bluuebunny/crossref_metadata_2025 huggingface dataset:
On the homogeneity of SnIa absolute magnitude in the Pantheon+ sample
Authors: Perivolaropoulos Leandros , Skara Foteini
Published: February 2023

We have analysed the Pantheon+ sample using a new likelihood model that replaces the single Type Ia supernovae (SnIa) absolute magnitude parameter M used in the standard likelihood model of Brout et. al. with two absolute magnitude parameters (M< and M>) and a transition distance (dcrit) that determines the distance at which M changes from M< to M>. The use of this likelihood dramatically changes the quality of fit to the Pantheon+ sample for a Lambda cold dark matter background by Δχ2 = −19.6. The tension between the M< and M> best-fitting values is at a level more than 3σ with a best-fitting dcrit very close to $20\, \mathrm{Mpc}$. The origin of this improvement of fit and M<–M> tension is that the new likelihood model successfully models two signals hidden in the data: (1) the volumetric redshift scatter bias systematic and (2) a mild signal for a change of intrinsic SnIa luminosity at about $20\, \mathrm{Mpc}$. This interpretation of the results is confirmed by truncating the z < 0.01 Hubble diagram data from the Pantheon+ data where the above systematic is dominant and showing that the M<–M> tension decreases from above 3σ to a little less than 2σ. It is also confirmed by performing a Monte Carlo simulation, which shows that the maximum significance of the SnIa luminosity transition ($\Sigma \equiv \frac{|M_{\gt} -M_{\lt} |}{\sqrt{\sigma _{M_{\gt} }^2+\sigma _{M_{\lt} }^2}}$) as obtained from the real SH0ES data is larger than the corresponding maximum significance of $94{{\ \rm per\ cent}}$ of the corresponding homogeneous simulated samples.
Simulations of triple microlensing events I: detectability of a scaled Sun–Jupiter–Saturn system
Authors: Kuang Renkun , Zang Weicheng , Mao Shude , Zhang Jiyuan , Jiang Haochang
Published: February 2023

Up to date, only 13 firmly established triple microlensing events have been discovered, so the occurrence rates of microlensing two-planet systems and planets in binary systems are still uncertain. With the upcoming space-based microlensing surveys, hundreds of triple microlensing events will be detected. To provide clues for future observations and statistical analyses, we initiate a project to investigate the detectability of triple-lens systems with different configurations and observational set-ups. As the first step, in this work we develop the simulation software and investigate the detectability of a scaled Sun–Jupiter–Saturn system with the recently proposed telescope for microlensing observations on the ‘Earth 2.0 (ET)’ satellite. With the same Δχ2 thresholds of detecting a single planet and two planets, we find that the detectability of the scaled Sun-Jupiter-Saturn analogue is about 1 per cent and the presence of the Jovian planet suppresses the detectability of the Saturn-like planet by ∼13 per cent regardless of the adopted detection Δχ2 threshold. This suppression probability could be at the same level as the Poisson noise of future space-based statistical samples of triple-lenses, so it is inappropriate to treat each planet separately during detection efficiency calculations.
The redshift evolution of the S0 fraction for z < 1 in COSMOS
Authors: Cavanagh Mitchell K , Bekki Kenji , Groves Brent A
Published: February 2023

Lenticular (S0) galaxies are galaxies that exhibit a bulge and disc component, yet lack any clear spiral features. With features considered intermediary between spirals and ellipticals, S0s have been proposed to be a transitional morphology, however their exact origin and nature is still debated. In this work, we study the redshift evolution of the S0 fraction out to z ∼ 1 using deep learning to classify F814W (i band) Hubble Space Telescope-Advanced Camera for Surveys (HST-ACS) images of 85 378 galaxies in the Cosmic Evolution Survey (COSMOS). We classify galaxies into four morphological categories: elliptical (E), S0, spiral (Sp), and irregular/miscellaneous (IrrM). Our deep learning models, initially trained to classify Sloan Digital Sky Survey (SDSS) images with known morphologies, have been successfully adapted to classify high-redshift COSMOS images via transfer learning and data augmentation, enabling us to classify S0s with superior accuracy. We find that there is an increase in the fraction of S0 galaxies with decreasing redshift, along with a corresponding reduction in the fraction of spirals. We find a bimodality in the mass distribution of our classified S0s, from which we find two separate S0s populations: high-mass S0s, which are mostly red and quiescent; and low-mass S0s, which are generally bluer and include both passive and star-forming S0s, the latter of which cannot solely be explained via the faded spiral formation pathway. We also find that the S0 fraction in high-mass galaxies begins rising at higher z than in low-mass galaxies, implying that high-mass S0s evolved earlier.
Systematic identification of factors involved in the silencing of germline genes in mouse embryonic stem cells
Authors: Al Adhami Hala , Vallet Judith , Schaal Celia , Schumacher Paul , Bardet Anaïs Flore , Dumas Michael , Chicher Johana , Hammann Philippe , Daujat Sylvain , Weber Michael
Published: February 2023

