bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflecting on the rule of law contestations narratives in the world trading system
Authors: Yenkong Ngangjoh Hodu
Published: January 2024

Contestations have emerged over the nearly three decades of the World Trade Organization (WTO) regarding the narratives on the rule of law (ROL) as a central tenet of the Multilateral Trading System. One of such contestation is whether the idea of ROL was ever internalized in the WTO at its formation or has been exaggerated. This article critically explores this narrative and locates it in the context of the events of the past two decades in the WTO. It challenges the notion of ROL in the world trading system. It argues that although significant progress was made in mainstreaming ROL in the Uruguay Round project, it would be an exaggeration to claim that ROL was embedded in the trading system from its inception. The article concludes that sceptics of the ROL project in the WTO have arguably been vindicated by how things have unfolded in the past two decades.
The Fann, a Genre of Oral Poetry in Antiochian Arabic: Remarks on Form and Performance Practice
Authors: Ağbaht Mahmut , Greve Martin
Published: January 2024

The fann is a genre of oral poetry in the vernacular Arabic of the Alawi community in the Antioch/Hatay province of Turkey. Until recently, it has hardly been mentioned in academic literature. Poetic form and rhythm structure are largely fixed in this genre and it is almost always performed in a similar way; when it comes to the quality of the voice, including a more or less clear melodic shape, there is more left up to the performer. During performances, the rhythmical element dominates the essence of melodic aspects. A preliminary comparison with related genres in the region demonstrates that both the form and performance practice of fann resemble genres in neighbouring Arab countries. Comparison also finds that there is hardly any connection with any Turkish and Kurdish singer-poem tradition as practised in nearby regions. Only recent changes indicate influences from contemporary Turkish music.
Exploring f(T) gravity via strongly lensed fast radio bursts
Authors: Jiang Xinyue , Ren Xin , Li Zhao , Cai Yi-Fu , Er Xinzhong
Published: January 2024

This study aims to investigate the strong gravitational lensing effects in f(T) gravity. We present the theoretical analytic expressions for the lensing effects in f(T) gravity, including deflection angle, magnification, and time delay. On this basis, we also take the plasma lensing effect into consideration. We compare the lensing effects between the General Relativity in a vacuum environment and the f(T) gravity in a plasma environment. From a strongly lensed fast radio burst, the results indicate that in a plasma environment, General Relativity and f(T) gravity can generate indistinguishable image positions, but the magnification and time delay on these positions are significantly different, which can be distinguished by current facilities in principle. Therefore, the discrepancies between observational results and theoretical expectations can serve as clues for a modified gravity theory and provide constraints on f(T) gravity.
Semisynthesis of homogeneous spike RBD glycoforms from SARS-CoV-2 for profiling the correlations between glycan composition and function
Authors: Ye Farong , Li Cheng , Liu Feng-Liang , Liu Xinliang , Xu Peng , Luo Rong-Hua , Song Wenping , Zheng Yong-Tang , Ying Tianlei , Yu Biao , Wang Ping
Published: January 2024

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019 (COVID-19). The receptor-binding domain (RBD) of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure–function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope (Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpep elicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpep conjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.
Paradoxical effects of ZIM3, a CRISPRi effector, on human induced pluripotent stem-cell-derived cardiomyocyte electrophysiology
Authors: Han Julie L , Heinson Yuli W , Pozo Maria R , Li Weizhen , Entcheva Emilia
Published: January 2024

We show that zinc finger imprinted 3 (Zim3), when used as Zim3-KRAB-dCas9 effector in interference CRISPR, without any guide RNAs, paradoxically up-regulates key cardiac ion channel genes in human-induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs), responsible for healthy resting membrane potential, repolarization of the action potential, and electrical transmission of signals. These were found to yield expected functional enhancements consistent with a more mature iPSC-CM phenotype, with potentially desirable properties.
The rising authority and agency of public–private partnerships in global health governance
Authors: de Bengy Puyvallée Antoine
Published: January 2024

Global public–private partnerships (PPPs) have become prominent in efforts to address global challenges, particularly in the health field. In the scholarly literature, global PPPs have been conceptualized as arenas for voluntary public–private cooperation rather than agents of global governance. This paper challenges this approach, arguing that a sub-class of highly institutionalized partnerships have developed into transnational bureaucracies that, much like international organizations, can draw from their administrative capacities to exercise agency and gain and consolidate authority over time. To substantiate this argument, I present an in-depth analysis of five global health partnerships that played a leading role in the Access to Covid-19 Tools Accelerator (ACT-A), the initiative that sought to coordinate the global response to covid-19. Based on extensive document review and analysis of the ACT-A PPPs —Gavi, the Vaccine Alliance, The Global Fund to Fight AIDS, Tuberculosis and Malaria, The Coalition for Epidemic Preparedness Innovation, Unitaid, and The Foundation for Innovative New Diagnostics — I show how these partnerships’ leadership role during the pandemic emerged from a decade long build-up of PPP agency. These organizations gained administrative capacities that enabled them to increase their authority vis-à-vis their donors, boards, and other external actors through three interlinked strategies: (a) developing greater financial autonomy; (b) expanding their mandates (including toward pandemic preparedness and response); and (c) establishing inter-partnership cooperation and mutual representation to other forums. My analysis suggests the need for future research to consider highly institutionalized PPPs as agents of global governance and to explore empirically and theoretically the consequences of their rising authority.
My first dance
Authors: Franklin Gustavo L
Published: January 2024

