bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review and meta-analysis of the effect of psychological interventions on anxiety in children and youth with chronic medical conditions
Authors: Tran Susan T , Bieniak Keely , Bedree Helen , Adler Michelle , Ogunmona Suliat , Kovar-Gough Iris , Ma Wenjuan , Thabrew Hiran , Cunningham Natoshia R
Published: November 2024

Objectives

Anxiety disorders affect 20%–50% of youth with chronic medical conditions (CMCs) and can interfere with medical care and treatment outcomes. Psychological therapies are typically designed for youth without CMCs; thus, this systematic review (Open Science Framework preregistration osf.io/a52nd/) assesses the effect of psychological therapies on anxiety, functional impairment and health-related quality of life (HRQOL) in this unique population.

Methods

We included randomized controlled trials of psychological therapies vs. any comparator for youth (ages 24 and younger) with CMCs that assessed child anxiety. We excluded studies of adults and those not in English. Medline, Embase, PsycInfo, and CENTRAL databases were searched, studies were screened using COVIDENCE software, and meta-analysis was undertaken in R. Study quality was assessed using the Cochrane Risk of Bias tool, version 2. Quality of evidence was assessed using the GRADE system.

Results

Thirty-three studies with 2676 participants (ages 5–21 years) were included in the meta-analysis. Nearly all had at least some risk of bias. Overall, psychological interventions resulted in lower anxiety (Hedges’ g = −0.48 [−0.71; −0.25]), but did not have a significant effect on functional impairment or HRQOL. Based on the GRADE criteria, we have moderate confidence in these results. Treatments with higher risk of bias and those with live therapist components had greater effects on anxiety.

Conclusions

Psychological interventions may be effective for improving anxiety for children and youth with CMCs, particularly those with a live therapist. More high-quality studies are needed to understand what components produce the best outcomes for patients.
Single-port laparoscopic surgery as a useful diagnostic tool for primary ovarian lymphoma: a case report
Authors: Osanai Kiyono , Misawa Akihiko , Mitsuya Shion , Osaka Makoto , Sato Yasunori , Suzuki Atsushi
Published: November 2024

The preoperative diagnosis of ovarian lymphoma, a rare pathology, is often difficult. Consequently, laparotomy is usually performed under the presumptive diagnosis of ovarian cancer. In cases where the initial curative surgery for ovarian cancer is challenging, diagnostic laparoscopy is performed. Herein, we report a case in which single-port laparoscopic surgery effectively diagnosed primary ovarian lymphoma. A 55-year-old woman presented with abnormal uterine bleeding. PET-CT findings suggested ovarian cancer with multiple metastases. Single-port laparoscopic surgery was performed because curative surgery was deemed difficult. She had an uneventful recovery and was discharged on the fourth postoperative day. After the pathological diagnosis was made, she was referred to the hematology department for treatment. Diagnostic laparoscopy is recommended for advanced ovarian cancer to facilitate early postoperative treatment. This case highlights the utility of single-port laparoscopic surgery in the accurate diagnosis and early treatment of intraperitoneal malignancies.
“My Back Went Out Again!”: You Are Seeing Them at 1:00
Authors: Barr Karen
Published: November 2024

Up to 75% of patients with low back pain (LBP) will have recurrences (flares), so recurrence of LBP is not a reason to suspect serious pathology. A systematic approach to the evaluation of recurrent LBP, management of associated risk factors and comorbidities, and education to teach self-management can help patients function better and reduce associated health care costs. Unnecessary medical investigations can lead to expensive but ineffective and potentially harmful health care and paradoxically increase the risk of long-term, back-related disability. Many of the risk factors for transition to chronic LBP can be reduced with lifestyle modifications and attention to mental health (as depression is seen in 30–50% of patients with persistent pain). Psychosocial distress and fear are significant contributors to LBP and disability. Teaching techniques to self-manage recurrent LBP and facilitating their is an effective way to reduce overutilization of health care and decrease back-related disability and pain.
“Of Course My Back Hurts—I Have Two Bulging Discs”
Authors: Davis Charles , Standaert Christopher J. , Jarvik Jeffrey G.
Published: November 2024

Although spinal imaging can be very helpful in identifying pathology, very few spines actually appear “normal” on MRI, and the majority of “abnormalities” are common, age-related changes. It is critical that medical providers understand the nature and prevalence of imaging findings and can translate and interpret the findings appropriately for their patients. Findings of disc degeneration are a normal manifestation of aging and are commonly seen on spinal imaging in people without LBP. “Degenerative disc disease” is an inaccurate, poorly defined phrase associated with harmful effects on patients and should not be used. Disc bulges and herniations are present in 50% and 33% of the population, respectively, by age 40. Spinal imaging without clear medical/neurological concerns is associated with higher costs and worse outcomes. Reinforcing unproven beliefs around causes of pain can be harmful to patients and lead to perceptions of disability or unrealistic expectations of a structural cure.
“They Told Me I Have a ‘Spondy.’ ”: A 52-Year-Old with Low Back Pain
Authors: Standaert Christopher J. , Standaert Jaxon E.
Published: November 2024

Isthmic spondylolysis with or without spondylolisthesis is seen on radiographs in about 6% of adults and is typically not a source of pain. Spondylolisthesis is defined as the anterior displacement of one vertebral body over the subjacent vertebral body and can be loosely translated to patients as a “spine-slip.” Isthmic spondylolisthesis is associated with fractures of the pars interarticularis that typically occur in childhood without symptoms. Most isthmic spondylolistheses occur at L5/S1 (twice as often in men as in women) and are not associated with or a cause of low back pain (LBP) in adults. Most adults with asymptomatic isthmic spondylolisthesis can be assured that the condition has been there since they were a child, is not causing LBP, and the risk of significant progression is very low. The presence of significant leg pain, however, suggests nerve root involvement associated with a spondylolisthesis and warrants further evaluation.
“I’ve Been Coughing a Lot, Too.”: A 68-Year-Old Smoker with a Cough and Back Pain
Authors: Bailey Robert L. , Sullivan Jessica
Published: November 2024

