Ito Mikako , Nishiwaki Hiroshi , Ogi Tomoo , Hirayama Masaaki , Ohkuma Moriya , Sakamoto Mitsuo , Ohno Kinji
Published: January 2025

Small, obligately anaerobic strains 13CB8CT, 13CB11CT, 13CB18CT and 13GAM1GT were isolated from a faecal sample in a patient with Parkinson’s disease with a history of duodenal resection. After conducting a comprehensive polyphasic taxonomic analysis including genomic analysis, we propose the establishment of one new genus and four new species. The novel bacteria are Desulfovibrio falkowii sp. nov. (type strain JCM 36128T = DSM 116810T), Porphyromonas miyakawae sp. nov. (type strain JCM 36129T = DSM 116947T), Mediterraneibacter flintii sp. nov. (type strain JCM 36130T = DSM 116866T) and Owariibacterium komagatae gen. nov. sp. nov. (type strain JCM 36131T = DSM 116982T), respectively.
Pseudobensingtonia carpini sp. nov., a novel yeast species isolated from plant leaves in China
Authors: Chai Chun-Yue , Song Bing-Yan , Lu Dan , Zhang Cai-Ying , Hui Feng-Li
Published: January 2025

Two novel yeast strains, NYNU 236247 and NYNU 23523, were isolated from the leaves of Carpinus turczaninowii Hance, collected in the Tianchi Mountain National Forest Park, Henan Province, central China. Phylogenetic analysis of the D1/D2 domain of the large subunit rRNA gene and the internal transcribed spacer (ITS) region revealed the closest relatives of the strains are three described Pseudobensingtonia species: Ps. fusiformis, Ps. musae and Ps. ingoldii. The novel species differed from the type strains of these three species by 12 to 22 nucleotide substitutions and 1 gap (~2.0–4.0%) in the D1/D2 domain and by 78 to 100 nucleotide mismatches (~12.0–16%) in the ITS region. Physiologically, the novel species differs from Ps. fusiformis and Ps. musae in its ability to assimilate dl-lactate and melezitose and from Ps. ingoldii by its inability to assimilate melibiose, soluble starch and ethanol. Pseudobensingtonia carpini sp. nov. is proposed for those two strains, with the holotype designated as GDMCC 2.483T (MycoBank MB 857072).
Transcriptional dynamics during Heliothis zea nudivirus 1 infection in an ovarian cell line from Helicoverpa zea
Authors: Petersen Jirka Manuel , Bryon Astrid , Bézier Annie , Drezen Jean-Michel , van Oers Monique M.
Published: January 2025

Nudiviruses (family Nudiviridae) are double-stranded DNA viruses that infect various insects and crustaceans. Among them, Heliothis zea nudivirus 1 (HzNV-1) represents the rare case of a lepidopteran nudivirus inducing a sexual pathology. Studies about molecular pathological dynamics of HzNV-1 or other nudiviruses are scarce. Hence, this study aims to provide a transcriptomic profile of HzNV-1 in an ovary-derived cell line of Helicoverpa zea (HZ-AM1), during early (3, 6 and 9 h post-infection) and advanced (12 and 24 h post-infection) stages of infection. Total RNA was extracted from both virus- and mock-infected cells, and RNA-seq analysis was performed to examine both virus and host transcriptional dynamics. Hierarchical clustering was used to categorize viral genes, while differential gene expression analysis was utilized to pinpoint host genes that are significantly affected by the infection. Hierarchical clustering classified the 154 HzNV-1 genes into four temporal phases, with early phases mainly involving transcription and replication genes and later phases including genes for virion assembly. In addition, a novel viral promoter motif was identified in the upstream region of early-expressed genes. Host gene analysis revealed significant upregulation of heat shock protein genes and downregulation of histone genes. The identification of temporal patterns in viral gene expression enhances the molecular understanding of nudivirus pathology, while the identified differentially expressed host genes highlight the key pathways most hijacked by HzNV-1 infection.
Unveiling the ghost: machine learning’s impact on the landscape of virology
Authors: Bowyer Sebastian , Allen David J. , Furnham Nicholas
Published: January 2025