Many emotions are generated within a medical consultation. These feelings are often shared among the doctor, patient, and family. In this piece, these emotions are explored as I describe them deeply during my first encounter with a Huntington’s disease patient, bringing the challenges of the situation, mistakes, and the learning that emerged. Understanding the possible sentiments and how to balance these emotions may be essential to prepare the neurologist in training for the challenges inherent in treating a patient with a rare disease.
Abnormal Oculomotor Corollary Discharge Signaling as a Trans-diagnostic Mechanism of Psychosis
Authors: Yao Beier , Rolfs Martin , Slate Rachael , Roberts Dominic , Fattal Jessica , Achtyes Eric D , Tso Ivy F , Diwadkar Vaibhav A , Kashy Deborah , Bao Jacqueline , Thakkar Katharine N
Published: January 2024

Background and Hypothesis

Corollary discharge (CD) signals are “copies” of motor signals sent to sensory areas to predict the corresponding input. They are a posited mechanism enabling one to distinguish actions generated by oneself vs external forces. Consequently, altered CD is a hypothesized mechanism for agency disturbances in psychosis. Previous studies have shown a decreased influence of CD signals on visual perception in individuals with schizophrenia—particularly in those with more severe positive symptoms. We therefore hypothesized that altered CD may be a trans-diagnostic mechanism of psychosis.

Study Design

We examined oculomotor CD (using the blanking task) in 49 participants with schizophrenia or schizoaffective disorder (SZ), 36 bipolar participants with psychosis (BPP), and 40 healthy controls (HC). Participants made a saccade to a visual target. Upon saccade initiation, the target disappeared and reappeared at a horizontally displaced position. Participants indicated the direction of displacement. With intact CD, participants can make accurate perceptual judgements. Otherwise, participants may use saccade landing site as a proxy of pre-saccadic target to inform perception. Thus, multi-level modeling was used to examine the influence of target displacement and saccade landing site on displacement judgements.

Study Results

SZ and BPP were equally less sensitive to target displacement than HC. Moreover, regardless of diagnosis, SZ and BPP with more severe positive symptoms were more likely to rely on saccade landing site.

Conclusions

These results suggest that altered CD may be a trans-diagnostic mechanism of psychosis.
Eye Movement Characteristics for Predicting a Transition to Psychosis: Longitudinal Changes and Implications
Authors: Zhang Dan , Xu Lihua , Liu Xu , Cui Huiru , Wei Yanyan , Zheng Wensi , Hong Yawen , Qian Zhenying , Hu Yegang , Tang Yingying , Li Chunbo , Liu Zhi , Chen Tao , Liu Haichun , Zhang Tianhong , Wang Jijun
Published: January 2024

Background and hypothesis

Substantive inquiry into the predictive power of eye movement (EM) features for clinical high-risk (CHR) conversion and their longitudinal trajectories is currently sparse. This study aimed to investigate the efficiency of machine learning predictive models relying on EM indices and examine the longitudinal alterations of these indices across the temporal continuum.

Study design

EM assessments (fixation stability, free-viewing, and smooth pursuit tasks) were performed on 140 CHR and 98 healthy control participants at baseline, followed by a 1-year longitudinal observational study. We adopted Cox regression analysis and constructed random forest prediction models. We also employed linear mixed-effects models (LMMs) to analyze longitudinal changes of indices while stratifying by group and time.

Study results

Of the 123 CHR participants who underwent a 1-year clinical follow-up, 25 progressed to full-blown psychosis, while 98 remained non-converters. Compared with the non-converters, the converters exhibited prolonged fixation durations, decreased saccade amplitudes during the free-viewing task; larger saccades, and reduced velocity gain during the smooth pursuit task. Furthermore, based on 4 baseline EM measures, a random forest model classified converters and non-converters with an accuracy of 0.776 (95% CI: 0.633, 0.882). Finally, LMMs demonstrated no significant longitudinal alterations in the aforementioned indices among converters after 1 year.

Conclusions

Aberrant EMs may precede psychosis onset and remain stable after 1 year, and applying eye-tracking technology combined with a modeling approach could potentially aid in predicting CHRs evolution into overt psychosis.
A trade-off between leaf hydraulic efficiency and safety across three xerophytic species in response to increased rock fragment content
Authors: Zhang Xiulong , Ma Shaowei , Hu Hui , Li Fanglan , Bao Weikai , Huang Long
Published: January 2024