It is critical to have an understanding of the clinical presentation and initial management of a patient with suspected vertebral metastases. Lung, breast, prostate, renal cell, myeloma, lymphoma, thyroid, and melanoma are the most likely primary tumors to metastasize to the spine. A history of cancer is the strongest predictive factor for metastatic disease in the spine, although night pain, older age, younger age, and constitutional symptoms also are relevant considerations. A patient presenting with potential metastatic disease of the spine and concurrent neurological loss should be referred for emergent evaluation and care. Magnetic resonance imaging is the diagnostic study of choice when spinal metastatic disease is a concern, and all patients require a thorough history and physical examination as well as plain radiographs of the spine. Decisions about surgery are made in the context of the clinical presentation, imaging findings, pathology, patient preferences, and a comprehensive approach to care.
“I Just Keep Getting Worse.”: Long-Standing Depression and Progressive Low Back Pain
Authors: Tuck Laura M. , Brier Moriah J. , Ho Erica , Anderson Derek R. , Williams Rhonda M. , Standaert Christopher J. , Turner Aaron P.
Published: November 2024

The comorbid presentation of chronic low back pain (LBP) and depression is common. Estimates suggest over half of patients with chronic pain also have major depression. Depression, in turn, can contribute to the maintenance of chronic pain through social withdrawal, negative thinking, and reduced activity. It is important therefore to assess biological, psychological, and social factors contributing to the pain experience and provide education about the interrelationship between pain and depression, neither of which can be treated in isolation. Individuals with comorbid mental health concerns (especially long-standing) and chronic pain are among the most complex patients to treat. Effective treatment entails a multifaceted approach focused on improving function, insight into the interrelationship of pain and mental health issues, self-efficacy in sustained lifestyle changes, and establishing clear functional goals. This requires buy-in and engagement from the patient and should be viewed as a collaboration between patients and providers.
“It Hurts, and I’m Not Walking Right.”: A Veteran with Back Pain and a Below Knee Prosthesis
Authors: Keszler Mary S. , Morgenroth David C. , Greis Ari , Williams Rhonda M. , Standaert Christopher J.
Published: November 2024

Low back pain (LBP) is more common in persons with lower limb loss (PWLL) than in the general population, and unique considerations arise in the evaluation and management of these individuals. Clinicians should consider intrinsic, prosthesis-related, and biopsychosocial factors. Military veterans with traumatic limb loss have relatively high rates of post-traumatic stress disorder, depression, anxiety, and kinesiophobia (fear of movement). While PWLL are also prone to the same spine pathologies that may affect anyone, limb loss adds specific considerations for examination and may limit the ability to perform a neurological examination. All PWLL with new, progressive, or limiting LBP need a thorough evaluation including an assessment of prosthetic fit and gait (when applicable), neurological status, and psychological status. Spinal imaging can be particularly helpful when clinical evaluation is clouded by some of the complexities associated with limb loss. Care should be taken to approaching PWLL comprehensively and promptly.
“I Have Tried Everything for My Back Pain!”: What to Do When There Is Nothing Left to Do
Authors: Standaert Christopher J.
Published: November 2024

Many with low back pain (LBP) are frustrated with their pain and their care, often noting that they “have tried everything.” Care for LBP centers around treating LBP as a nonspecific, self-limiting problem, or chasing “pain generators” identified on imaging that can be “fixed” by some type of intervention. Both of these are wrong. There is no medication, interventional procedure, or surgery shown to reliably provide long-term relief of LBP. Those with LBP often develop a misunderstanding of their medical evaluation, the role of physical therapy, and the potential for medical/ surgical approaches to “fix” their problem. a Effective treatment requires understanding the complexities of their life, education, and empowerment. Sleep, exercise, diet, social engagement, and goals/ passions are fundamental human needs and care is structured around rebuilding these. The solution lies in helping people to improve their life rather than eliminating their pain.
Material mixing in pulsar wind nebulae of massive runaway stars
Authors: Meyer D M -A , Torres D F
Published: November 2024

In this study we quantitatively examine the manner pulsar wind, supernova ejecta, and defunct stellar wind materials distribute and melt together into plerions. We performed 2.5D magnetohydrodynamical simulations of the entire evolution of their stellar surroundings and different scenarios are explored, whether the star dies as a red supergiant and Wolf–Rayet supernova progenitors, and whether it moved with velocity 20 or $40\, \rm km\, \rm s^{-1}$ through the interstellar medium. Within the post-explosion, early $10\, \rm kyr$, the H-burning-products rich red supergiant wind only mixes by $\le 20~{{\rm per\ cent}}$, due to its dense circumstellar medium filling the progenitor’s bow shock trail, still unaffected by the supernova blast wave. Wolf–Rayet materials, enhanced in C, N, O elements, distribute circularly for the $35\, \rm M_\odot$ star moving at $20\, \rm km\, \rm s^{-1}$ and oblongly at higher velocities, mixing efficiently up to 80 per cent. Supernova ejecta, filled with Mg, Si, Ca, Ti, and Fe, remain spherical for longer times at $20\, \rm km\, \rm s^{-1}$ but form complex patterns at higher progenitor speeds due to earlier interaction with the bow shock, in which they mix more efficiently. The pulsar wind mixing is more efficient for Wolf–Rayet (25 per cent) than red supergiant progenitors (20 per cent). This work reveals that the past evolution of massive stars and their circumstellar environments critically shapes the internal distribution of chemical elements on plerionic supernova remnants, and, therefore, governs the origin of the various emission mechanisms at work therein. This is essential for interpreting multifrequency observations of atomic and molecular spectral lines, such as in optical, infrared, and soft X-rays.
Identifying dark matter signals by the radio continuum spectral data of the cool-core cluster RX J1720.1+2638
Authors: Chan Man Ho , Lee Chak Man
Published: November 2024