In mammals, many germline genes are epigenetically repressed to prevent their illegitimate expression in somatic cells. To advance our understanding of the mechanisms restricting the expression of germline genes, we analyzed their chromatin signature and performed a CRISPR-Cas9 knock-out screen for genes involved in germline gene repression using a Dazl-GFP reporter system in mouse embryonic stem cells (mESCs). We show that the repression of germline genes mainly depends on the polycomb complex PRC1.6 and DNA methylation, which function additively in mESCs. Furthermore, we validated novel genes involved in the repression of germline genes and characterized three of them: Usp7, Shfm1 (also known as Sem1) and Erh. Inactivation of Usp7, Shfm1 or Erh led to the upregulation of germline genes, as well as retrotransposons for Shfm1, in mESCs. Mechanistically, USP7 interacts with PRC1.6 components, promotes PRC1.6 stability and presence at germline genes, and facilitates DNA methylation deposition at germline gene promoters for long term repression. Our study provides a global view of the mechanisms and novel factors required for silencing germline genes in embryonic stem cells.
Genomic targets of the IRE1-XBP1s pathway in mediating metabolic adaptation in epithelial plasticity
Authors: Qiao Dianhua , Skibba Melissa , Xu Xiaofang , Brasier Allan R
Published: February 2023

Epithelial mesenchymal plasticity (EMP) is a complex cellular reprogramming event that plays a major role in tissue homeostasis. Recently we observed the unfolded protein response (UPR) triggers EMP through the inositol-requiring protein 1 (IRE1α)–X-box-binding protein 1 spliced (XBP1s) axis, enhancing glucose shunting to protein N glycosylation. To better understand the genomic targets of XBP1s, we identified its genomic targets using Cleavage Under Targets and Release Using Nuclease (CUT&RUN) of a FLAG-epitope tagged XBP1s in RSV infection. CUT&RUN identified 7086 binding sites in chromatin that were enriched in AP-1 motifs and GC-sequences. Of these binding sites, XBP1s peaks mapped to 4827 genes controlling Rho-GTPase signaling, N-linked glycosylation and ER-Golgi transport. Strikingly, XBP1s peaks were within 1 kb of transcription start sites of 2119 promoters. In addition to binding core mesenchymal transcription factors SNAI1 and ZEB1, we observed that hexosamine biosynthetic pathway (HBP) enzymes were induced and contained proximal XBP1s peaks. We demonstrate that IRE1α -XBP1s signaling is necessary and sufficient to activate core enzymes by recruiting elongation-competent phospho-Ser2 CTD modified RNA Pol II. We conclude that the IRE1α-XBP1s pathway coordinately regulates mesenchymal transcription factors and hexosamine biosynthesis in EMP by a mechanism involving recruitment of activated pSer2-Pol II to GC-rich promoters
Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment
Authors: Tang Shijie , Xue Yun , Qin Zhen , Fang Zhaoyuan , Sun Yihua , Yuan Chongzhe , Pan Yunjian , Zhao Yue , Tong Xinyuan , Zhang Jian , Huang Hsinyi , Chen Yuting , Hu Liang , Huang Dasong , Wang Ruiqi , Zou Weiguo , Li Yuan , Thomas Roman K , Ventura Andrea , Wong Kwok-Kin , Chen Haiquan , Chen Luonan , Ji Hongbin
Published: February 2023

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, harbors strong plasticity and is significantly associated with poor prognosis. We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation. Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development. Dynamic dysregulation of the counteracting lineage-specific transcription factors (TFs), containing adenomatous TFs NKX2-1 and FOXA2, and squamous TFs TP63 and SOX2, finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration. Genomic clustering identified the most malignant subtype featured with STK11-inactivation, and targeting LSD1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors. These data collectively uncover the comprehensive molecular landscape, oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS.
Lightweight, highly tough and durable YBa2Cu3O7–x superconductor
Authors: Zhang Baoqiang , Zhang Xingyi , Zhou You-He
Published: February 2023

The inherent brittleness and low sustainability of YBa2Cu3O7–x (YBCO) bulk superconductor seriously impede its wide applications. It is a great challenge to achieve toughening of this material and maintain its invariable superconductivity at the same time. Here, we fabricate bulk YBCO composite superconductor with a density of 2.15 g cm−3, which consists of interlocking dual network construction and shows high toughness and durability. The results show that its unit normalized fracture energy at 77 K reaches 638.6 kN m−2, which is ∼14.8 times that of YBCO bulk prepared by the top-seeded melt textured growth (TSMTG) method. Its critical current shows no degradation during the toughening process. Moreover, after 10 000 cycles, the sample does not fracture with the decay of critical current at 4 K of 14.6% whereas the TSMTG sample fractures only after 25 cycles.
Clinico-radiological correlation and prognostic value of baseline chest computed tomography in eosinophilic granulomatosis with polyangiitis
Authors: Delestre Florence , Brun Anne-Laure , Thoreau Benjamin , Taillé Camille , Limal Nicolas , Puéchal Xavier , Mouthon Luc , Guillevin Loïc , Revel Marie-Pierre , Terrier Benjamin
Published: February 2023