Limited information is available on the variation of plant leaf hydraulic traits in relation to soil rock fragment content (RFC), particularly for xerophytes native to rocky mountain areas. In this study, we conducted a field experiment with four gradients of RFC (0, 25, 50 and 75% ν ν−1) on three different xerophytic species (Sophora davidii, Cotinus szechuanensis and Bauhinia brachycarpa). We measured predawn and midday leaf water potential (Ψleaf), leaf hydraulic conductance (Kleaf), Ψleaf induced 50% loss of Kleaf (P50), pressure–volume curve traits and leaf structure. A consistent response of hydraulic traits to increased RFC was observed in three species. Kleaf showed a decrease, whereas P50 and turgor loss point (Ψtlp) became increasingly negative with increasing RFC. Thus, a clear trade-off between hydraulic efficiency and safety was observed in the xerophytic species. In all three species, the reduction in Kleaf was associated with an increase in leaf mass per area. In S. davidii, alterations in Kleaf and P50 were driven by leaf vein density (VLA) and Ψtlp. In C. szechuanensis, Ψtlp and VLA drove the changes in Kleaf and P50, respectively. In B. brachycarpa, changes in P50 were driven by VLA, whereas changes in both Kleaf and P50 were simultaneously influenced by Ψtlp. Our findings suggest that adaptation to increased rockiness necessarily implies a trade-off between leaf hydraulic efficiency and safety in xerophytic species. Additionally, the trade-off between leaf hydraulic efficiency and safety among xerophytic species is likely to result from processes occurring in the xylem and the outside-xylem hydraulic pathways. These findings contribute to a better understanding of the survival strategies and mechanisms of xerophytes in rocky soils, and provide a theoretical basis for the persistence of xerophytic species in areas with stony substrates.
Impact of Preoperative Symptom Duration on Patient-reported Outcomes After Minimally Invasive Transforaminal Interbody Fusion for Degenerative Spondylolisthesis
Authors: Hartman Timothy J. , Nie James W. , Anwar Fatima N. , Roca Andrea M. , Loya Alexandra C. , Medakkar Srinath S. , MacGregor Keith R. , Oyetayo Omolabake O. , Zheng Eileen , Federico Vincent P. , Massel Dustin H. , Sayari Arash J. , Lopez Gregory D. , Singh Kern
Published: January 2024

Study Design:

Retrospective cohort study.

Objective:

To assess the impact of preoperative symptom duration (PSD) on patient-reported outcome measures (PROMs) after minimally invasive (MIS) transforaminal lumbar interbody fusion (TLIF) for degenerative spondylolisthesis (DSpond).

Background:

A prolonged duration of preoperative symptoms may implicate inferior long-term outcomes postsurgery. Prior studies of lumbar fusion recipients are limited by the inclusion of heterogeneous populations.

Methods:

A single-surgeon registry was retrospectively queried for privately insured patients who had undergone primary, elective, single-level MIS-TLIF for DSpond with a recorded symptom start date. Cohorts were formed by PSD: shorter duration (PSD <1 y) or greater duration (GD; PSD ≥1 y). PROMs evaluated included Patient-reported Outcomes Measurement Information System–Physical Function, Oswestry Disability Index, Visual Analog Scale–Back, Visual Analog Scale–Leg, and 9-item Patient Health Questionnaire. The magnitude of PROM (∆PROM) improvement from preoperative baseline to 6 weeks and final follow-up (∆PROM-FF) were compared between cohorts. Intercohort achievement rates of a minimum clinically important difference in each PROM were compared.

Results:

A total of 133 patients included 85 patients with GD cohort. There were no significant differences in pre hoc demographics and perioperative characteristics between cohorts, as well as preoperative, 6-week, or final follow-up PROMs between cohorts. Both cohorts demonstrated significant improvement in all PROMs at 6 weeks and final follow-up (P ≤ 0.049, all). There were no significant intercohort differences demonstrated in minimum clinically important difference achievement rates, ∆PROM-6W, or ∆PROM-FF in any PROM.

Conclusions:

Regardless of the symptom duration before MIS-TLIF for DSpond, patients demonstrate significant improvement in physical function, pain, disability, and mental health. Patients with a GD of preoperative symptoms did not report inferior scores in any PROM domain. Patients with a GD of preoperative symptoms did not suffer inferior rates of clinically meaningful improvement after surgical intervention. These findings should be considered when counseling patients before surgical intervention for DSpond.
Prediction and Detection of Glaucomatous Visual Field Progression Using Deep Learning on Macular Optical Coherence Tomography
Authors: Huang Jonathan , Galal Galal , Mukhin Vladislav , Etemadi Mozziyar , Tanna Angelo P.
Published: January 2024

Précis:

A deep learning model trained on macular OCT imaging studies detected clinically significant functional glaucoma progression and was also able to predict future progression.

Objective:

To use macular optical coherence tomography (OCT) imaging to predict the future and detect concurrent visual field progression, respectively, using deep learning.

Design:

A retrospective cohort study.

Subjects:

A pretraining data set was comprised of 7,702,201 B-scan images from 151,389 macular OCT studies. The progression detection task included 3902 macular OCT imaging studies from 1534 eyes of 828 patients with glaucoma, and the progression prediction task included 1346 macular OCT studies from 1205 eyes of 784.

Methods:

A novel deep learning method was developed to detect glaucoma progression and predict future progression using macular OCT, based on self-supervised pretraining of a vision transformer (ViT) model on a large, unlabeled data set of OCT images. Glaucoma progression was defined as a mean deviation (MD) rate of change of ≤ −0.5 dB/year over 5 consecutive Humphrey visual field tests, and rapid progression was defined as MD change ≤ −1 dB/year.