Investigating the signals of dark matter annihilation is one of the most popular ways to understand the nature of dark matter. In particular, many recent studies are focussing on using radio data to examine the possible signals of dark matter revealed in galaxies and galaxy clusters. In this article, we investigate on the spectral data of the central radio halo of the cool-core cluster RX J1720.1+2638. We show that the radio spectral data can be best accounted by the synchrotron emission due to dark matter annihilation via $\tau$ lepton channel (with dark matter mass $m=15$ GeV) or b quark channel (with dark matter mass $m=110$ GeV), although using the very coarse spectral data with notable errors. Despite the fact that cosmic-ray emission can also provide a good explanation for the observed radio spectrum, our results suggest a possible positive evidence for dark matter annihilation revealed in the form of radio emission in RX J1720.1+2638 cluster.
A possible misaligned orbit for the young planet AU Mic c
Authors: Yu H , Garai Z , Cretignier M , Szabó Gy M , Aigrain S , Gandolfi D , Bryant E M , Correia A C M , Klein B , Brandeker A , Owen J E , Günther M N , Winn J N , Heitzmann A , Cegla H M , Wilson T G , Gill S , Kriskovics L , Barragán O , Boldog A , Nielsen L D , Billot N , Lafarga M , Meech A , Alibert Y , Alonso R , Bárczy T , Barrado D , Barros S C C , Baumjohann W , Bayliss D , Benz W , Bergomi M , Borsato L , Broeg C , Cameron A Collier , Csizmadia Sz , Cubillos P E , Davies M B , Deleuil M , Deline A , Demangeon O D S , Demory B -O , Derekas A , Doyle L , Edwards B , Egger J A , Ehrenreich D , Erikson A , Fortier A , Fossati L , Fridlund M , Gazeas K , Gillon M , Güdel M , Helling Ch , Isaak K G , Kiss L L , Korth J , Lam K W F , Laskar J , Lecavelier des Etangs A , Lendl M , Magrin D , Maxted P F L , McCormac J , Merín B , Mordasini C , Nascimbeni V , O’Brien S M , Olofsson G , Ottensamer R , Pagano I , Pallé E , Peter G , Piazza D , Piotto G , Pollacco D , Queloz D , Ragazzoni R , Rando N , Rauer H , Ribas I , Santos N C , Scandariato G , Ségransan D , Simon A E , Smith A M S , Sousa S G , Southworth R , Stalport M , Steinberger M , Sulis S , Udry S , Ulmer B , Ulmer-Moll S , Van Grootel V , Venturini J , Villaver E , Walton N A , Wheatley P J
Published: November 2024

The AU Microscopii planetary system is only 24 Myr old, and its geometry may provide clues about the early dynamical history of planetary systems. Here, we present the first measurement of the Rossiter–McLaughlin effect for the warm sub-Neptune AU Mic c, using two transits observed simultaneously with the European Southern Observatory's (ESO's) Very Large Telescope (VLT)/Echelle SPectrograph for Rocky Exoplanets and Stable Spectroscopic Observations (ESPRESSO), CHaracterising ExOPlanet Satellite (CHEOPS), and Next-Generation Transit Survey (NGTS). After correcting for flares and for the magnetic activity of the host star, and accounting for transit-timing variations, we find the sky-projected spin–orbit angle of planet c to be in the range $\lambda _{\mathrm{c}}=67.8_{-49.0}^{+31.7}$ degrees (1$\sigma$). We examine the possibility that planet c is misaligned with respect to the orbit of the inner planet b ($\lambda _{\mathrm{b}}=-2.96_{-10.30}^{+10.44}$), and the equatorial plane of the host star, and discuss scenarios that could explain both this and the planet’s high density, including secular interactions with other bodies in the system or a giant impact. We note that a significantly misaligned orbit for planet c is in some degree of tension with the dynamical stability of the system, and with the fact that we see both planets in transit, though these arguments alone do not preclude such an orbit. Further observations would be highly desirable to constrain the spin–orbit angle of planet c more precisely.
Appeal and Sensory Characteristics of Oral Nicotine Products in Young Adults Who Vape E-Cigarettes
Authors: Peraza Natalia , Han Dae Hee , Whaley Reid C , Vogel Erin A , Monterosso John R , Gonzalez Anaya Maria J , Patel Devaki J , Jafarzadeh Nikki S , Hong Kurt , Mason Tyler B , Tackett Alayna P , Leventhal Adam M
Published: November 2024

Introduction

This study applied a novel tobacco regulatory science paradigm to characterize inter-product variation in the appeal and sensory features of emerging commercial and therapeutic oral nicotine products (ONPs) among young adults who vape e-cigarettes.

Aims and Methods

Twenty-three young adults without ONP experience who use e-cigarettes completed a single-blind, single-visit remote lab study. Participants rated appeal and sensory characteristics during 5-minute standardized self-administrations of eight ONPs (four fruits and four mints) from various brands (Lucy, Rouge, Solace, Nicorette, On!, and Velo). Participants were randomized between-subjects to ONP type (pouches or gum).