Objectives

While chest high-resolution CT (HRCT) is correlated to severity and prognosis in asthma, it has not been studied in eosinophilic granulomatosis with polyangiitis (EGPA). Our objective is to study the prognostic value of baseline HRCT in EGPA patients.

Methods

Retrospective, multicentre observational study in three French hospitals, including EGPA patients with available chest HRCT before any systemic treatment. Two experienced radiologists blinded to clinical data evaluated HRCT images using semi-quantitative scoring. HRCT characteristics were correlated with clinical features and outcome.

Results

Among 46 patients, 38 (82.6%) had abnormal parenchymal findings on HRCT, including bronchial wall thickening (69.6%), mosaic perfusion (63.0%), ground-glass opacities (32.6%), bronchiectasis (30.4%), mucous plugging (21.7%) and consolidations (17.4%). Patients were clustered into three groups depending on HRCT features: ground-glass pattern, i.e. with ground-glass opacities with or without bronchial abnormalities (group 1, 28.3%), bronchial pattern (group 2, 41.3%) and extra-pulmonary pattern with no significant abnormality (group 3, 30.4%). Group 2 showed less frequent cardiac involvement (31.6 vs 46.2 and 42.9% in groups 1 and 3), more frequent positive ANCA (52.6 vs 0.0 and 14.3%) and higher eosinophil count (median 7510 vs 4000 and 4250/mm3). Group 1 showed worse prognosis with more frequent steroid-dependency (58.3 vs 11.1 and 28.6%) and requirement for mepolizumab (25.0 vs 11.1 and 7.1%). Conversely, group 2 showed a better outcome with higher rates of remission (88.9 vs 41.6 and 71.4%).

Conclusion

Chest HRCT at diagnosis of EGPA may have prognostic value and help clinicians better manage these patients.
Spatiotemporal Alterations in Working Memory-Related Beta Band Neuromagnetic Activity of Patients With Schizophrenia On and Off Antipsychotic Medication: Investigation With MEG
Authors: Rubinstein Daniel Y , Eisenberg Daniel P , Carver Frederick W , Holroyd Tom , Apud Jose A , Coppola Richard , Berman Karen F
Published: February 2023

Background and Hypothesis

We used the uniquely high combined spatial and temporal resolution of magnetoencephalography to characterize working memory (WM)-related modulation of beta band activity in neuroleptic-free patients with schizophrenia in comparison to a large sample of performance-matched healthy controls. We also tested for effects of antipsychotic medication on identified differences in these same patients.

Study Design

Inpatients with schizophrenia (n = 21) or psychotic disorder not otherwise specified (n = 4) completed N-back and control tasks during magnetoencephalography while on placebo and during antipsychotic medication treatment, in a blinded, randomized, counterbalanced manner. Healthy, performance-matched controls (N = 100) completed the same tasks. WM-related neural activation was estimated as beta band (14–30 Hz) desynchronization throughout the brain in successive 400 ms time windows. Voxel-wise statistical comparisons were performed between controls and patients while off-medication at each time window. Significant clusters resulting from this between-groups analysis were then used as regions-of-interest, the activations of which were compared between on- and off-medication conditions in patients.

Study Results

Controls showed beta-band desynchronization (activation) of a fronto-parietal network immediately preceding correct button press responses–the time associated with WM updating and task execution. Altered activation in medication-free patients occurred largely during this time, in prefrontal, parietal, and visual cortices. Medication altered patients’ neural responses such that the activation time courses in these regions-of-interest more closely resembled those of controls.

Conclusions

These findings demonstrate that WM-related beta band alterations in schizophrenia are time-specific and associated with neural systems targeted by antipsychotic medications. Future studies may investigate this association by examining its potential neurochemical basis.
‘Trust and safety’: exchange, protection and the digital market–fortress in platform capitalism
Authors: Denyer Willis Graham
Published: February 2023

