bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of active and environmental tobacco smoke on susceptibility to osteoporosis in women undergoing dual-X-ray absorptiometry
Authors: Vergatti A. , Abate V. , Giaquinto A. , Altavilla N. , D’Elia L. , Evangelista M. , De Filippo G. , Piccinocchi G. , Gennari L. , Merlotti D. , Galletti F. , Strazzullo P. , Rendina D.
Published: October 2023

Purpose

Current smoking is a risk factor for osteoporosis (Op), but few data are available regarding the passive smoke impact on Op susceptibility. This cross-sectional study aimed to evaluate the association between the smoking habits and Op in community-dwelling women undergoing dual-energy X-ray absorptiometry (DXA).

Methods

On 01/06/2018, general practitioners from “COMEGEN” Medical Cooperative, Naples, Italy, selected the medical records from the last 10 years of women who had a measurement of bone mineral density performed and simultaneously completed a questionnaire about their smoking behaviour and their cohabiters’. The binary logistic regression analysis was used to estimate the role of passive smoke on the risk of Op, adjusting for age and body mass index (BMI).

Results

Among 10,616 subjects, 3942 were currently smokers [CS; mean age 69.4 ± 10.4 years; BMI 27.0 ± 4.9 kg/m2], 873 were passive smokers (PS; mean age 67.8 ± 11.6 years; BMI 27.0 ± 4.9 kg/m2) and 5781 were never smokers (NS; mean age 67.8 ± 11.6 years; body mass index (BMI) 27.0 ± 4.9 kg/m2). Of all, 8562 women (mean age 70.3 ± 10.2 yrs; BMI 27.0 ± 4.9 kg/m2) received the Op diagnosis. PS showed an increased Op risk compared to NS [odds ratio (OR) 1.38 (1.14–1.67)] and comparable to CS [OR 1.02 (0.84–1.24)].

Conclusion

The study results demonstrate an association between passive smoke and Op in community-dwelling women already presenting with susceptibility to Op according to Italian essential assistance levels, suggesting that passive and active smoke are equivalent Op risk factors in women.
Chronic spontaneous urticaria—status quo and future
Authors: Melchers Susanne , Nicolay Jan P.
Published: October 2023

Chronic spontaneous urticaria (CsU) is a chronic inflammatory dermatosis whose etiology is not yet fully understood. In affected patients, it is often associated with a high limitation of health-related quality of life, which necessitates effective therapeutic management. Different immune cell populations such as mast cells, eosinophilic and basophilic granulocytes, and T cells are involved in the pathogenesis of CsU, whereby mast cells playing a key role. In addition, type I autoallergic reactions with auto IgE antibodies or type IIb autoimmune reactions with auto IgG antibodies have been identified in a proportion of patients. The current international guideline initially recommends the use of second-generation H1 antihistamines, first in standard, then in off-label quadruple dosing. Subsequently, the anti-IgE antibody omalizumab should be added. However, this therapy algorithm does not lead to freedom from manifestations in all patients. Therefore, various targeted therapies are currently being evaluated for their efficacy in CsU, such as off-label use of the anti-interleukin receptor alpha (IL4Rα) antibody dupilumab, the anti-IL-17A antibody secukinumab, or interleukin‑5 blockade using mepolizumab, reslizumab, or benralizumab. In addition, new promising compounds such as the Bruton tyrosine kinase (BTK) inhibitors remibrutinib and fenebrutinib, the anti-cKIT antibody barzolvolimab, the anti-SIGLEC8 antibody lirentelimab, the anti-TSLP antibody tezepelumab, the anti-C5aR1 antibody advoralimab, or the topical application of Syk kinase inhibitors are being tested, which were developed according to new insights into the pathogenesis of CsU. The BTK inhibitor fenebrutinib is currently not being pursued due to a less favorable side effect profile compared to remibrutinib, as well as the anti-IgE antibody ligelizumab, which was inferior to omalizumab therapy in a phase 3 study. Overall, there is a high need for new therapeutic strategies to better treat CsU both symptomatically and curatively. This requires a more comprehensive understanding of pathogenesis of the disease in order to develop new targeted therapies.
Jejunal perforation and multiple intestinal contusions following blunt abdominal trauma: A case report
Authors: Hammami Mahdi , ben Safta Amine , Samaali Imen , Haddad Salah , Sarhane Iheb , Jerraya Hichem , Bouasker Ibtissem , Nouira Ramzi
Published: October 2023

Abstract

Introduction

and Importance: Trauma, particularly from motor vehicle accidents, causes significant morbidity and mortality worldwide. Isolated jejunal perforation resulting from blunt abdominal trauma is rare but challenging to diagnose. This article sheds light on this infrequent condition, emphasizing the need for early recognition for optimal outcomes.