The complexity and speed of evolution in viruses with RNA genomes makes predictive identification of variants with epidemic or pandemic potential challenging. In recent years, machine learning has become an increasingly capable technology for addressing this challenge, as advances in methods and computational power have dramatically improved the performance of models and led to their widespread adoption across industries and disciplines. Nascent applications of machine learning technology to virus research have now expanded, providing new tools for handling large-scale datasets and leading to a reshaping of existing workflows for phenotype prediction, phylogenetic analysis, drug discovery and more. This review explores how machine learning has been applied to and has impacted the study of viruses, before addressing the strengths and limitations of its techniques and finally highlighting the next steps that are needed for the technology to reach its full potential in this challenging and ever-relevant research area.
Conceptualising the context and mechanisms for tackling loneliness in older adults through interventions: A Critical Interpretive Synthesis
Authors: Ratcliffe John , Matcham Faith , Molteni Erika , Antonelli Michela , Rees Jessica , Shi Yu , Liu Jingqi , Ourselin Sebastian , Tinker Anthea , Zhou Yi , Liu Wei
Published: January 2025

Background

Loneliness in later life has been widely associated with poor mental and physical health. However, despite many reviews, current evidence does not provide a clear picture of how to tackle loneliness in older adults through interventions. Research examining the contexts and mechanisms for reducing loneliness through interventions is required to identify how, why, and for who interventions work or do not work.

Methods

A critical interpretive synthesis, a review method designed to rigorously and reflexively re-examine existing literature, was conducted to re-consider and identify what matters in interventions. This was enacted through a broad search strategy incorporating database searches, contacting experts, reference-chaining, and team discussions, enabling a flexible and iterative review able to generate new theory.

Results

274 papers were included in the analysis. We identified four dimensions to whether and how interventions worked.Intended outcomemirrored different theoretical perspectives on how to reduce loneliness. Four intended outcomes were identified: cognitive change; improved social connections; physiological change; and a more meaningful life. The second dimension was thelevelof an intervention - whether it intended to intervene at a micro, meso, or macro level. Thirdly, 13positive featuresof interventions were noted to have been evidenced to lead to or constitute more effective interventions. These were interventions that are organised, adaptable, have good staff/volunteers, provide support to attend, routinised, built on shared interests/identities, personalised, culturally aware, co-produced, involve active participation, strengths-based, lasting, and targeted at the appropriate people. Lastly, nineemotions that represent less lonelinesswere identified: a feeling of reciprocated interactions; emotional and social support; belonging; perspective; self-efficacy; mattering; pride; purpose; and empowerment.

Conclusions

Interventions and evaluations should look beyond comparing activities to see which are best and recognise that multidimensionality and variation is vital for individuals and communities with different needs. Identifying what the intended outcome of an intervention is, what level of society it intends to impact, and whether it actions the positive features identified in this study, can be employed to better target the variety of emotions that represent less loneliness.
Retinal vascularization rate predicts retinopathy of prematurity and remains unaffected by low-dose bevacizumab treatment
Authors: Chang Emer , Josan Amandeep , Purohit Ravi , Aslam Sher A , Hartley Caroline , Patel Chetan K , Xue Kanmin
Published: January 2025

Purpose

To assess the rate of retinal vascularisation derived from ultra-widefield (UWF) imaging-based retinopathy of prematurity (ROP) screening as predictor of type 1 ROP and characterise the effect of anti-VEGF therapy on vascularisation rate.

Design

Retrospective, consecutive cohort study.

Subjects

132 eyes of 76 premature infants with mean gestational age (GA) of 26.0(±2.0SD) weeks and birth weight (BW) of 815(±264) g, who underwent longitudinal UWF imaging for ROP screening.