Main Outcome Measures:

Diagnostic performance of the ViT model for prediction of future visual field progression and detection of concurrent visual field progression using area under the receiver operating characteristic curve (AUC), sensitivity, and specificity.

Results:

The model distinguished stable eyes from progressing eyes, achieving an AUC of 0.90 (95% CI, 0.88–0.91). Rapid progression was detected with an AUC of 0.92 (95% CI, 0.91–0.93). The model also demonstrated high predictive ability for forecasting future glaucoma progression, with an AUC of 0.85 (95% CI 0.83–0.87). Rapid progression was predicted with an AUC of 0.84 (95% CI 0.81–0.86).

Conclusions:

A deep learning model detected clinically significant functional glaucoma progression using macular OCT imaging studies and was also able to predict future progression. Early identification of patients undergoing glaucoma progression or at high risk for future progression may aid in clinical decision-making.
Technique of corneal allogenic ring segment preparation using femtosecond laser: preclinical study on human corneal grafts
Authors: Mechleb Nicole , Flamant Roxane , Panthier Christophe , Ghazal Wassim , Dubois Mathieu , Gatinel Damien , Saad Alain
Published: January 2024

Purpose:

To describe a new technique for preparing corneal allogenic ring segments (CAIRSs) using femtosecond laser technology.

Setting:

Hospital Foundation Adolphe de Rothschild-Noémie de Rothschild institute, Paris, France.

Design:

Preclinical study conducted on human corneal grafts.

Methods:

The corneal grafts were mounted on an artificial chamber pressurizer (ACP) with preset constant pressure, and the FSL was used to create a circular annulus with specific dimensions. The resulting CAIRSs were analyzed for their thickness and width after air drying.

Results:

A total of 25 CAIRSs were prepared using the FSL. The mean width and thickness of the CAIRSs were 803 ± 77 μm and 83 ± 16 μm, respectively. Statistical analysis revealed no significant differences in width among the various quadrants of each CAIRS or between different CAIRSs. Significantly thicker CAIRSs were obtained with a higher ACP pressure.

Conclusions:

The technique of CAIRS preparation using FSL technology and controlled artificial anterior chamber pressure demonstrated reproducibility and precision. This approach holds the potential for customizing and personalizing CAIRSs based on individual corneal characteristics.
Ablation Therapy of the Biliary Tree
Authors: Kim Marina , Parekh Darshan , Kahaleh Michel
Published: January 2024

Malignant biliary obstruction is typically referred to endoscopists for palliation. A curative resection is indeed rarely an option in this condition. Photodynamic therapy and radiofrequency ablation are 2 modalities that can be offered in those patients. Many studies have demonstrated improved stent patency and survival after ablation. Photodynamic therapy is unfortunately very expensive and is associated with photosensitivity; however, it transmits to the entire biliary tree. Radiofrequency ablation is more affordable and easier to apply but requires contact with the tumor to be efficient. This review explores both modalities in terms of their safety and efficacy for bile duct cancer palliation.
Unraveling the blood microbiome: novel insights into inflammasome responses in Crohn’s disease
Authors: Kirkik Duygu , Kalkanli Tas Sevgi , Tanoglu Alpaslan
Published: January 2024

Objective

Crohn’s disease (CD), an inflammatory bowel disease with unknown etiology, is influenced by genetic, environmental, and immunological factors. This study aimed to analyze the blood microbiome and inflammasome responses, emphasizing NLRP3 protein expression and IL-1β and IL-18 plasma levels, between Crohn’s patients and healthy subjects.

Methods

A total of 40 volunteers were included in this study. The 16S rRNA technique was used to sequence the V3-V4 regions of the blood sample. NLRP3 protein levels in plasma were ascertained through Western Blot, and IL-1β and IL-18 plasma profiles were examined using ELISA.

Results

Analysis highlighted five unique phyla in patients’ plasma, emphasizing the role of the blood microbiome in CD. Compared to controls, Crohn’s patients exhibited elevated NLRP3 protein expression. Plasma IL-1β levels were diminished in patients (P = 0.0041), whereas IL-18 levels were comparably higher (P = 0.8209). In patients with CD, the presence of Staphylococcus sciuri in blood samples highlights its potential role in the disease’s onset. The study also underscored the interplay between dietary habits, specifically increased meat consumption, and the progression of CD.

Conclusion

Our pioneering research discerns the variations in the blood microbiome and inflammasome responses between Crohn’s patients and healthy individuals. Significant microbiome alterations and the detection of the Staphylococcus sciuri pathogen in Crohn’s patients were notable. The pronounced NLRP3 protein in patients suggests its potential as a diagnostic biomarker. Future explorations into IL-1β and IL-18 pathways promise to unveil innovative insights into CD.
Effect of cognitive behavior therapy based on the health education pathway on psychology of papillary thyroid carcinoma patients: a randomized controlled trial
Authors: Zhao Chunyan , Diao Wei , Xu Xin , Li Lin , Jia Zhiyun
Published: January 2024

Objectives

Our main aim was to explore whether cognitive behavior therapy based on the health education pathway (CBT-HEP) can effectively alleviate the distress, anxiety, and depression of papillary thyroid carcinoma (PTC) patients after 131I treatment. In addition, we investigated the critical factors that can significantly affect the distress and quality of life in PTC patients before 131I treatment.