Case presentation

A 30-year-old male presented with abdominal pain after a motor vehicle accident. Examination and tests showed signs of jejunal perforation. Urgent surgery revealed a 2 cm perforation, contusions, and deserosalizations. The perforation was repaired, and the patient recovered well postoperatively.

Clinical discussion

Blunt abdominal trauma is a major cause of injury, with motor vehicle accidents being prominent. Hollow visceral injuries, though rare, pose diagnostic and management challenges. In this context, recognizing the indications for surgical intervention is complex. Imaging, especially CT scans, plays a critical role in diagnosis. This case underscores the importance of CT findings in diagnosing and deciding the need for surgical exploration.

Conclusion

Isolated jejunal perforation from blunt abdominal trauma is rare but demands clinical attention. Timely diagnosis through CT scans and immediate surgical intervention are crucial for successful outcomes. Surgery involves careful exploration, repairing the perforation and associated injuries, and meticulous postoperative care. Research and knowledge sharing are vital for improving approaches and reducing complications and mortality in these cases.

Highlights
COVID-19 Vaccine Acceptance Among Pregnant, Lactating, and Nonpregnant Women of Reproductive Age in Turkey: A Cross-Sectional Analytical Study
Authors: Daşıkan Zeynep , Ekrem Ebru Cirban , Kıratlı Didem
Published: October 2023

Objective:

This study aims to identify the rates of coronavirus disease 2019 (COVID-19) vaccine acceptance, the reasons for receiving and not receiving the vaccine, and the associated factors among pregnant, lactating, and nonpregnant women of reproductive age.

Methods:

This cross-sectional and analytical study was conducted online in Turkey, at the end of the fourth wave of the COVID-19 pandemic, between February and May 2022. A total of 658 women (230; 35% pregnant) (187; 28.4% lactating) (241; 36.6% nonpregnant) women of reproductive age participated in the study.

Results:

Vaccine acceptance rates were found to be 91.7% in nonpregnant women of reproductive age, 77% in lactating women, and 59% in pregnant women (P < 0.05). The highest rate of vaccine hesitancy was observed in pregnant women (31.3%), and vaccine rejection rate was the highest in lactating women (10.2%). Pregnancy (odds ratio [OR] = 3.98; confidence interval [CI] = 1.13-14.10), and the breastfeeding period (OR = 3.84; CI = 1.15-12.78), increased vaccine hesitancy approximately four times.

Conclusions:

Lack of knowledge about and confidence in the COVID-19 vaccine is still one of the barriers to vaccine acceptance today. Health-care providers (HCPs) should provide effective counseling to pregnant, lactating, and nonpregnant reproductive-aged women based on current information and guidelines.
Less is More: Improving by Removing
Authors: Foster Colin
Published: October 2023

The pressures currently on teachers of mathematics at every level seem greater than ever, whether that is university mathematics lecturers, school teachers or those who work with very young learners. So, I began my Presidential Address with the hope that no one would leave the Joint Conference of Mathematics Subject Associations 2023 feeling as though they were not good enough and must do more. I did not want anyone to go home with a lengthy to-do guilt list of additional things they must try to incorporate into their practice. Instead, I advocated giving attention to the ancient proverb “less is more”, versions of which are found within many cultures; e.g., “brevity is the soul of wit” (Hamlet), “Sometimes diminishing a thing adds to it; Sometimes adding to a thing diminishes it” (Tao Te Ching). I offered five aspects of mathematics teaching and learning that might benefit from ‘less of’ something, in each case trying to see how this might create space for more of something else. In this article, I present these five suggestions for improving by removing.
Some generalisations of Weitzenböck’s inequality
Authors: Tran Quang Hung
Published: October 2023