Setting/Venue

Level 3 neonatal unit in Oxford, United Kingdom

Methods

The extent of retinal vascularisation on each UWF image was measured as the ratio between ‘disc-to-temporal vascular front’ and ‘disc-to-fovea’ distance along a straight line bisecting the vascular arcades. Measurements from ≥3 timepoints plotted against post-menstrual age (PMA) enabled calculation of temporal vascularisation rate (TVR) for each eye. Using TVR, GA and BW as predictors, a machine learning model was created to classify eyes as either Group AB (no ROP and type 2 ROP) or Group C (type 1 ROP). The model was validated in a withheld cohort of 32 eyes (19 infants) of which 8 eyes (5 infants) required treatment. TVR in 37 eyes (20 infants) was compared before and after ultra-low-dose (0.16 mg) intravitreal bevacizumab treatment.

Main Outcome Measures

Rate of retinal vascularisation.

Results

Slower retinal vascularisation correlated with increasing ROP severity, with TVR being 29% slower in Group C eyes (n=50) than Group AB eyes (n=33 no ROP and n=49 type 2 ROP) (p=0.04). Our model correctly predicted ROP outcomes of 30/32 eyes, achieving a balanced accuracy of 95.8%. No significant change in TVR was found before and after bevacizumab treatment with mean post-treatment imaging follow-up of 7.7(±7.9) weeks (p=0.60 right eyes, p=0.71 left eyes).

Conclusions

UWF imaging-based ROP screening enables quantification of retinal vascularisation rate, which can provide early prediction of type 1 ROP independent of BW and GA. Rate of physiological retinal vascularisation does not appear to be significantly affected by ultra-low-dose anti-VEGF treatment, which has significant implications for the development of peripheral avascular retina and timing of anti-VEGF intervention to prevent disease progression in high risk infants.
Mixtures of multiple air pollutants from specific industrial or residential sources and mortality from ischemic heart disease, cardiovascular disease, and non-accidental causes: A large general population Canadian cohort study
Authors: Zhao Naizhuo , Olaniyan Toyib , Mitchell Kimberly , Rouleau Mathieu , Popadic Ivana , Anastasopolos Angelos , Tjepkema Michael , Cakmak Sabit
Published: January 2025

Background

Previous studies on ambient air pollution and mortality typically focus on individual pollutants rather than their mixtures, and overall pollution rather than air pollution from specific sources. We aimed to assess the associations between ambient mixtures of fine particulate matter (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) from various industrial and residential sources, and deaths from ischemic heart disease (IHD), cardiovascular disease (CVD) and non-accidental causes.

Methods

We linked the 2006 Canadian Census Health and Environment Cohort (CanCHEC) with the Canadian Vital Statistics Database, identifying 56190, 98185, and 381050 deaths between 2006 and 2019 from IHD, CVD, and non-accidental causes, respectively. Annual average concentrations of PM2.5, SO2, NO2, and O3from upstream petroleum, downstream petroleum, non-ferrous smelting, chemical industry and residential fuel combustion were estimated using the Global Environmental Multiscale-Modelling Air Quality and Chemistry (GEM-MACH) model. These concentrations were assigned to CanCHEC participants based on their annual residential postal codes. Quantile g-computation models were used to calculate hazard ratios (HRs) for deaths from IHD, CVD, and non-accidental causes per quartile increase in all four air pollutants from each specific sector.

Results

We observed significant associations between the mixture of air pollutants and deaths from IHD, CVD, and non-accidental causes for emissions from upstream petroleum [HR: 1.18 (95% CI: 1.12-1.24), 1.12 (1.08-1.16), and 1.05 (1.04-1.05)], downstream petroleum [1.06 (1.05-, 1.04 (1.03-1.05), and 1.03 (1.02-1.03)], the chemical industry [1.10 (1.08-1.13), 1.07 (1.06-1.09), and 1.10 (1.08-1.13)], and residential fuel combustion [1.18 (1.12-1.23), 1.12 (1.08-1.16), and 1.07 (1.05-1.09)]. PM2.5and SO2contributed more to the increased risk of death than NO2and O3. Mortality from CVD or non-accidental causes was not associated with the mixtures of air pollutants from non-ferrous smelting.