As a space of exchange that transcends historic jurisdictions, the Internet lacks a dominant security provider. This research examines how and why firms in platform capitalism have developed their own method and means of protection. ‘Trust and Safety’ (T&S) is a novel division of labour that has become nearly ubiquitous in the industry, encompassing many of the concerns raised about the influence of technology on politics, society and economy. The making of capitalist exchange online requires a similarly discrete making of protection beyond the state. T&S work ensures that interaction and exchange are sheltered, doing so by curating trust between atomized individuals, and asserting what belongs and what does not. T&S’ centrality to platform capitalism can be explained—in part—by Weber’s notion of the city as market–fortress; a spatialized condition of exchange protection that is foundational for fastening capitalism together and seeking to make it, and inequality, inevitable.
Handling Logical Character Dependency in Phylogenetic Inference: Extensive Performance Testing of Assumptions and Solutions Using Simulated and Empirical Data
Authors: Simões Tiago R , Vernygora Oksana V , de Medeiros Bruno A S , Wright April M
Published: February 2023

Logical character dependency is a major conceptual and methodological problem in phylogenetic inference of morphological data sets, as it violates the assumption of character independence that is common to all phylogenetic methods. It is more frequently observed in higher-level phylogenies or in data sets characterizing major evolutionary transitions, as these represent parts of the tree of life where (primary) anatomical characters either originate or disappear entirely. As a result, secondary traits related to these primary characters become “inapplicable” across all sampled taxa in which that character is absent. Various solutions have been explored over the last three decades to handle character dependency, such as alternative character coding schemes and, more recently, new algorithmic implementations. However, the accuracy of the proposed solutions, or the impact of character dependency across distinct optimality criteria, has never been directly tested using standard performance measures. Here, we utilize simple and complex simulated morphological data sets analyzed under different maximum parsimony optimization procedures and Bayesian inference to test the accuracy of various coding and algorithmic solutions to character dependency. This is complemented by empirical analyses using a recoded data set on palaeognathid birds. We find that in small, simulated data sets, absent coding performs better than other popular coding strategies available (contingent and multistate), whereas in more complex simulations (larger data sets controlled for different tree structure and character distribution models) contingent coding is favored more frequently. Under contingent coding, a recently proposed weighting algorithm produces the most accurate results for maximum parsimony. However, Bayesian inference outperforms all parsimony-based solutions to handle character dependency due to fundamental differences in their optimization procedures—a simple alternative that has been long overlooked. Yet, we show that the more primary characters bearing secondary (dependent) traits there are in a data set, the harder it is to estimate the true phylogenetic tree, regardless of the optimality criterion, owing to a considerable expansion of the tree parameter space. [Bayesian inference, character dependency, character coding, distance metrics, morphological phylogenetics, maximum parsimony, performance, phylogenetic accuracy.]
Effectiveness of rational emotive behavior therapy in reducing depression among undergraduate medical students
Authors: Victor-Aigbodion Vera , Eseadi Chiedu , Ardi Zadrian , Sewagegn Abatihun Alehegn , Ololo Kennedy , Abonor Lazarus Bassey , Aloh Henry Egi , Falade Temitope Ayodeji , Effanga Offiong Asuquo
Published: February 2023

Background:

Studies reporting the incidence of depression among medical students have been on the increase. This research sought to determine whether rational emotive behavior therapy (REBT) can be applied to help manage depression in Nigerian undergraduate medical students.

Methods:

A randomized pretest/posttest control group design was used in this study. Ninety medical students with depression participated in the study and were assisted using the REBT depression manual. Using a mixed-model repeated measures analysis of variance, the researchers examined the intervention data.

Results:

The depressive symptoms and its associated irrational beliefs among medical students in the treatment arm were significantly altered by REBT intervention at posttest and this positive outcome was sustained at follow-up in contrast to the control arm.

Conclusion:

REBT intervention significantly improves medical students’ ability to overcome depression and irrational beliefs. Similar studies could be conducted in a variety of academic settings where these students can be found to expand the findings of this study.
Choriocarcinoma masquerading as lumbar spinal tumor: Case report and literature review
Authors: Liu Yitong , Li Chan , Sun Haiyan , Kang Fuli , Zhang Zhenhong , Yue Chen
Published: February 2023

Rationale:

Choriocarcinoma is a highly invasive gestational trophoblastic neoplasm, usually metastasis to lung and brain, but occurrence of choriocarcinoma following spontaneous abortion presenting as a vertebral tumor is extremely rare, to the best of our knowledge. Because of the poor diagnosis and high malignancy, the low progression-free survival follows up.

Patient concerns:

We here are reporting a case of choriocarcinoma that presented with vertebral tumor induced paralysis of limbs and incontinence of urine.

Diagnosis:

Combined with the childbearing history, high β-human chorionic gonadotrophinin levels, and imaging examination, a clinical diagnosis was made exactly. Till the pathological results after the operation of lumbar spinal canal tumorectomy, the diagnosis was exactly clear.

Interventions:

After performing the laminectomy, the fierce bleeding follows up, just did the temporary limited decompression. Because of the vertebral artery embolization, lumbar spinal canal tumorectomy, spinal canal and root canal decompression, subdural decompression and hematoma removal were performed.