Results

Gum ONPs were rated sweeter (B = 19.5, 95% Confidence Interval (CI) = 4.3, 34.7), stronger in flavor (B = 25.6, 95% CI = 12.2, 39.0), and lower in tingling sensation (B = −14.0, 95% CI = −27.8, −0.2) than pouches. Fruit-flavored ONPs were sweeter (B = 12.9, 95% CI = 6.1, 19.7) and caused less burning (B = −12.0, 95% CI = −19.5, −4.5) than mint. Product type × flavor interactions found that gum versus pouch enhanced sweetness and flavor strength more for fruit than mint, while pouch versus gum increased burning and harshness more for mint. Nicorette White Ice was most appealing, while Rogue Fruit and Nicorette Mint were less so. Appeal correlated with most types of sensory experiences (rs = −0.33–0.54), except for tingling and burning.

Conclusions

Nicotine gums may offer a more pleasant sensory experience than pouches for young adults who use e-cigarettes, with variation across brand/flavor variants.

Implications

Results indicate that gum ONPs and fruit flavors may offer greater appeal and a more pleasant sensory experience than pouch ONPs and mint flavors for young adults who use e-cigarettes and are ONP-naïve, with heterogeneity in user experience across some brand/flavor variants. This study also introduces a method for assessing the appeal and sensory features of ONPs, which can inform regulatory efforts and strategies to reduce nicotine dependence among young adults who use e-cigarettes.
Protein phosphatase PP2C19 controls hypocotyl phototropism through the phosphorylation modification of NONPHOTOTROPIC HYPOCOTYL3 in Arabidopsis
Authors: Sakai Tatsuya , Haga Ken , Kimura Taro , Kawaura Keita
Published: November 2024

Plants exhibit shoot growth in the direction of the light source to facilitate photosynthesis, known as positive phototropism. In Arabidopsis hypocotyl phototropism, it is thought that a gradient of the signal intensity of the blue light (BL) photoreceptor phototropin1 (phot1) between the light-irradiated and shaded sides leads to the differential growth of hypocotyls. The intensity of phot1 signal is regulated not only by the protein kinase activity of phot1 but also by the phosphorylation status of the NONPHOTOTROPIC HYPOCOTYL3 (NPH3) protein, which has a dark form and a BL form of the phosphorylation modification. Previous studies have shown that phot1 drives the forward reaction from the dark form to the BL form of NPH3. However, the molecular mechanism underlying the reverse reaction remains unknown. Here, we show that protein phosphatase PP2C19 controls the reverse reaction that converts the BL form of NPH3 to the dark form of NPH3. The PP2C19 protein possesses the protein phosphatase type 2C (PP2C) domain, two cyclic nucleoside monophosphate (cNMP)-binding domains, and the protein kinase domain. Similar to phot1 and NPH3, PP2C19 localizes to the plasma membrane, and its PP2C domain is necessary and sufficient for PP2C19 function in hypocotyl phototropism. The pp2c19 mutants show abnormalities in second positive hypocotyl phototropism with a delay in the reverse reaction of NPH3 phosphorylation modification. The present study suggests that continuous BL irradiation induces an equilibrium state of the reversible reaction of NPH3 phosphorylation, which acts as a phot1 signaling gradient with phot1 kinase activity to induce the second positive phototropism.
Mitochondrial DNA copy number and risk of cardiovascular disease and all-cause mortality: a systematic review and meta-analysis of observational studies
Authors: Fu Xueru , Zhao Yang , Ke Yamin , Gao Yajuan , Wang Mengmeng , Chen Yaobing , Huo Weifeng , Wang Longkang , Zhang Wenkai , Wu Yuying , Li Xi , Zhang Dongdong , Hu Fulan , Hu Dongsheng , Zhang Ming
Published: November 2024

Increasing studies have explored the correlation of mitochondrial DNA copy number (mtDNA-CN) abnormalities with cardiovascular disease (CVD) and all-cause mortality; however, their findings are contradictory. This systematic review and meta-analysis sought to quantitatively summarize current studies to elucidate the impact of mtDNA-CN on CVD outcomes and all-cause mortality. Relevant studies were searched for in PubMed, Embase and Web of Science databases, up to 23 October 2023. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated with the random-effects model. In total, 22 articles were included in the systematic review, 13 of which were included in the meta-analysis of CVD outcomes and 8 in all-cause mortality. Compared to the highest mtDNA-CN level, the summary RR (95% CI) for the lowest mtDNA-CN level was 2.09 (95% CI 1.59–2.75) for CVD, 1.70 (95% CI 1.29–2.24) for coronary heart disease (CHD), 1.43 (95% CI 1.15–1.79) for heart failure (HF), 1.88 (95% CI 1.08–3.28) for stroke and 1.33 (95% CI 1.21–1.47) for all-cause mortality. Lower mtDNA-CN may increase the risk of CVD, including CHD, HF and stroke, as well as all-cause mortality. MtDNA-CN is a potential predictor of CVD and all-cause mortality.
Exploring research quality and journal representation: a comparative study of African Journals Online, Scopus, and Web of Science
Authors: Alonso-Álvarez Patricia
Published: November 2024