Methods

In total, 496 people were screened and 357 were enrolled, followed by randomization of those with a distress thermometer (DT) ≥4. Patients in the experimental group received CBT-HEP intervention, and patients in the control group were given casual conversation.

Results

The scores of DT, Hamilton Anxiety Scale (HAMA) and Patient Health Questionnaire-9 (PHQ-9) in CBT-HEP group decreased gradually after intervention. In control group, DT scores decreased significantly, while HAMA and PHQ-9 scores did not change significantly.

Conclusion

CBT-HEP is effective in relieving distress, anxiety and depression in PTC patients. In addition, female sex, lifestyle, hypothyroidism, negative emotions, related symptoms, fear of tumor recurrence and radiation safety are the critical factors affecting mental health and quality of life.
Norms of prejudice: political identity and polarization
Authors: Amalia Alvarez-Benjumea , Winter Fabian , Zhang Nan
Published: January 2024

The USA is fast becoming a ‘majority–minority’ country in which Whites will no longer comprise the numerically dominant racial group. Prior studies have linked Whites’ status decline to heightened in-group solidarity and the feeling that Whites, as a group, face growing discrimination. In the light of these findings, we examine the extent to which a social norm controllinganti-White prejudiceis now discernible in the USA. Drawing from an original survey measuring Americans’ reactions to racially-offensive speech, we examine second-order beliefs about the social inappropriateness of offensive statements targeting White Americans. We find that White Americans (in comparison to non-Whites) are indeed more likely to profess a social norm governing anti-white prejudice. The pattern is most discernible among white Republicans whom we expect to be most fearful of demographic change.

This article is part of the theme issue ‘Social norm change: drivers and consequences’.
Risk, sanctions and norm change: the formation and decay of social distancing norms
Authors: Vriens Eva , Andrighetto Giulia , Tummolini Luca
Published: January 2024

Global challenges like the climate crisis and pandemic outbreaks require collective responses where people quickly adapt to changing circumstances. Social norms are potential solutions, but only if they themselves are flexible enough. The COVID-19 pandemic provided a unique opportunity to study norm formation and decay in real-world contexts. We tracked empirical and normative expectations about social distancing and empirical and normative expectations of sanctioning from June 2021 to February 2022 to explore how norms and meta norms evolved as COVID-19 risk decreased and increased. We found that norms and meta norms partially coevolve with risk dynamics, although they recover with some delay. This implies that norms should be enforced as soon as risk increases. We therefore tested how sanctioning intentions vary for different hypothetical norms and find them to increase with a clear meta norm of sanctioning, yet decrease with a clear social norm of distance. In conclusion, social norms evolve spontaneously with changing risk, but might not be adaptive enough when the lack of meta norms of sanctioning introduce tolerance for norm violations. Moreover, norm nudges can potentially have negative externalities if strengthening the social norm increases tolerance for norm violations. These results put some limits to social norms as solutions to guide behaviour under risk.

This article is part of the theme issue ‘Social norm change: drivers and consequences’.
OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria
Authors: Madhu Vedavathi , Hernandaz-Meadows Miriam , Coleman Ashley , Sao Kimheak , Inguito Kameron , Haslam Owen , Boneski Paige K , Sesaki Hiromi , Collins John A , Risbud Makarand V.
Published: January 2024

Due to their glycolytic nature and limited vascularity, nucleus pulposus (NP) cells of the intervertebral disc and articular chondrocytes were long thought to have minimal reliance on mitochondrial function. Recent studies have challenged this long-held view and highlighted the increasingly important role of mitochondria in the physiology of these tissues. We investigated the role of mitochondrial fusion protein OPA1 in maintaining the spine and knee joint health in aging mice. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate without affecting ATP synthesis. OPA1 governed the morphology of multiple organelles, and its loss resulted in the dysregulation of NP cell autophagy. Metabolic profiling and13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy,Opa1AcanCreERT2mice showed age- dependent disc, and cartilage degeneration and vertebral osteopenia. Our findings suggest that OPA1 regulation of mitochondrial dynamics and multi-organelle interactions is critical in preserving metabolic homeostasis of disc and cartilage.

Teaser

OPA1 is necessary for the maintenance of intervertebral disc and knee joint health in aging mice
Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: the devil is in the details
Authors: Beaudart Charlotte , Douxfils Jonathan , Musuamba Flora , Dogné Jean-Michel
Published: January 2024

Several trials of different designs were conducted to investigate the efficacy and safety of hydroxychloroquine (HCQ) for the prevention and/or the treatment of COVID-19 patients. Recently, it has been reported that HCQ might have been associated with an excess of 16,990 deaths during the first wave of the COVID-19 pandemic in 6 countries. Such attributable risk analysis is associated with many limitations. These previous findings did not adequately address dose-subgroup and sensitivity analyses which precludes any overall firm conclusions on in-hospital mortality attributable to HCQ.