Outcomes:

After performing the operation and chemotherapy timely and positively, the patient lost consciousness and died due to the pulmonary embolism at last.

Lessons:

This is the first case report describing choriocarcinoma with metastases to the spine amongst Chinese population as well. Early metastasis is one of the marked tendencies of choriocarcinoma, but spine metastasis and the related spinal oppressional symptoms were found instead of vaginal bleeding in this case, which is indeed rare.
Biomechanical and functional analysis of the shoulder complex and thoracic spine in patients with subacromial impingement syndrome: A case control study
Authors: Choi Moonyoung , Chung Jinwook
Published: February 2023

The motions of the shoulder are mainly carried out through the glenohumeral joint, but are also assisted by the scapulothoracic joint. Therefore, changes in the biomechanics of the thoracic spine and scapula affect the function of the shoulder. However, there is limited information on the biomechanical and functional characteristics of the shoulder complex and thoracic spine in patients with subacromial impingement syndrome (SIS). In this study, the biomechanical and functional characteristics of the shoulder complex and thoracic spine were analyzed in patients with SIS compared to healthy individuals. A total of 108 participants were included in this study. Participants were classified into 2 groups, the SIS (n = 55) and healthy (n = 53) groups. The shoulder and thoracic range of motion (ROM), scapular position, and isokinetic shoulder strength were measured in all participants. The shoulder ROM was significantly decreased in the SIS group compared to the healthy group (P < .001). The thoracic spine ROM showed significantly limited extension in the SIS group (P < .001). The scapular position showed significantly increased anterior tilting (P = .005), internal rotation (P = .032), protraction (P < .001), and decreased upward rotation (P = .002) in the SIS group. The isokinetic shoulder external rotation (P < .001) and abduction (P < .001) strength were significantly lower in the SIS group. Patients with SIS showed reduced shoulder ROM and end-range extension of the thoracic spine compared to healthy individuals, and the scapula was in a more anterior-tilted, protracted, and downward rotated position. In addition, it showed lower external rotation and abduction strength. These results suggest the need for interventions to improve the limited thoracic extension and altered scapular position, which may affect shoulder ROM and muscle strength in the rehabilitation of patients with SIS.
Coexistence of primary mediastinal MALT lymphoma and multiple myeloma like POEMS syndrome: A case report and literature review
Authors: Yin Shangjin , Zhou Kuangguo , Wang Zhiqiong , Gong Duanhao , Huang Wei
Published: February 2023

Rationale:

The coexistence of the extranidal marginal zone lymphoma (MZL) of mucosa–associated lymphoid tissue (MALT) and multiple myeloma (MM) is an exceedingly rare situation. The rare situation precludes any evidence-based guidelines for MZL or MM.

Patient concerns and diagnoses:

We presented a unique case of the coexistence of primary mediastinal MALT lymphoma and MM like polyneuropathy, organomegaly, endocrinopathy, M-protein, skin syndrome.

Interventions and outcomes:

The patient was first diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin syndrome in the department of neurology, then MM in the department of hematology, and the mediastinal MALT simultaneously coexisting with MM was found by biopsy in the department of thoracic surgery. The patient received combination therapy with rituximab and bortezomib followed by lenalidomide maintenance. To understand MZL lymphoma with plasmacytic differentiation better, we analyzed cases of MZL lymphomas with plasma cell neoplasms. Most of these cases were MZL lymphomas with light chain-restricted plasmacytic differentiation. The lymphomas relapsed with plasma cell neoplasms or transformed into plasma cell neoplasms after anti-lymphoma therapy.

Lessons:

The case demonstrated clinical complexity and the importance of the detailed assessment. The case and literature review demonstrated the value of detecting light chain-restricted plasmacytic differentiation for the treatment of MZL lymphoma with rituximab plus lenalidomide or bortezomib.
A case report of paraneoplastic bullous pemphigoid associated with mantle cell lymphoma: A rare presentation
Authors: Md Radzi Ahmad Bakhtiar , Kasim Sazzli Shahlan
Published: February 2023

Rationale:

We report a rare case of paraneoplastic bullous pemphigoid associated with mantle cell lymphoma.

Patients concerns:

The patient presented with 5 months’ history of generalized skin itchiness, night sweat and loss of weight. The skin manifestations started over the foot and hand area. However, he started to developed tense blisters over the face, trunk and limbs 3 days prior to this admission.

Diagnoses:

The skin biopsy report showed subepidermal bullae, in which the immunofluorescence findings in keeping with bullous pemphigoid. The peripheral blood immunophenotyping was suggestive of mantle cell lymphoma. Hence, a diagnosis of paraneoplastic bullous pemphigoid associated with mantle cell lymphoma was made.

Interventions:

The patient was initiated with a cytoreduction chemotherapy.

Outcomes:

Unfortunately, patient’s condition deteriorated further due to neutropenic sepsis and he succumbed after 2 weeks of intensive care.