Based on its perceived objectivity, Scopus and Web of Science (WoS) have been largely considered as sources of journal authority. However, its status has recently been contested due to its linguistic, geographical, and disciplinary biases. This paper studies journal quality and journal representation, focusing on the African publishing environment. It compares three academic data sources: two international indexes—Scopus and WoS—, and a regional journal indexing platform—African Journals Online (AJOL). First, it revises and compares the quality criteria of the three sources to explore the similarities and differences among them. Then, the paper develops a methodology to compare journal coverage of the three data sources in terms of countries, research areas, and language. The results show the importance of implementing a situated notion of research quality and the existing biases of mainstream and alternative academic sources toward specific countries, research areas, and languages. The findings also contribute to the ongoing conversation about diversity and inclusion in science and can be used to assess the limitations of our current bibliometric analysis.
Health, Disability, and Economic Inactivity Following a Diagnosis of a Severe Mental Illness: Cohort Study of Electronic Health Records Linked at the Individual-Level, to Census from England
Authors: Cybulski L , Dewey M E , Hildersley R , Morgan C , Stewart R , Wuerth M , Das-Munshi J
Published: November 2024

Background

The association of social and clinical indicators with employment, disability, and health outcomes among individuals with severe mental illnesses (SMI) remains unclear. Existing evidence primarily comes from smaller cohort studies limited by shorter follow-up and high attrition, or registry-based research, which lacks information on important social determinants.

Study Design

We utilized a novel data linkage consisting of clinical records of individuals diagnosed with schizophrenia-spectrum or bipolar disorders from the South London and Maudsley Mental Health Trust, linked at the individual-level to the 2011 UK Census, a rich source for sociodemographic information. Using logistic regression, we estimated adjusted odds ratios (aORs) and 95% confidence intervals to determine associations between socioeconomic and clinical indicators and economic inactivity, self-rated health, and disability outcomes.

Results

The sample comprised 8249 people with SMI diagnoses. Economic inactivity (77.3%), disability (68.3%) and poor health (61.1%) were highly prevalent. Longer duration of illness and comorbid substance misuse were associated with economic inactivity, poorer self-rated health, and disability, with associations noted between living alone and all outcomes (aORs and 95% CI: Economic inactivity: 1.72, 1.45-2.03; disability: 1.48, 1.31-1.68; poor health: 1.32, 1.18-1.49). Relative to the White British group, Black African, South Asian, and Other Black groups were more likely to be economically inactive. Black Caribbean and other groups were less likely to report poorer self-rated health or disability.

Conclusions

Our findings highlight considerable disability, poorer health, and economic inactivity experienced by people with SMI. Addressing comorbid substance misuse and social isolation could play a role in improving outcomes.
“My Whole Life Was the Two Suburbs That Surrounded the Church”: LGBTQ+ Participation in Australian Pentecostal-Charismatic Churches as “Greedy Institutions”
Authors: Jennings Mark A C
Published: November 2024

Over the course of interviews with Lesbian, Gay, Bisexual, Transgender, Queer/Questioning and other (LGBTQ+) participants (or former participants) in Australian Pentecostal-Charismatic Christian (PCC) churches, a question emerged: why do LGBTQ+ people remain in churches which do not affirm their sexuality and/or gender identity (or, in the case of those who leave, why did they stay as long as they did)? Understanding these churches as “Greedy Institutions,” which stake a claim for participants’ undivided commitment, offers one explanation. Greedy institutions ostensibly maximize loyalty and assent without coercion, and this fits well with the reports of respondents, whose churches became the center of their spiritual and social lives. However, recognising the presence of a “morality of extremes,” divergence from which is punished as disloyalty, requires an analysis which discloses the exercise of “symbolic violence.” This perspective reveals that assent is also ensured through the threat of loss of ministry opportunities and community, and even eternal consequences.
Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage
Authors: Zhang Xuetao , Jacobs Kyle A , Raygor Kunal P , Li Shang , Li Jiajun , Wang Rong A
Published: November 2024

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder with manifestations including severe nose bleeding and microhemorrhage in brains. Despite being the second most common inherited bleeding disorder, the pathophysiological mechanism underlying HHT-associated hemorrhage is poorly understood. HHT pathogenesis is thought to follow a Knudsonian two-hit model, requiring a second somatic mutation for lesion formation. Mutations in activin receptor-like kinase 1 (ALK1) gene cause HHT type 2. We hypothesize that somatic mutation ofAlk1in arterial endothelial cells (AECs) leads to arterial defects and hemorrhage. Here, we mutatedAlk1in AECs in postnatal mice usingBmx(PAC)-CreERT2and found that somatic arterial endothelial mutation ofAlk1was sufficient to induce spontaneous epistaxis and multifocal cerebral microhemorrhage. This bleeding occurred in the presence of tortuous and enlarged blood vessels, loss of arterial molecular markerEfnb2, disorganization of vascular smooth muscle, and impaired vasoregulation. Our data suggest that arterial endothelial deletion ofAlk1leading to reduced arterial identity and disrupted vascular smooth muscle cell coverage is a plausible molecular mechanism for HHT-associated severe epistaxis. This work provides the first evidence that somaticAlk1mutation in AECs can cause hemorrhagic vascular lesions, offering a novel preclinical model critically needed for studying HHT-associated epistaxis, and delineating an arterial mechanism to HHT pathophysiology.
An Omics approach onMarchantia polymorphasingle FERONIA and MARIS homologs confirms links between cell wall integrity and abscisic acid
Authors: Jobe Timothy Owen , Litholdo Celso Gaspar , Stolze Sara Christina , Stephan Lisa , Westermann Jens , Harzen Anne , Hülskamp Martin , Nakagami Hirofumi , Boisson-Dernier Aurélien
Published: November 2024

Plant cells are surrounded by an extracellular cell wall that shields them from their abiotic and biotic environment. To coordinate their growth with their cell wall status, plant cells have developed cell wall integrity (CWI) mechanisms, at the center of which lies the transmembrane Malectin-like receptor kinase FERONIA (FER). FER controls a myriad of plant developmental processes including sexual reproduction, cell growth and morphogenesis, often intersecting with phytohormones-dependent pathways such as abscisic acid (ABA) signaling or plant immunity. Interestingly, FER together with its downstream receptor-like cytoplasmic kinase MARIS (MRI) was shown to similarly control root hair and rhizoid integrity in the vascular angiosperm Arabidopsis and the early diverging bryophyteMarchantia polymorpha, respectively.