We performed a meta-analysis and proposed a stratification by doses of HCQ. By pooling studies employing HCQ doses < or = 2400mg/5 days (i.e., k=12, n patients treated with HCQ=947, n controls=745), an OR of 0.94 (95%CI 0.56; 1.59) was found, indicating no increase in the mortality rate anymore. Importantly, there was no significant reduction in mortality rate with HCQ at < or = 2400mg/5 days neither. The same observation held true when pooling studies employing HCQ doses < or = 4800mg/5 days (i.e., k=25, n patients treated with HCQ=1672, n controls=1479) with an OR of 0.97 (95% CI 0.73; 1.29). Only high dose regimens of HCQ are associated with a significant increase in mortality.

Applying an excess of mortality in the population treated with doses where no increase of mortality is found creates a misleading overestimation of deaths associated with the use of HCQ in hospitalized patients with COVID-19. On the other hand, even at low doses HCQ regimen, no reduction in mortality with HCQ was observed suggesting that, when it comes to mortality as the outcome, HCQ did not show a benefit in hospitalized patients suffering from COVID-19. This mainly justifies the past and still up-to-date recommendations and guidelines to not use HCQ in this indication.
Predicting response to immune checkpoint blockade therapy among mismatch repair-deficient patients using mutational signatures
Authors: Gulhan Doga C. , Viswanadham Vinay , Muyas Francesc , Jin Hu , Foote Michael B , Lee Jake June-Koo , Barras David , Jung Youngsook L. , Ljungstrom Viktor , Rousseau Benoit , Galor Alon , Diplas Bill H , Maron Steven B , Cleary James M. , Cortés-Ciriano Isidro , Park Peter J.
Published: January 2024

Despite the overall efficacy of immune checkpoint blockade (ICB) for mismatch repair deficiency (MMRD) across tumor types, a sizable fraction of patients with MMRD still do not respond to ICB. We performed mutational signature analysis of panel sequencing data (n = 95) from MMRD cases treated with ICB. We discover that T>C-rich single base substitution (SBS) signatures—SBS26 and SBS54 from the COSMIC Mutational Signatures catalog—identify MMRD patients with significantly shorter overall survival. Tumors with a high burden of SBS26 show over-expression and enriched mutations of genes involved in double-strand break repair and other DNA repair pathways. They also display chromosomal instability (CIN), likely related to replication fork instability, leading to copy number losses that trigger immune evasion. SBS54 is associated with transcriptional activity and not with CIN, defining a distinct subtype. Consistently, cancer cell lines with a high burden of SBS26 and SBS54 are sensitive to treatments targeting pathways related to their proposed etiology. Together, our analysis offers an explanation for the heterogeneous responses to ICB among MMRD patients and supports an SBS signature-based predictor as a prognostic biomarker for differential ICB response.
Social Norms and Security and Justice Services for Gender-based Violence in Nepal: Programmatic Implications from a Baseline Mixed-Methods Assessment
Authors: Clark Cari Jo , Batayeh Brian , Shao Iris , Bergenfeld Irina , Pandey Manoj , Sharma Sudhindra , Shrestha Shikha , Gourisankar Amritha , Gautam Anudeeta , Sohail Tehnyat J. , Shakya Holly , Morrow Grace , Shervinskie Abbie , Soti Subada
Published: January 2024

Background

Gender-based violence (GBV) is highly prevalent throughout the world. Only a small fraction of survivors seek help from security and justice providers (S&J) such as the police or courts, due in part to social norms that discourage help-seeking. Social norms interventions have proven effective in combatting GBV but have not been tested alongside S&J interventions. The Strengthening Access to Holistic, Gender Responsive, and Accountable Justice in Nepal (SAHAJ) project was designed to fill this gap. We provide a comprehensive mixed-methods situation analysis of GBV-related social norms, help-seeking, S&J service provision.

Methods

The SAHAJ evaluation is a 3-armed, mixed-methods evaluation of the impact of social norms programming alone, S&J programming alone, and combined programming in 17 communities in Nepal. Baseline data included a household survey (N=3830), a sub-study of youth (N=143) and married adults (N=464) in one site and qualitative data collection including interviews with S&J service providers, help-seeking GBV survivors and families (N=68), and focus group discussions with police, youth groups, and school management committees (N=20) in four sites. Descriptive analysis of survey data was triangulated with findings from a modified grounded theory analysis of the qualitative data to elucidate the role of social norms and other barriers limiting help-seeking.

Results

GBV was perceived to be common, especially child marriage, domestic violence, eve-teasing, and dowry-related violence. Formal help-seeking was low, despite positive attitudes towards S&J providers. Participants described injunctive norms discouraging formal reporting in cases of GBV and sanctions for women violating these norms.