Lessons:

Bullous pemphigoid associated with mantle cell lymphoma are very rare. The presentation of bullous pemphigoid led to the detection of mantle cell lymphoma. Early diagnosis and appropriate treatment is crucial in managing this aggressive type of the disease. Both, bullous pemphigoid and mantle cell lymphoma had a parallel clinical course which suggests a paraneoplastic phenomenon in this reported case.
Confirmation of theMIR204n.37C>T heterozygous variant as a cause of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma
Authors: Jedlickova J. , Vajter M. , Barta T. , Black G. , Mares J. , Fichtl M. , Kousal B. , Dudakova L. , Liskova P.
Published: February 2023

Four members of a three-generation family with early-onset chorioretinal dystrophy were shown to be heterozygous carriers of the n.37C>T inMIR204. The identification of this previously reported pathogenic variant confirms the existence of a distinct clinical entity caused by a sequence change inMIR204. The chorioretinal dystrophy was variably associated with iris coloboma, congenital glaucoma, and premature cataracts extending the phenotypic range of the condition. In silico analysis of the n.37C>T variant revealed 713 novel targets. Additionally, family members were shown to be affected by albinism resulting from biallelic pathogenicOCA2variants.
Collaborative Clinical Reasoning: a scoping review
Authors: Lee Ching-Yi , Lai Hung-Yi , Lee Ching-Hsin , Chen Mi-Mi , Yau Sze-Yuen
Published: February 2023

Introduction

Team approaches in healthcare highlight the importance and benefits of collaboration on maximising clinical outcomes and patient safety. Based on extant literature, the authors aimed to explore collaborative clinical reasoning (CCR) among healthcare professionals.

Methods

A scoping review was undertaken to examine CCR related studies in healthcare. Medline, PsychInfo, SciVerse Scopus, and Web of Science were searched. Inclusion criteria included full-text articles published between 2011 to 2020. Search terms included cooperative, collaborative, shared, team, collective, reasoning, problem solving, decision making, combined with clinical or medicine or medical, but excluded shared decision making.

Results

A total of 24 articles were identified in the review. Analysis of the articles resulted in four major content themes: (1) Decision-making process (n=14); (2) Quality assessment by MDTs-MODe (Multidisciplinary Team-Metric for the Observation of Decision Making; n=5) (3) CCR theory and definitions(n=3); and (4) Problem-solving process (n=2). Most articles focused on communication associated with collaborative decision-making processes. The discussion of team impacts among all studies was merely the notion of clinical reasoning as an essential component of the collaborative or interprofessional practice. None provided direct evidence on the process of CCR or its impact on clinical outcomes. Only two articles provided specific definitions on CCR.

Discussion

We illuminate the necessity of further research in CCR, specifically with a focus on cognitive components of CCR. A better understanding of current CCR research in healthcare may inform future discussions around establishing strategies to enhance CCR development, and hence provide positive influence on medical education and patient safety.
Combining organotypic tissue culture with multi-color fluorescence light-sheet microscopy (OTCxLSFM) – a novel tool to study glioma invasion/migration
Authors: Haydo Alicia , Wehle Andrej , Herold-Mende Christel , Kögel Donat , Pampaloni Francesco , Linder Benedikt
Published: February 2023

Glioblastoma is a very aggressive tumor and represents the most common primary brain malignancy. Key characteristics include its high resistance against conventional treatments, such as radio- and chemotherapy and its diffuse tissue infiltration, preventing complete surgical resection. The analysis of migration and invasion processes in a physiological microenvironment allows for enhanced understanding of these processes and can lead to improved therapeutic approaches. Here, we combine two state-of-the-art techniques, adult organotypic brain tissue slice culture (OTC) and light sheet fluorescence microscopy (LSFM) of cleared tissues in a combined method termed OTCxLSFM. Using this methodology, we can show that glioblastoma tissue infiltration can be effectively blocked through treatment with arsenic trioxide, as well as genetic depletion of the tetraspanin, transmembrane receptor CD9. With our analysis-pipeline we gain single-cell level, three-dimensional information, as well as insights into the morphological appearance of the tumor cells.
Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2
Authors: Yin Kailin , Peluso Michael J. , Luo Xiaoyu , Thomas Reuben , Shin Min-Gyoung , Neidleman Jason , Andrew Alicer , Young Kyrlia , Ma Tongcui , Hoh Rebecca , Anglin Khamal , Huang Beatrice , Argueta Urania , Lopez Monica , Valdivieso Daisy , Asare Kofi , Deveau Tyler-Marie , Munter Sadie E. , Ibrahim Rania , Ständker Ludger , Lu Scott , Goldberg Sarah A. , Lee Sulggi A. , Lynch Kara L. , Kelly J. Daniel , Martin Jeffrey N. , Münch Jan , Deeks Steven G. , Henrich Timothy J. , Roan Nadia R.
Published: February 2023