Here, we performed comparative transcriptomics and proteomics on theM. polymorphamutant plants, Mpfer-1and Mpmri-1,and their corresponding wild-type accessions Tak-1 and Tak-2. Large and significant overlaps were observed between differentially expressed genes and differentially abundant proteins in both mutants. Our multi-omics approach revealed that MpFER and MpMRI largely cooperate to negatively regulate transcriptional and translational networks, particularly those related to plant defense and ABA responses. Moreover, our phenotypic analyses showed that Mpfer-1plants are hypersensitive to ABA-dependent growth inhibition, indicating that FER’s function of negatively regulating ABA-related growth responses is conserved between bryophytes and vascular plants.
The effects of early-life ambient temperature on the gut microbiome of a wild bird? an experimental approach
Authors: Ruuskanen Suvi , Hollmen Lotta , Stier Antoine , Hsu Bin-Yan , Cossin-Sevrin Nina , Marciau Coline , Hukkanen Mikaela , Vesterinen Eero
Published: November 2024

Vertebrate gut microbiome has significant effects on host development, health, and fitness. Multiple external factors contribute to gut microbiome variation, and the role of ambient temperature has gained increasing attention. Yet, temperature effects are often tested in extremes and in captive systems. We experimentally studied the effect of subtle temperature decreases during post-natal development on gut microbiome diversity and composition in wild pied flycatchers (Ficedula hypoleuca). We also performed partial cross-fostering to study the relative contribution of genetic and rearing environment on microbiome. Nest-box cold treatment did not influence gut microbiome diversity or composition, which may be due to the small temperature change, ontogenetic stage, or other factors, such as diet, causing large variation in the data. Rearing environment explained more of the variation in gut microbiome than genetic background, but the variance explained was relatively small. Future studies need to further address the drivers of the large intraspecific variation in microbiome in natural populations.
Systemic exposure to COVID-19 virus-like particles modulates firing patterns of cortical neurons in the living mouse brain
Authors: Das Aniruddha , Icardi Jacob , Borovicka Julie , Holden Sarah , Harrison Henry F. , Hirsch Alec J. , Raber Jacob , Dana Hod
Published: November 2024

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) causes a systemic infection that affects the central nervous system. We used virus-like particles (VLPs) to explore how exposure to the SARS-CoV-2 proteins affects brain activity patterns in wild-type (WT) mice and in mice that express the wild-type human tau protein (htau mice). VLP exposure elicited dose-dependent changes in corticosterone and distinct chemokine levels. Longitudinal two-photon microscopy recordings of primary somatosensory and motor cortex neurons that express the jGCaMP7s calcium sensor tracked modifications of neuronal activity patterns following exposure to VLPs. There was a substantial short-term increase in stimulus-evoked activity metrics in both WT and htau VLP-injected mice, while htau mice showed also increased spontaneous activity metrics and increase activity in the vehicle-injected group. Over the following weeks, activity metrics in WT mice subsided, but remained above baseline levels. For htau mice, activity metrics either remain elevated or decreased to lower levels than baseline. Overall, our data suggest that exposure to the SARS-CoV-2 VLPs leads to strong short-term disruption of cortical activity patterns in mice with long-term residual effects. The htau mice, which have a more vulnerable genetic background, exhibited more severe pathobiology that may lead to more adverse outcomes.
A widely-occurring family of pore-forming effectors broadens the impact of theSerratiaType VI secretion system
Authors: Reglinski Mark , Hurst Quenton W. , Williams David J. , Gierlinski Marek , Şahin Alp Tegin , Mathers Katharine , Ostrowski Adam , Bergkessel Megan , Zachariae Ulrich , Pitt Samantha J. , Coulthurst Sarah J.
Published: November 2024

The ability to compete with diverse competitors is essential for bacteria to succeed in microbial communities. A widespread strategy for inter-bacterial competition is the delivery of antibacterial toxins, or effector proteins, directly into rival cells using the Type VI secretion system (T6SS). Whilst a large number of broad-spectrum enzymatic T6SS effectors have been described, relatively few which form pores in target cell membranes have been reported. Here, we describe a widely-occurring new family of T6SS-dependent pore-forming effectors, exemplified by Ssp4 ofSerratia marcescensDb10. We showin vitrothat Ssp4 forms regulated pores that have higher selectivity for cations and use molecular dynamics simulations to support a high resolution structural model of a tetrameric membrane pore formed by Ssp4. Notably, Ssp4 displays a distinct ion selectivity, phylogenetic distribution and impact on intoxicated cells compared with Ssp6, the other cation-selective pore-forming toxin delivered by the same T6SS. Ssp4 is also active against a wider range of target species than Ssp6, highlighting that T6SS effectors are not always broad-spectrum. Finally, use of Tn-seq to identify Ssp4-resistant mutants reveals that amucAmutant ofPseudomonas fluorescens, which overproduces extracellular polysaccharide, provides resistance to T6SS attacks. We conclude that possession of two distinct T6SS-dependent pore-forming toxins may be a common strategy to ensure effective de-energisation of closely- and distantly-related competitors.
HelD is a Global Transcription Factor Enhancing Gene Expression in Rapidly Growing Mycobacteria
Authors: Vaňková Hausnerová Viola , Kumar Dilip , Shoman Mahmoud , Schwarz Marek , Modrák Martin , Jirát Matějčková Jitka , Neva Silvia , Havelková Jarmila , Šiková Michaela , Pospíšilová Debora , Halada Petr , Šanderová Hana , Holubová Jana , Dohál Matúš , Převorovský Martin , Staněk Ondřej , Knejzlík Zdeněk , Dvořáková Věra , Hnilicová Jarmila
Published: November 2024