Conclusions

Ambient PM2.5and SO2from certain sectors, but not all, greatly contribute to the increased risk of non-accidental, IHD, and CVD deaths.
Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation
Authors: Fitzgerald Liam S. , Reynoso Spurrier Connor S. , Lau Nathan J. , Melamed Miles D. , Burnett Lindsey A. , Meyer Gretchen A. , Gui Chang , Hevener Andrea L. , Sanford James A. , Schenk Simon
Published: January 2025

Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial biogenesis, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximum uncoupled respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times (ZT), ZT 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genesBmal1andDbpexhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.
BASTA, a simple whole blood assay for measuring β-cell antigen specific CD4+T-cell responses in type 1 diabetes
Authors: Lacorcia Matthew , Bhattercharjee Pushpak , Foster Abby , Hardy Melinda Y. , Tye-Din Jason , Karas John , Wentworth John M , Cameron Fergus , Mannering Stuart I.
Published: January 2025

Type 1 diabetes (T1D) is an autoimmune disease where T-cells mediate the destruction of the insulin-producing β-cells found within the Islets of Langerhans in the pancreas. Currently, autoantibodies to β-cell antigens are the only tests available to detect β-cell autoimmunity. T-cell responses to β-cell antigens, which are known to cause T1D, can only be measured in research settings due to the complexity of assays and the large blood volumes required. Here we describe theβ-cellantigenspecificT-cellassay – BASTA. BASTA is a simple whole blood assay that can detect human CD4+T-cell responses to β-cell antigens by measuring antigen-stimulated IL-2 production. BASTA is both more sensitive and specific than the CFSE-based Proliferation Assay. We used BASTA to identify the regions of preproinsulin which stimulated T-cell responses specifically in blood from people with T1D. BASTA can be done with as little as 2-3 mL of blood. We found that effector memory CD4+T cells are the primary producers of IL-2 in response to preproinsulin peptides. We then evaluated responses to individual and pooled preproinsulin peptides in a cross-sectional study of pediatric subjects: without T1D, without T1D but with a first-degree relative with T1D, or diagnosed with T1D. In contrast to other preproinsulin peptides, full-length C-peptide (PI33-63) showed excellent specificity for T1D (AUC = 0.86). We suggest that BASTA will be a useful tool for monitoring changes in β-cell specific CD4+T-cell responses both in research and clinical settings.

One Sentence Summary

β-cell antigen specific CD4+T-cell responses in children with T1D can be measured using a simple whole blood assay.
Effective prediction of IL-17 inducing peptides using hybrid approach: iIL17pred
Authors: Arora Pooja , Periwal Neha , Aggarwal Lakshay , Sood Vikas , Kaur Baljeet
Published: January 2025

Background

Interleukin 17 (IL-17) plays a crucial role in regulating the immune system and is associated with numerous diseases. Modulating IL-17 levels has demonstrated potential in mitigating disease symptoms, positioning it as a compelling target for drug development. Therefore, identifying and characterizing novel drug molecules capable of influencing IL-17 levels is critical. Recent advances in therapeutic peptides underscore their promise as attractive drug candidates, inspiring the development of IL-17 modulating peptides.

Results

This study aimed to enhance existing methods for efficiently classifying IL-17 inducing peptides. Positive and negative datasets were obtained from the Immune Epitope Database, and peptide features were extracted using the pfeature algorithm. A three-stage hybrid approach combining BLAST, MERCI, and machine learning techniques was employed to accurately classify IL-17-inducing peptides.

Conclusions

Extensive benchmarking experiments revealed that our proposed method outperforms existing techniques i.e IL17eScan, across key performance metrics, including sensitivity, accuracy, and area under the curve-receiver operating characteristics (AUC-ROC). Our algorithm achieved an accuracy of 88.08% and a Matthews Correlation Coefficient (MCC) of 0.68 on an external dataset, significantly surpassing the accuracy of 78.57% and MCC of 0.57 achieved by existing methods under comparable conditions. This demonstrates a substantial improvement in IL-17 peptide classification. The results are accessible via a user-friendly web server (http://www.soodlab.com/iil17pred/). These findings hold significant potential for predicting IL-17-inducing peptides, which can be further validated experimentally.
PHYSICAL EXERCISE RESTORES NEUROCOGNITIVE HOMEOSTASIS DISRUPTED BY NON-SEVERE MURINE MALARIA
Authors: de Sousa Luciana Pereira , de Oliveira Lavigne Ingrid , da Silva Nogueira Mônica , Daniel-Ribeiro Cláudio Tadeu
Published: January 2025