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq/scRNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. RNAseq/scRNAseq and Olink analyses similarly revealed immune dysregulatory mechanisms, along with non-immune associated perturbations, in individuals with LC. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
Childhood cognitive ability and self-harm and suicide in later life
Authors: Iveson Matthew H. , Ball Emily L. , Whalley Heather C. , Deary Ian J. , Cox Simon R. , Batty G. David , John Ann , McIntosh Andrew M.
Published: February 2023

Self-harm and suicide remain prevalent in later life. For younger adults, work has highlighted an association between higher early-life cognitive ability and lower self-harm and suicide risk. Comparatively little is known about its association with self-harm and suicide among older adults. Furthermore, most work has measured cognitive ability in early adulthood, raising issues of potential confounding by emerging psychiatric conditions.

The present study examined the association between childhood (age 11) cognitive ability and self-harm and suicide risk among a Scotland-wide cohort of older adults (N = 53037), using health data linkage to follow individuals from age 34 to 85. Self-harm events were extracted from hospital admissions and suicide deaths were extracted from national mortality records. Multistate models were used to model transitions between unaffected, self-harm, and then suicide or non-suicide death, and to examine the association between childhood cognitive ability and each transition.

After adjusting for childhood and adulthood socioeconomic conditions, higher childhood cognitive ability was significantly associated with reduced risk of self-harm among older females (N events = 516; HR = 0.90, 95% CI = [0.81, 0.99]). A similar, though non-significant, association was observed among older males (N events = 451; HR = 0.90, 95% CI = [0.82, 1.00]). Although suicide risk was higher among older adults experiencing self-harm, childhood cognitive ability was not significantly associated with suicide risk among either older adults experiencing no self-harm events (Male: N events = 118, HR = 1.17, 95% CI = [0.84, 1.63]; Female: N events = 31, HR = 1.30, 95% CI = [0.70, 2.41]) or those experiencing a self-harm event during follow-up (Male: N events = 16, HR = 1.05, 95% CI = [0.61, 1.80]; Female: N events = 13, HR = 1.08, 95% CI = [0.55, 2.14]). Higher suicide risk was significantly associated with covariates including higher adulthood deprivation and longer time in the self-harm state. These results extend work on cognitive ability and mental health, demonstrating that these associations can span across the life course and into older age.
Maternal adverse childhood experiences on child growth and development in rural Pakistan: an observational cohort study
Authors: Chung Esther O. , Scherer Elissa , LeMasters Katherine , Bates Lisa , Hagaman Ashley , Staley Brooke S. , Zalla Lauren , Sikander Siham , Maselko Joanna
Published: February 2023

Maternal adverse childhood experiences (ACEs) have been associated with negative impacts on children. However, not all types or levels of adversity are similarly deleterious and research from diverse contexts is needed to better understand why and how intergenerational transmission of adversity occurs. We examined the role of maternal ACEs on child growth and development at 36 months postpartum in rural Pakistan. We used data from 877 mother-child dyads in the Bachpan Cohort, a birth cohort study. Maternal ACEs were captured using an adapted version of the ACE- International Questionnaire. Outcomes included child growth, fine motor and receptive language development, and socioemotional and behavioral development at 36 months of age. To estimate the associations between maternal ACEs and child outcomes, we used multivariable generalized linear models with inverse probability weights to account for sampling and loss to follow-up. Over half of mothers in our sample (58%) experienced at least one ACE. Emotional abuse, physical abuse, and emotional neglect were the most commonly reported. We found null relationships between the number of maternal ACEs and child growth. Maternal ACEs were associated with higher fine motor and receptive language development and worse socioemotional and behavioral outcomes. Maternal ACE domains had similarly varying relationships with child outcomes. Our findings highlight the complexity of intergenerational associations between maternal ACEs and children’s growth and development. Further work is necessary to examine these relationships across cultural contexts and identify moderating factors to mitigate potential negative intergenerational effects.
Public toilets have reduced enteric pathogen hazards in San Francisco
Authors: Barker Troy , Capone Drew , Amato Heather K. , Clark Ryan , Henderson Abigail , Holcomb David A. , Kim Elizabeth , Pape Jillian , Parker Emily , VanderYacht Thomas , Graham Jay , Brown Joe
Published: February 2023