HelD protein, also named HelR (encoded byMSMEG_2174inMycobacterium smegmatis), interacts with mycobacterial RNA polymerase (RNAP) and affects rifampicin resistance inMycobacterium abscessus. Here, we provide data on rifampicin resistance andhelDpresence in the genomes of other clinically relevant nontuberculous mycobacteria.

We show thathelDis primarily found in rapidly growing mycobacteria, such asM. smegmatis, where we detected HelD at a subset of promoters that can also associate with CarD and RbpA. Transcriptome analysis of ahelDdeletion strain using RNA-seq revealed that HelD enhances gene expression during exponential growth and decreases it in stationary phase, during which we observed reduced levels of CarD, RbpA, and GTP, the initiation nucleotide for the majority ofM. smegmatistranscripts. We propose a model in which HelD releases abortive RNAP complexes and confirm that HelD dissociates RNAP from the promoterin vitro.

HelD not only helps mycobacteria overcome rifampicin treatment but also supports efficient transcription during rapid growth, which indicates a dual role of this transcription regulator.
Comparative genomic analysis of a metagenome-assembled genome reveals distinctive symbiotic traits in a Mucoromycotina fine root endophyte arbuscular mycorrhizal fungus
Authors: Cole Joshua , Raguideau Sébastien , Abbaszadeh-Dahaji Payman , Hilton Sally , Muscatt George , Mushinski Ryan M. , Nilsson R. Henrik , Ryan Megan H. , Quince Christopher , Bending Gary D.
Published: November 2024

Recent evidence shows that arbuscular mycorrhizal (AM) symbiosis is established by two distinct fungal groups, with the distinctive ‘fine root endophyte’ morphotype formed by fungi from the sub-phylum Mucoromycotina rather than the sub-phylum Glomeromycotina. While Mucoromycotina AM fungi are globally distributed, their genomic basis for the symbiosis or how this compares to other mycorrhizal symbionts is unknown.

We used culture-independent metagenome sequencing to assemble and characterise the metagenome-assembled genome (MAG) of a putative fine root endophyte, which we show belonged to the family Planticonsortiaceae within the order Densosporales.

The MAG shares key traits with Glomeromycotina fungi, which indicate obligate biotrophy, including absence of fatty acid and thiamine biosynthesis pathways, limited enzymatic abilities to degrade plant cell walls, and a high abundance of calcium transporters. In contrast to Glomeromycotina fungi, it exhibited a higher capacity for degradation of microbial cell walls, a complete cellulose degradation pathway, low abundances of copper, nitrate and ammonium transporters, and a complete pathway for vitamin B6 biosynthesis.

These differences highlight the potential for contrasting interactions between Mucoromycotina and Glomeromycotina AM fungi with their host plant and the environment which could support niche differentiation and complementary ecological functions.
Rac1 inhibition prevents axonal cytoskeleton dysfunction in Transthyretin Amyloid Polyneuropathy
Authors: Magalhães Joana , Dias Vítor , Eira Jessica , Nóvoa Guilherme , Oliveira da Silva Marina I. , Kan Yu Yu , Dias Andreia , Carvalho Estefânia , Santos Mariana , Seixas Ana I , Coelho Teresa , Taipa Ricardo , Paes de Faria Joana , Lemos Carolina , Hsieh Sung-Tsang , Liz Márcia A.
Published: November 2024

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is characterized by the deposition of amyloidogenic TTR, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting in sensorimotor axonopathy with autonomic dysfunction. Here, we investigated cytoskeleton alterations in peripheral axons from an ATTRv-PN mouse model, the hTTRA97S knock-in mice. Proteomics of hTTRA97S sural nerves revealed dysregulation of actin-related proteins. hTTRA97S DRG neurons presented a defective actin distribution in growth cones along with a reduction in axonal actin trails, and an associated impairment in the pool of pre-synaptic vesicles. Microtubule dynamics and axonal transport abnormalities were also observed in mutant axons. Importantly, cytoskeletal defects in hTTRA97S neurons preceded axonal degeneration and were mediated by Rac1 hyperactivation in DRG neurites and sciatic nerves of pre-symptomatic mice. Rac1 inhibition rescued cytoskeleton alterations, preventing degeneration. Remarkably, in ATTRv-PN patients with late-onset disease, a variant in RACGAP1, encoding a Rac1 inactivator, supported the neuroprotective role of Rac1 inhibition. Our findings demonstrate that cytoskeletal defects precede axonal degeneration in ATTRv-PN and highlight Rac1 as a promising therapeutic target.
In vivoregulation of an endogenously-tagged protein by a light-regulated kinase
Authors: Bao Mengjing , Lepeta Katarzyna , Aguilar Gustavo , Schnider Sophie , Affolter Markus , Vigano Maria Alessandra
Published: November 2024