Malaria disrupts neurocognitive homeostasis in humans, including in the non-severe manifestation of the disease - which is the most prevalent form of malaria in the world. This disruption is classically observed in human and experimental models of cerebral malaria. More recently, we demonstrated that this can also be observed in an experimental model of non-severe malaria and that Th2-immune response improves cognition and attenuates anxiety-like behavior associated to malaria. Complementarily, we have been studying the effect of physical exercise in restoring the neurocognitive homeostasis lost after non-severe murine malaria.
Single-nuclei transcriptomics revealed auxin-driven mechanisms of wood plasticity and severe drought tolerance in poplar
Authors: Gómez-Soto Daniela , Pereira Wendell J. , Piedrabuena-Díaz Alejandro , Dervinis Christopher , Kirst Matias , Allona Isabel , Perales Mariano , Conde Daniel
Published: January 2025

Drought significantly affects forests and woody crops by limiting their growth, increasing their susceptibility to diseases, and reducing productivity. Wood anatomical plasticity is a crucial adaptive mechanism that enables trees to cope with fluctuations in water availability. During severe drought, trees develop more and narrower vessels, enhancing hydraulic safety and reducing the risk of embolism. However, the molecular regulation of vessel formation is still not well understood. Using single-nucleus transcriptomics, we generated a cell type-specific gene expression map of the mature poplar stem under well-watered and drought conditions. Our findings revealed extensive gene expression reprogramming in xylem-forming cells, with changes in auxin homeostasis identified as a key mechanism for anatomical adaptation. Specifically, we showed that poplarWAT1-like genes control vessel spatial patterning. Additionally, the downregulation ofWAT1-like gene expression in the dividing cells of the vascular cambium and the upregulation ofMP-like gene in cells undergoing early vessel differentiation facilitate the formation of secondary xylem with narrower and more numerous vessels. Furthermore, thewat2mutant exhibited greater drought tolerance than wild-type trees, underscoring its potential for developing drought-resilient tree varieties. These insights enhance our understanding of xylem plasticity and provide valuable targets for improving drought tolerance in woody plants.
Regenerative failure of sympathetic axons contributes to deficits in functional recovery after nerve injury
Authors: Tian Tina , Kim David , Yu Kuai , Hartzell Criss , Ward Patricia J.
Published: January 2025

Renewed scientific interest in sympathetic modulation of muscle and neuromuscular junctions has spurred a flurry of new discoveries with major implications for motor diseases. However, the role sympathetic axons play in the persistent dysfunction that occurs after nerve injuries remains to be explored. Peripheral nerve injuries are common and lead to motor, sensory, and autonomic deficits that result in lifelong disabilities. Given the importance of sympathetic signaling in muscle metabolic health and maintaining bodily homeostasis, it is imperative to understand the regenerative capacity of sympathetic axons after injury. Therefore, we tested sympathetic axon regeneration and functional reinnervation of skin and muscle, both acute and long-term, using a battery of anatomical, pharmacological, chemogenetic, cell culture, analytical chemistry, and electrophysiological techniques. We employed several established growth-enhancing interventions, including electrical stimulation and conditioning lesion, as well as an innovative tool called bioluminescent optogenetics. Our results indicate that sympathetic regeneration is not enhanced by any of these treatments and may even be detrimental to sympathetic regeneration. Despite the complete return of motor reinnervation after sciatic nerve injury, gastrocnemius muscle atrophy and deficits in muscle cellular energy charge, as measured by relative ATP, ADP, and AMP concentrations, persisted long after injury, even with electrical stimulation. We suggest that these long-term deficits in muscle energy charge and atrophy are related to the deficiency in sympathetic axon regeneration. New studies are needed to better understand the mechanisms underlying sympathetic regeneration to develop therapeutics that can enhance the regeneration of all axon types.
AUTO-SP: automated sample preparation for analyzing proteins and protein modifications
Authors: Lih T. Mamie , Jiao Liyuan , Chen Lijun , Woo Jongmin , Wang Yuefan , Zhang Hui
Published: January 2025