Throughout this Article, we use the following notations for the triangle ABC

a, b and c are the lengths of the sides BC, CA and AB, respectively,

Δ denotes the area of triangle ABC,

ha, hb and hc are the lengths of the altitudes through the vertices A, B and C, respectively,

ma, mb and mc are the lengths of the medians through the vertices A, B and C, respectively.
Researching post-independence Africa in regional archives: possibilities and limits in Benin, Cabo Verde, Ghana and Congo-Brazzaville
Authors: Keese Alexander , Urbano Annalisa
Published: October 2023

Africa’s regional archives offer crucial records to explore the continent’s postcolonial past. Although these archives are often difficult to locate and access and are exposed to several challenges that might even threaten their existence, this article presents a solid case for reconsidering their importance. Recent trends, aptly labelled ‘postcolonial African archival pessimism’, have mainly pointed to problems and often to the limited accessibility of state archives in some regional and local contexts. This article instead engages with their potential, discussing four case studies in Benin, Cabo Verde, Ghana and Congo-Brazzaville. Results stemming from these case studies are brought into contact with wider debates on custodial cultures and the regional archives’ role in contemporary sub-Saharan Africa. The intention is to provide a more positive and empirically based overview of research possibilities at regional archives and ultimately to change the nature of our approach to these resources.
The Old Conflict in the New Economy? Courier Resistance on Outsourcing Platforms in China
Authors: Zhao Bo , Luo Siqi
Published: October 2023

In contrast to Western platforms, which are dominated by crowdsourced labour, China's food-delivery platforms rely heavily on outsourced couriers to provide high-quality services. The conflicts emerging from outsourced labour relations have been inadequately examined. Based on extensive fieldwork in south China, this study reveals an intriguing fact: the outsourcing model frequently triggers yet largely conceals couriers’ strikes. This study uses the work regime approach and labour bargaining power theory to analyse the complex dynamics created by the platforms. By scrutinizing state institutions, relationships among various organizations and workplace interactions, this study finds that the platform firms have dominant power but that inherent tensions exist between outsourcing platform firms, outsourced agencies, human supervisors and workers, forming a regime that this study calls “contentious despotism.” Importantly, labour conflict is alive and potentially enduring in China's gigantic platform economy.
Structuring Spectra in Electroacoustic Music
Authors: Howe Hubert
Published: October 2023

This article describes the ways in which the spectra of electroacoustic music compositions can be structured coherently. It begins by describing the straightjacket that composers and listeners are constrained by when using the concept of ‘source bonding’ and how this needs to be discarded for effective listening. It then describes the concept of spectral merging and how ideas of musical timbre are formed, and finally discusses the many ways that spectra can be structured with both harmonic and inharmonic components. Examples are given from the author’s own music and other well-known works in the literature of electroacoustic music.
Comparing Legal Disciplines as an Approach to Understanding the Role of Law in Decarbonizing Societies
Authors: Huhta Kaisa , Romppanen Seita
Published: October 2023

Law plays an important role in reshaping and enforcing governance efforts in radical shifts and can function as a catalyst for transitioning governance towards sustainability. This article assesses the capacity of law to facilitate decarbonization as a radical societal shift. It argues that decarbonization demands fundamental and systemic restructuring in law and legal thinking. This should also be reflected in legal scholarship and, most importantly from the point of view of this article, in the methodological choices and approaches that legal scholarship relies on to study societal challenges. To that end, the article develops a new methodological approach (disciplinary comparison) through which to study law's capacities in respect of decarbonization as a radical societal shift. Disciplinary comparison can be used to gain information on both the friction and the synergies between legal disciplines. This new methodological approach will contribute to increasing insight into law's capacities for the radical, cross-sectoral change necessitated by the need to decarbonize societies.
Standardized State Assessment
Authors: Freudenstein Jan-Philipp , Schulze Julian , Schäpers Philipp , Mussel Patrick , Krumm Stefan
Published: October 2023