Post-translational modifications (PTMs) are indispensable modulators of protein activity. Most cellular behaviours, from cell division to cytoskeletal organization, are controlled by PTMs, their miss-regulation being associated with a plethora of human diseases. Traditionally, the role of PTMs has been studied employing biochemical techniques. However, these approaches fall short when studying PTM dynamicsin vivo. In recent years, functionalized protein binders have allowed the post-translational modification of endogenous proteins by bringing an enzymatic domain in close proximity to the protein they recognize. To date, most of these methods lack the temporal control necessary to understand the complex effects triggered by PTMs. In this study, we have developed a method to phosphorylate endogenous Myosin in a light-inducible manner. The method relies both on nanobody-targeting and light-inducible activation in order to achieve both tight specificity and temporal control. We demonstrate that this technology is able to disrupt cytoskeletal dynamics duringDrosophilaembryonic development. Together, our results highlight the potential of combining optogenetics and protein binders for the study of the proteome in multicellular systems.
Inflammatory Mesenchymal Stromal Cells and IFN-responsive T cells are key mediators of human bone marrow niche remodeling in CHIP and MDS
Authors: Prummel Karin D. , Woods Kevin , Kholmatov Maksim , Schmitt Eric C. , Vlachou Evi P. , Poschmann Gereon , Stühler Kai , Wehner Rebekka , Schmitz Marc , Winter Susann , Oelschlaegel Uta , Schwartz Logan S. , Moura Pedro L. , Hellström-Lindberg Eva , Theobald Matthias , Trowbridge Jennifer J. , Platzbecker Uwe , Zaugg Judith B. , Guezguez Borhane
Published: November 2024

Somatic mutations in hematopoietic stem/progenitor cells (HSPCs) can lead to clonal hematopoiesis of indeterminate potential (CHIP), potentially progressing to myelodysplastic syndromes (MDS). Here, we investigated how CHIP and MDS remodel the human bone marrow (BM) niche relative to healthy elderly donors, using single cell and anatomical analyses in a large BM cohort. We found distinct inflammatory remodeling of the BM in CHIP and MDS. Furthermore, the stromal compartment progressively lost its HSPC-supportive adipogenic CXCL12-abundant reticular cells while an inflammatory mesenchymal stroma cell (iMSCs) population emerged in CHIP, which expanded in MDS. iMSCs exhibited distinct functional signatures in CHIP and MDS, retaining residual HSPC-support and angiogenic activity in MDS, corresponding with an increase in microvasculature in the MDS niche. Additionally, an IFN-responsive T cell population was linked to fueling inflammation in the stroma. Overall, these findings open new avenues for early intervention in hematological malignancies.
Notch Signaling Drives Pro-Regenerative and Migratory Traits in Glandular Stem/Progenitor cells
Authors: Cinat Davide , Maturi Rufina , Gunawan Jeremy P. , Bruin Anne L Jellema-de , Kracht Laura , Martinez Paola Serrano , Wu Yi , Soto-Gamez Abel , van Goethem Marc-Jan , Holtman Inge R. , Pringle Sarah , Barazzuol Lara , Coppes Rob P.
Published: November 2024

Organoid models have advanced our understanding of adult stem/progenitor cell dynamics and function. However, uncovering the regulatory mechanisms of scarce and often quiescent stem cells in organs like the salivary glands remains challenging. Using single-cell RNA sequencing and bulk ATAC and RNA-sequencing analysis, we conducted in-depth profiling of the cellular populations and key signaling pathways characterizing a mouse submandibular salivary gland organoid (mSGO) model at different temporal stages and in response to radiation damage. We identifiedSox9-andItgb1-expressing cells as the most primitive adult stem/progenitor populations and uncover novel stemness and migratory roles forCd44-expressing cells. Moreover, we revealed that Notch signaling is essential for maintaining self-renewal and migration potential of these stem/progenitor cells post-irradiation. Extending these findings to patient-derived mSGOs, as well as murine and patient-derived mammary and thyroid gland organoids, we confirmed Notch signaling as a conserved regulator of stem/progenitor cell function under migrative and regenerative conditions.
Paired CRISPR screens to map gene regulation incisandtrans
Authors: Xue Xinhe , Gajic Zoran Z. , Caragine Christina M. , Legut Mateusz , Walker Conor , Kim James Y.S. , Wang Xiao , Yan Rachel E. , Wessels Hans-Hermann , Lu Congyi , Bapodra Neil , Gürsoy Gamze , Sanjana Neville E.
Published: November 2024

Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of eithercis-regulatory elements (CREs) ortrans-acting factors. Here, we develop a scalable approach that pairscis- andtrans-regulatory CRISPR screens to systematically dissect how the key immune checkpointPD-L1is regulated. In human pancreatic ductal adenocarcinoma (PDAC) cells, we tile thePD-L1locus using ∼25,000 CRISPR perturbations in constitutive and IFNγ-stimulated conditions. We discover 67 enhancer- or repressor-like CREs and show that distal CREs tend to contact the promoter ofPD-L1and related genes. Next, we measure how loss of all ∼2,000 transcription factors (TFs) in the human genome impacts PD-L1 expression and, using this, we link specific TFs to individual CREs and reveal novel PD-L1 regulatory circuits. For one of these regulatory circuits, we confirm the binding of predictedtrans-factors (SRF and BPTF) using CUT&RUN and show that loss of either the CRE or TFs potentiates the anti-cancer activity of primary T cells engineered with a chimeric antigen receptor. Finally, we show that expression of these TFs correlates withPD-L1expressionin vivoin primary PDAC tumors and that somatic mutations in TFs can alter response and overall survival in immune checkpoint blockade-treated patients. Taken together, our approach establishes a generalizable toolkit for decoding the regulatory landscape of any gene or locus in the human genome, yielding insights into gene regulation and clinical impact.