Liquid chromatography (LC) tandem mass spectrometry (MS/MS) is one of the widely used proteomic techniques to study the alterations occurred at protein expression level as well as post-translation modifications (PTMs) of proteins that are relevant to different physiological or pathological statuses. The mass spectrometric analysis of peptides fragmented from proteins (bottom-up proteomics) has emerged as one of the major approaches for proteomics. In this approach, proteins are first cleaved into peptides for mass spectrometric analysis and peptides with PTMs are further enriched followed by the LC-MS/MS analysis. To achieve a reproducible and quantitative proteomic characterization, a well-established protease digestion and PTM peptide enrichment protocol is critical. In this study, we developed an automated sample preparation (AUTO-SP) for analyzing proteins and protein modifications utilizing Patient-Derived Xenograft (PDX) breast cancer tumors (basal-like and luminal subtypes). The protein amount was quantified and proteins were further digested by using AUTO-SP for each PDX sample. Based on the data-independent acquisition (DIA)-MS data, we observed samples of the same breast cancer subtypes were highly correlated (>0.98). Additionally, >14,000 ubiquitinated peptides were identified in the PDX samples when using AUTO-SP for ubiquitin enrichment, while unique pathways were enriched from the basal-like and luminal subtypes. AUTO-SP demonstrated its efficacy to provide reliable and reproducible sample preparation procedure for MS-based proteomic and PTM analyses.
A cationic liposome-formulated Toll Like Receptor (TLR)7/8 agonist enhances the efficacy of a vaccine against fentanyl toxicity
Authors: Hamid Fatima A , Le Nguyet-Minh Nguyen , Song Daihyun , Amin Hardik , Hicks Linda , Bird Sophia , Siram Karthik , Hoppe Brooke , Demeler Borries , Evans Jay T. , Burkhart David , Pravetoni Marco
Published: January 2025

The U.S. opioid epidemic is an extraordinary public health crisis that started in 1990 and significantly accelerated in the last decade. Since 2020, over 100,000 fatal drug overdoses have been reported annually, and 75% of those involved fentanyl and its analogs (F/FA). Accelerating the translation of innovative, effective, and safe treatments is needed to augment existing measures to counteract such a crisis. Active immunization against F/FA and other opioids represents a promising therapeutic and prophylactic strategy for opioid use disorder (OUD) and opioid-induced overdose toxicity. Previously we demonstrated that the anti-fentanyl vaccine comprising a fentanyl-based hapten (F) conjugated to the diphtheria cross-reactive material (CRM), admixed with the novel lipidated toll-like receptor 7/8 (TLR7/8) agonist INI-4001 adsorbed on Alhydrogel®(alum) induced high-affinity fentanyl-specific polyclonal antibodies that protected against fentanyl-induced pharmacological effects in mice, rats, and mini-pigs. Here, INI-4001 was formulated into liposomes with different surface charges, and their impact on F-CRM adsorption, INI-4001 adjuvanticity, and vaccine efficacy were explored. Additionally, as the role of innate immunity in mediating the efficacy of addiction vaccines is largely unknown, we tested these formulations on the activation of innate immunityin vitro. Cationic INI-4001 liposomes surpassed other liposomal and aluminum-based formulations of INI-4001 by enhancing the efficacy of fentanyl vaccines and protecting rats against bradycardia and respiratory depression by blocking the distribution of fentanyl to the brain. Fentanyl vaccines adjuvanted with either cationic INI-4001 liposomes or the aqueous INI-4001 adsorbed to alum induced significant surface expression of co-stimulatory molecules and maturation markers in a murine dendritic cell line (JAWS II), while the former was superior in enhancing the macrophages surface expression of CD40, CD86 and inducible nitric oxide synthase (iNOS), indicative of maturation and activation. These results warrant further investigation of liposome-based formulations of TLR7/8 agonists for improving the efficacy of vaccines targeting F/FA and other opioids of public health interest.

Graphical abstract