Abstract: Contemporary theories of personality require psychological assessments that take person-situation processes into account. This is most commonly achieved via ambulatory assessments that sample individuals within their real-life environments. An alternative approach aims at measuring person-situation processes by incorporating hypothetical situation descriptions. However, thus far, no detailed guidelines exist on how to develop such measures so that they validly assess person-situation processes. In this article, we propose Standardized State Assessment as a methodological framework for the assessment of situation-specific states in hypothetical situations. We build on theoretical advances in personality research and previous assessment approaches to derive guidelines for a theory-driven development of hypothetical situation descriptions. We further describe how states should be measured in these situations. Finally, we propose that appropriate latent measurement models and validation strategies may help to develop assessments that are similar to real-life person-situation processes. In the first empirical example ( N = 238), we demonstrate the suitability of the framework. Standardized State Assessment may offer economically advantageous alternatives for research or applied settings in which ambulatory assessments are unfeasible. Moreover, we discuss how this framework may help to answer theoretical questions on person-situation processes.
Langmuir and Upper Hybrid Waves in Earth's Magnetotail
Authors: Graham D. B. , Khotyaintsev Y. V. , André M.
Published: October 2023

Waves at the electron plasma frequency are found throughout the heliosphere. They provide indicators of unstable electron distributions, are routinely used to estimate the local electron number density, and can lead to radio wave emission at the plasma frequency and its harmonics. Although they have been studied extensively in various solar and heliospheric plasma regions, there is a lack of statistical studies of plasma frequency waves in Earth's magnetotail. Here, the occurrence and properties of plasma frequency waves, namely Langmuir and upper hybrid (UH) waves, are investigated in Earth's magnetotail using the four Magnetospheric Multiscale spacecraft. In Earth's magnetotail plasma frequency waves are observed about 1% of the time. About 80% of the waves are identified as Langmuir waves, while about 20% are identified as UH waves. The waves are primarily found in the plasma sheet boundary layer. By comparing with the local electron distributions it is shown that the Langmuir waves are generated by the bump‐on‐tail instability, while UH waves are typically associated with broad electron beams or loss‐cone‐like distributions. The majority of the waves are found in close proximity to ion outflow regions associated with magnetic reconnection in the magnetotail. The waves are likely generated by plasma sheet electrons escaping along newly reconnected magnetic field lines or electron beams propagating toward the distant magnetotail.
Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis
Authors: Wu Qiong , Liang Zongwen , Jiang Jing , Feng Xiaoming , Liu Jinming , Zhang Zongfeng , Wang Honglin , Wang Ning , Gou Yanling , Li Zhi , Cao Yingying
Published: October 2023

Endometriosis is a gynecological inflammatory disease that is linked with immune cells, specifically macrophages. IL-33 secreted from macrophages is known to accelerate the progression of endometriosis. The periodic and repeated bleeding that occurs in women with endometriosis leads to excess iron in the microenvironment that is conducive to ferroptosis, a process related to intracellular ROS production, lipid peroxidation and mitochondrial damage. It is suggested that eESCs may specifically be able to inhibit ferroptosis. However, it is currently unclear whether IL-33 directly regulates ferroptosis to influence the disease course in endometriosis. In this study, eESCs co-cultured with macrophages or stimulated with IL-33/ST2 were observed to have increased cell viability and migration. Additionally, IL-33/ST2 decreased intracellular iron levels and lipid peroxidation in eESCs exposed to erastin treatment. Furthermore, IL-33/ST2 treatment resulted in a notable upregulation in SLC7A11 expression in eESCs due to the downregulation of negative transcription factor ATF3, thereby suppressing ferroptosis. The P38/JNK pathway activated by IL-33/ST2 was also found to inhibit the transcription factor ATF3. Therefore, we concluded that IL-33/ST2 inhibits the ATF3-mediated reduction in SLC7A11 transcript levels via the P38/JNK pathway. The findings reveal that macrophage-derived IL-33 upregulates SLC7A11 in eESCs through the p38/JNK/ATF3 pathway, ultimately resulting in protection against ferroptosis in eESCs. Moreover, we conducted an experiment using endometriosis model mice that showed that a combination of IL-33-Ab and erastin treatment alleviated the disease, showing the promise of combining immunotherapy and ferroptosis therapy.
USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC
Authors: Zheng Jingyi , Wu Shasha , Tang Mao , Xi Shaoyan , Wang Yanchen , Ren Jun , Luo Hao , Hu Pengchao , Sun Liangzhan , Du Yuyang , Yang Hui , Wang Fenfen , Gao Han , Dai Ziwei , Ou Xijun , Li Yan
Published: October 2023

Abnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1 and U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remains largely elusive. We observed that hepatocyte-specific overexpression of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection in transgenic mice. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represented a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy.
The immune response to SARS-CoV-2 in people with HIV
Authors: Höft Maxine A. , Burgers Wendy A. , Riou Catherine
Published: October 2023

This review examines the intersection of the HIV and SARS-CoV-2 pandemics. People with HIV (PWH) are a heterogeneous group that differ in their degree of immune suppression, immune reconstitution, and viral control. While COVID-19 in those with well-controlled HIV infection poses no greater risk than that for HIV-uninfected individuals, people with advanced HIV disease are more vulnerable to poor COVID-19 outcomes. COVID-19 vaccines are effective and well tolerated in the majority of PWH, though reduced vaccine efficacy, breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in PWH. This is likely a result of suboptimal humoral and cellular immune responses after vaccination. People with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants, but initiation or resumption of antiretroviral therapy (ART) can effectively clear persistent infection. COVID-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely immunocompromised. We recommend continued research and monitoring of PWH with SARS-CoV-2 infection, especially in areas with a high HIV burden.
Neuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images
Authors: Wang Weiwei , Zhao Yuanshen , Teng Lianghong , Yan Jing , Guo Yang , Qiu Yuning , Ji Yuchen , Yu Bin , Pei Dongling , Duan Wenchao , Wang Minkai , Wang Li , Duan Jingxian , Sun Qiuchang , Wang Shengnan , Duan Huanli , Sun Chen , Guo Yu , Luo Lin , Guo Zhixuan , Guan Fangzhan , Wang Zilong , Xing Aoqi , Liu Zhongyi , Zhang Hongyan , Cui Li , Zhang Lan , Jiang Guozhong , Yan Dongming , Liu Xianzhi , Zheng Hairong , Liang Dong , Li Wencai , Li Zhi-Cheng , Zhang Zhenyu
Published: October 2023

Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort (n = 1362) and a validation cohort (n = 340), and tested on an internal testing cohort (n = 289) and two external cohorts (n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.
Single-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis
Authors: Nishide Masayuki , Nishimura Kei , Matsushita Hiroaki , Edahiro Ryuya , Inukai Sachi , Shimagami Hiroshi , Kawada Shoji , Kato Yasuhiro , Kawasaki Takahiro , Tsujimoto Kohei , Kamon Hokuto , Omiya Ryusuke , Okada Yukinori , Hattori Kunihiro , Narazaki Masashi , Kumanogoh Atsushi
Published: October 2023

The immunological basis of the clinical heterogeneity in autoimmune vasculitis remains poorly understood. In this study, we conduct single-cell transcriptome analyses on peripheral blood mononuclear cells (PBMCs) from newly-onset patients with microscopic polyangiitis (MPA). Increased proportions of activated CD14+ monocytes and CD14+ monocytes expressing interferon signature genes (ISGs) are distinctive features of MPA. Patient-specific analysis further classifies MPA into two groups. The MPA-MONO group is characterized by a high proportion of activated CD14+ monocytes, which persist before and after immunosuppressive therapy. These patients are clinically defined by increased monocyte ratio in the total PBMC count and have a high relapse rate. The MPA-IFN group is characterized by a high proportion of ISG+ CD14+ monocytes. These patients are clinically defined by high serum interferon-alpha concentrations and show good response to immunosuppressive therapy. Our findings identify the immunological phenotypes of MPA and provide clinical insights for personalized treatment and accurate prognostic prediction.
Electrically programmable magnetic coupling in an Ising network exploiting solid-state ionic gating
Authors: Yun Chao , Liang Zhongyu , Hrabec Aleš , Liu Zhentao , Huang Mantao , Wang Leran , Xiao Yifei , Fang Yikun , Li Wei , Yang Wenyun , Hou Yanglong , Yang Jinbo , Heyderman Laura J. , Gambardella Pietro , Luo Zhaochu
Published: October 2023