Uncontained fecal wastes in cities may present exposure risks to the public. We collected discarded feces from public spaces in San Francisco for analysis by RT-qPCR for a range of enteric pathogens. Out of 59 samples, we found 12 (20%) were of human origin and 47 (80%) were non-human; 30 of 59 stools were positive for ≥1 of the 35 pathogens assessed, including pathogenicE. coli, Shigella, norovirus,Cryptosporidium, andTrichuris. Using quantitative enteric pathogen estimates and data on observed fecal waste from a public reporting system, we modeled pathogens removed from the environment attributable to a recently implemented program of public toilet construction. We estimated that each new public toilet reduced the annual number of enteric pathogens released into the immediate environment (within 500 m walking distance), including 6.3 × 1012enteropathogenicE. coli(95% CI: 4.0 × 1012– 7.9 × 1012), 3.2 × 1011enteroaggregativeE. coli(95% CI: 1.3 × 1011– 6.3 × 1011), and 3.2 × 108Shigella(6.3 × 107– 2.5 × 109). Improving access to public sanitation can reduce enteric pathogen hazards in cities. Interventions must also consider the hygienic disposal of animal waste to reduce microbial hazards with zoonotic infection potential.

SYNOPSIS

This paper describes enteric pathogen hazards from discarded feces on the streets of San Francisco and estimates their reduction following a public toilet intervention.

TOC/Abstract art

Created with BioRender and a photograph by author Jay Graham
Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
Authors: Bhattarai Kashi Raj , Mobley Robert J. , Barnett Kelly R. , Ferguson Daniel C. , Hansen Baranda S. , Diedrich Jonathan D. , Bergeron Brennan P. , Yang Wenjian , Crews Kristine R. , Manring Christopher S. , Jabbour Elias , Paietta Elisabeth , Litzow Mark R. , Kornblau Steven M. , Stock Wendy , Inaba Hiroto , Jeha Sima , Pui Ching-Hon , Cheng Cheng , Pruett-Miller Shondra M. , Relling Mary V. , Yang Jun J. , Evans William E. , Savic Daniel
Published: February 2023

Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome to ALLcis-regulatory elements and investigated their gene regulatory potential and genomic connectivity using massively parallel reporter assays and promoter capture Hi-C, respectively. We identified 53 variants with reproducible allele-specific effects on transcription and high-confidence gene targets. Subsequent functional interrogation of the top variant (rs1247117) determined that it disrupted a PU.1 consensus motif and PU.1 binding affinity. Importantly, deletion of the genomic interval containing rs1247117 sensitized ALL cells to vincristine. Together, these data demonstrate that noncoding regulatory variation associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to chemotherapeutic agents in ALL.
ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions
Authors: Durand Simon , Tang Yaqi , Pommier Roxane M. , Benboubker Valentin , Grimont Maxime , Boivin Felix , Barbollat-Boutrand Laetitia , Cumunel Eric , Dupeuble Florian , Eberhardt Anaïs , Plaschka Maud , Dalle Stéphane , Caramel Julie
Published: February 2023

Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significancein vivoin both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.

Graphical Abstract
A targetable N-terminal motif orchestrates α-Synuclein oligomer to fibril conversion
Authors: Santos Jaime , Cuellar Jorge , Pallarès Irantzu , Byrd Emily J , Lends Alons , Moro Fernando , Abdul-Shukkoor Muhammed Bilal , Pujols Jordi , Velasco-Carneros Lorea , Sobott Frank , Otzen Daniel E , Calabrese Antonio N , Muga Arturo , Pedersen Jan S , Loquet Antoine , Valpuesta Jose María , Radford Sheena E , Ventura Salvador
Published: February 2023

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson’s disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. PSMα3 is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer to fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the monomeric and oligomeric states. This α-synuclein region plays a pivotal role in oligomer to fibril conversion, as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early-onset Parkinson’s disease, causes a conformational fluctuation in this region, leading to delayed oligomer to fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer to amyloid fibril conversion and reveal a new facet of α-synuclein pathogenic mutations.
Identification of the aldolase responsible for the production of 22-hydroxy-23,24-bisnorchol-4-ene-3-one from natural sterols inMycolicibacterium smegmatis
Authors: Hernández-Fernández Gabriel , Acedos Miguel G. , García José L. , Galán Beatriz
Published: February 2023

Mycobacterial mutants blocked in ring degradation constructed to achieve C19 synthons production, also accumulate by-products such as C22 intermediates throughout an alternative pathway reducing the production yields and complicating the downstream purification processing of final products. In this work, we have identified theMSMEG_6561gene, encoding the only aldolase on the chromosome responsible for the transformation of 22-hydroxy-3-oxo-cholest-4-ene-24-carboxyl-CoA (22-OH-BCN-CoA) into the 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC) precursor (20S)-3-oxopregn-4-ene-20-carboxaldehyde (3-OPA). The deletion of this gene increases the production yield of the C-19 steroidal synthon 4-androstene-3,17-dione (AD) from natural sterols, avoiding the production of 4-HBC as by-product and the drawbacks in the AD purification. The molar yield of AD production using the MS6039-5941-6561 triple mutant strain was checked in flasks and bioreactor improving very significantly compared with the previously described MS6039-5941 strain.