Conclusions

Norms favoring family- and community-based mediation remain strong. Sanctions for formal reporting remain a deterrent to help-seeking. Leveraging gender-equitable role models, such as female S&J providers, and connecting S&J providers to women and youth may capitalize on existing shifts.
DNA Damage Accelerates G-Quadruplex Folding in a Duplex-G-Quadruplex-Duplex Context
Authors: Fleming Aaron M. , Jenkins Brandon Leonel Guerra Castañaza , Buck Bethany A. , Burrows Cynthia J.
Published: January 2024

Molecular details for DNA damage impact on the folding of potential G-quadruplex sequences (PQS) to non-canonical DNA structures that are involved in gene regulation are poorly understood. Here, the effects of DNA base damage and strand breaks on PQS folding kinetics were studied in the context of theVEGFpromoter sequence embedded between two DNA duplex anchors, referred to as a duplex-G-quadruplex-duplex (DGD) motif. This DGD scaffold imposes constraints on the PQS folding process that more closely mimic those found in genomic DNA. Folding kinetics were monitored by circular dichroism (CD) to find folding half-lives ranging from 2 s to 12 min depending on the DNA damage type and sequence position. The presence of Mg2+ions and the G-quadruplex (G4)-binding protein APE1 facilitated the folding reactions. A strand break placing all four G runs required for G4 formation on one side of the break accelerated the folding rate by >150-fold compared to the undamaged sequence. Combined 1D1H-NMR and CD analyses confirmed that isothermal folding of theVEGF-DGD constructs yielded spectral signatures that suggest formation of G4 motifs, and demonstrated a folding dependency with the nature and location of DNA damage. Importantly, the PQS folding half-lives measured are relevant to replication, transcription, and DNA repair time frames.

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DMD Human iPSC-derived skeletal muscle cells recapitulate selective calcium dysregulation pathways
Authors: Delafenêtre Arnaud , Chapotte-Baldacci Charles-Albert , Dorémus Léa , Massouridès Emmanuelle , Bernard Marianne , Régnacq Matthieu , Piquereau Jérôme , Chatelier Aurélien , Cognard Christian , Pinset Christian , Sebille Stéphane
Published: January 2024

This study investigates the functional characteristics of induced pluripotent stem cell-derived muscle cells (hiPSC-skMCs) from Duchenne muscular dystrophy (DMD) patients, focusing on their regulation of intracellular calcium concentration. DMD, a progressive muscle degenerative disease, arises from mutations in the dystrophin gene and is characterized by elevated intracellular calcium levels, exacerbating disease progression. This work highlights that DMD hiPSC-skMCs demonstrate unique calcium signatures with increased intracellular calcium compared to healthy counterparts. These cells also exhibit both heightened calcium response when stimulated by electrical fields or acetylcholine and more pronounced constitutive calcium entries. While RNAseq data from these cells reaffirmed known dysregulation mechanisms seen in other dystrophin-deficient models, certain pathways like purinergic or store-operated calcium entries did not show disruption in this DMD model. This discrepancy suggests that not all mechanisms observed in animal models may be equally relevant in human cases, pointing towards specific molecular targets that could be more effective for DMD treatment strategies.
Root-associatedStreptomycesproduce galbonolides to modulate plant immunity and promote rhizosphere colonisation
Authors: Nicolle Clément , Gayrard Damien , Noël Alba , Hortala Marion , Amiel Aurélien , Grat Sabine , Le Ru Aurélie , Marti Guillaume , Pernodet Jean-Luc , Lautru Sylvie , Dumas Bernard , Rey Thomas
Published: January 2024

The rhizosphere, which serves as the primary interface between plant roots and the soil, constitutes an ecological niche for a huge diversity of microbial communities. Currently, there is little knowledge on the nature and the function of the different metabolites released by rhizospheric microbes to facilitate colonization of this highly competitive environment. Here, we demonstrate how the production of galbonolides, a group of polyene macrolides that inhibit plant and fungal Inositol Phosphorylceramide Synthase (IPCS), empowers the rhizosphericStreptomycesstrain AgN23, to thrive in the rhizosphere by triggering the plant’s defence mechanisms. Metabolomic analysis of AgN23-inoculatedArabidopsisroots revealed a strong induction in the production of an indole alkaloid, camalexin, which is a major phytoalexin inArabidopsis. By using a plant mutant compromised in camalexin synthesis, we show that camalexin production is necessary for the successful colonization of the rhizosphere by AgN23. Conversely, hindering galbonolides biosynthesis in AgN23 knock-out mutant resulted in loss of inhibition of IPCS, a deficiency in plant defence activation, notably the production of camalexin, and a strongly reduced development of the mutant bacteria in the rhizosphere. Together, our results identified galbonolides as important metabolites mediating rhizosphere colonisation byStreptomyces.

Abstract Figure

Graphical Abstract

Model summarizing the mode of action of galbonolides in stimulating plant defence to support AgN23 colonization of the rhizosphere. Galbonolides secretion byStreptomycessp. AgN23 trigger Inositol Phosphoceramide Synthase (IPCS) inhibition inArabidopsisroot cells (orange arrow). The resulting raise in Ceramide precursors of the IPCS may result in the different defence responses associated to AgN23: Hypersensitive Responses (HR), Salicylic Acid (SA) signalling, nuclear Ca2+influx, defence gene expression and camalexin biosynthesis. This production of camalexin (blue arrow) exert a positive effect on AgN23 growth in the rhizosphere, presumably by restricting the growth of bacterial and fungal competitors sensitive to this phytoalexin. In addition, galbonolides secretion in the rhizosphere may also directly interfere with fungal competitors of AgN23.
Novel, active, and uncultured hydrocarbon degrading microbes in the ocean
Authors: Howe Kathryn L. , Zaugg Julian , Mason Olivia U.
Published: January 2024

Given the vast quantity of oil and gas input to the marine environment annually, hydrocarbon degradation by marine microorganisms is an essential ecosystem service. Linkages between taxonomy and hydrocarbon degradation capabilities are largely based on cultivation studies, leaving a knowledge gap regarding the intrinsic ability of uncultured marine microbes to degrade hydrocarbons. To address this knowledge gap, metagenomic sequence data from the Deepwater Horizon (DWH) oil spill deep-sea plume was assembled to which metagenomic and metatranscriptomic reads were mapped. Assembly and binning produced new DWH metagenome assembled genomes that were evaluated along with their close relatives, all of which are from the marine environment (38 total). These analyses revealed globally distributed hydrocarbon degrading microbes with clade specific substrate degradation potentials that have not been reported previously. For example, methane oxidation capabilities were identified in allCycloclasticus. Further, allBermanellaencoded and expressed genes for non-gaseous n-alkane degradation; however, DWHBermanellaencoded alkane hydroxylase, not alkane 1-monooxygenase. All but one previously unrecognized DWH plume members in the SAR324 and UBA11654 coded for aromatic hydrocarbon degradation. In contrast,Colwelliawere diverse in the hydrocarbon substrates they could degrade. All clades encoded nutrient acquisition strategies and response to cold temperatures, while sensory and acquisition capabilities were clade specific. These novel insights regarding hydrocarbon degradation by uncultured planktonic microbes provided missing data, allowing for better prediction of the fate of oil and gas when hydrocarbons are input to the ocean, leading to a greater understanding of the ecological consequences to the marine environment.

Importance

Microbial degradation of hydrocarbons is a critically important process promoting ecosystem health, yet much of what is known about this process is based on physiological experiments with a few hydrocarbon substrates and cultured microbes. Thus, the ability to degrade the diversity of hydrocarbons that comprise oil and gas by microbes in the environment, particularly in the ocean, is not well characterized. Therefore, this study aimed to utilize non-cultivation based ‘omics’ data to explore novel genomes of uncultured marine microbes involved in degradation of oil and gas. Analyses of newly assembled metagenomic data and metagenomic and metatranscriptomic read recruitment revealed globally distributed hydrocarbon degrading marine microbes with clade specific substrate degradation potentials that have not been previously reported. This new understanding of oil and gas degradation by uncultured marine microbes suggested that the global ocean harbors a diversity of hydrocarbon degrading Bacteria, that can act as primary agents regulating ecosystem health.
Lifespan regulation by targeting heme signaling in yeast
Authors: Patnaik Praveen K. , Nady Nour , Barlit Hanna , Gülhan Ali , Labunskyy Vyacheslav M.
Published: January 2024

Heme is an essential prosthetic group that serves as a co-factor and a signaling molecule. Heme levels decline with age, and its deficiency is associated with multiple hallmarks of aging, including anemia, mitochondrial dysfunction, and oxidative stress. Dysregulation of heme homeostasis has been also implicated in aging in model organisms suggesting that heme may play an evolutionarily conserved role in controlling lifespan. However, the underlying mechanisms and whether heme homeostasis can be targeted to promote healthy aging remain unclear. Here we usedSaccharomyces cerevisiaeas a model to investigate the role of heme in aging. For this, we have engineered a heme auxotrophic yeast strain expressing a plasma membrane-bound heme permease fromCaenorhabditis elegans(ceHRG-4). This system can be used to control intracellular heme levels independently of the biosynthetic enzymes by manipulating heme concentration in the media. We observed that heme supplementation leads to significant lifespan extension in yeast. Our findings revealed that the effect of heme on lifespan is independent of the Hap4 transcription factor. Surprisingly, heme-supplemented cells had impaired growth on YPG medium, which requires mitochondrial respiration to be used, suggesting that these cells are respiratory deficient. Together, our results demonstrate that heme homeostasis is fundamentally important for aging biology and manipulating heme levels can be used as a promising therapeutic target for promoting longevity.
Lecanemab Blocks the Effects of the Aβ/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture
Authors: Singh Pradeep Kumar , Simoes Pires Elisa Nicoloso , Chen Zu-Lin , Torrente Daniel , Calvano Marissa , Sharma Anurag , Strickland Sidney , Norris Erin H.
Published: January 2024

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer’s disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen’s interaction with the amyloid-beta (Aβ) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, shows promising results in facilitating reduction of Aβ from the brain and slowing cognitive decline. Here we show that lecanemab blocks fibrinogen’s binding to Aβ protofibrils, normalizing Aβ/fibrinogen-mediated delayed fibrinolysis and clot abnormalitiesin vitroand in human plasma. Additionally, we show that lecanemab dissociates the Aβ/fibrinogen complex and prevents fibrinogen from exacerbating Aβ-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.