Two-dimensional arrays of magnetically coupled nanomagnets provide a mesoscopic platform for exploring collective phenomena as well as realizing a broad range of spintronic devices. In particular, the magnetic coupling plays a critical role in determining the nature of the cooperative behavior and providing new functionalities in nanomagnet-based devices. Here, we create coupled Ising-like nanomagnets in which the coupling between adjacent nanomagnetic regions can be reversibly converted between parallel and antiparallel through solid-state ionic gating. This is achieved with the voltage-control of the magnetic anisotropy in a nanosized region where the symmetric exchange interaction favors parallel alignment and the antisymmetric exchange interaction, namely the Dzyaloshinskii-Moriya interaction, favors antiparallel alignment of the nanomagnet magnetizations. Applying this concept to a two-dimensional lattice, we demonstrate a voltage-controlled phase transition in artificial spin ices. Furthermore, we achieve an addressable control of the individual couplings and realize an electrically programmable Ising network, which opens up new avenues to design nanomagnet-based logic devices and neuromorphic computers.
A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus
Authors: Liu Qiang , Bell Benjamin J. , Kim Dong Won , Lee Sang Soo , Keles Mehmet F. , Liu Qili , Blum Ian D. , Wang Annette A. , Blank Elijah J. , Xiong Jiali , Bedont Joseph L. , Chang Anna J. , Issa Habon , Cohen Jeremiah Y. , Blackshaw Seth , Wu Mark N.
Published: October 2023

Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal’s active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.
C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy
Authors: Zhang Shen , Tong Mindan , Zheng Denghao , Huang Huiying , Li Linsen , Ungermann Christian , Pan Yi , Luo Hanyan , Lei Ming , Tang Zaiming , Fu Wan , Chen She , Liu Xiaoxia , Zhong Qing
Published: October 2023

The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a “hook-up” model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.
Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications
Authors: Hong Kemiao , Zhou Yi , Yuan Haoxuan , Zhang Zhijing , Huang Jingjing , Dong Shanliang , Hu Wenhao , Yu Zhi-Xiang , Xu Xinfang
Published: October 2023

Cyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5-endo-dig process, 4-exo-dig carbocyclization is mainly due to lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step. Using less reactive catalysts Rh2(carboxylate)4 is critical for high selectivity, which is explained as catalyst-substrate hydrogen bonding interaction. This method is proved successful to direct access previously inaccessible and unknown furan-fused cyclobutanone scaffolds, which can participate in a variety of post-functionalization reactions as versatile synthetic blocks. In addition, preliminary antitumor activity study of these products indicates that some molecules exhibite significant anticancer potency against different human cancer cell lines.
Structure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo
Authors: Mendoza Johnny , Purchal Meredith , Yamada Kazuhiro , Koutmos Markos
Published: October 2023

Cobalamin-dependent methionine synthase (MS) is a key enzyme in methionine and folate one-carbon metabolism. MS is a large multi-domain protein capable of binding and activating three substrates: homocysteine, folate, and S-adenosylmethionine for methylation. Achieving three chemically distinct methylations necessitates significant domain rearrangements to facilitate substrate access to the cobalamin cofactor at the right time. The distinct conformations required for each reaction have eluded structural characterization as its inherently dynamic nature renders structural studies difficult. Here, we use a thermophilic MS homolog (tMS) as a functional MS model. Its exceptional stability enabled characterization of MS in the absence of cobalamin, marking the only studies of a cobalamin-binding protein in its apoenzyme state. More importantly, we report the high-resolution full-length MS structure, ending a multi-decade quest. We also capture cobalamin loading in crystallo, providing structural insights into holoenzyme formation. Our work paves the way for unraveling how MS orchestrates large-scale domain rearrangements crucial for achieving challenging chemistries.
Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation
Authors: Xu Minxuan , Tan Jun , Liu Xin , Han Li , Ge Chenxu , Zhang Yujie , Luo Fufang , Wang Zhongqin , Xue Xiaoqin , Xiong Liangyin , Wang Xin , Zhang Qinqin , Wang Xiaoxin , Tian Qin , Zhang Shuguang , Meng Qingkun , Dai Xianling , Kuang Qin , Li Qiang , Lou Deshuai , Hu Linfeng , Liu Xi , Kuang Gang , Luo Jing , Chang Chunxiao , Wang Bochu , Chai Jie , Shi Shengbin , Han Lianyi
Published: October 2023

Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression. Inversely, transgenic Trim26 overexpression attenuates the NASH-associated phenotype in a rodent or rabbit model. We provide mechanistic evidence that, in response to metabolic insults, TRIM26 directly interacts with C/EBPδ and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.
Multiple reaction pathway on alkaline earth imide supported catalysts for efficient ammonia synthesis
Authors: Li Zichuang , Lu Yangfan , Li Jiang , Xu Miao , Qi Yanpeng , Park Sang-Won , Kitano Masaaki , Hosono Hideo , Chen Jie-Sheng , Ye Tian-Nan
Published: October 2023

The tunability of reaction pathways is required for exploring efficient and low cost catalysts for ammonia synthesis. There is an obstacle by the limitations arising from scaling relation for this purpose. Here, we demonstrate that the alkali earth imides (AeNH) combined with transition metal (TM = Fe, Co and Ni) catalysts can overcome this difficulty by utilizing functionalities arising from concerted role of active defects on the support surface and loaded transition metals. These catalysts enable ammonia production through multiple reaction pathways. The reaction rate of Co/SrNH is as high as 1686.7 mmol·gCo−1·h−1 and the TOFs reaches above 500 h−1 at 400 °C and 0.9 MPa, outperforming other reported Co-based catalysts as well as the benchmark Cs-Ru/MgO catalyst and industrial wüstite-based Fe catalyst under the same reaction conditions. Experimental and theoretical results show that the synergistic effect of nitrogen affinity of 3d TMs and in-situ formed NH2− vacancy of alkali earth imides regulate the reaction pathways of the ammonia production, resulting in distinct catalytic performance different from 3d TMs. It was thus demonstrated that the appropriate combination of metal and support is essential for controlling the reaction pathway and realizing highly active and low cost catalysts for ammonia synthesis.
Asymmetric gating of a human hetero-pentameric glycine receptor
Authors: Liu Xiaofen , Wang Weiwei
Published: October 2023

Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments.
Enhanced multi-year predictability after El Niño and La Niña events
Authors: Liu Yiling , Donat Markus. G. , England Matthew. H. , Alexander Lisa. V. , Hirsch Annette L. , Delgado-Torres Carlos
Published: October 2023

Several aspects of regional climate including near-surface temperature and precipitation are predictable on interannual to decadal time scales. Despite indications that some climate states may provide higher predictability than others, previous studies analysing decadal predictions typically sample a variety of initial conditions. Here we assess multi-year predictability conditional on the phase of the El Niño–Southern Oscillation (ENSO) at the time of prediction initialisation. We find that predictions starting with El Niño or La Niña conditions exhibit higher skill in predicting near-surface air temperature and precipitation multiple years in advance, compared to predictions initialised from neutral ENSO conditions. This holds true in idealised prediction experiments with the Community Climate System Model Version 4 and to a lesser extent also real-world predictions using the Community Earth System Model and a multi-model ensemble of hindcasts contributed to the Coupled Model Intercomparison Project Phase 6 Decadal Climate Prediction Project. This enhanced predictability following ENSO events is related to phase transitions as part of the ENSO cycle, and related global teleconnections. Our results indicate that certain initial states provide increased predictability, revealing windows of opportunity for more skillful multi-year predictions.
Revealing invisible cell phenotypes with conditional generative modeling
Authors: Lamiable Alexis , Champetier Tiphaine , Leonardi Francesco , Cohen Ethan , Sommer Peter , Hardy David , Argy Nicolas , Massougbodji Achille , Del Nery Elaine , Cottrell Gilles , Kwon Yong-Jun , Genovesio Auguste
Published: October 2023

Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and microscope observation. However, most cellular phenotypic changes are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. In this study, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, or by the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs, or by low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to more accessible discovery of biological and disease biomarkers.
SARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition
Authors: Erickson Rachel , Huang Chang , Allen Cameron , Ireland Joanna , Roth Gwynne , Zou Zhongcheng , Lu Jinghua , Lafont Bernard A. P. , Garza Nicole L. , Brumbaugh Beniah , Zhao Ming , Suzuki Motoshi , Olano Lisa , Brzostowski Joseph , Fischer Elizabeth R. , Twigg Homer L. , Johnson Reed F. , Sun Peter D.
Published: October 2023

Severe COVID-associated lung injury is a major confounding factor of hospitalizations and death with no effective treatments. Here, we describe a non-classical fibrin clotting mechanism mediated by SARS-CoV-2 infected primary lung but not other susceptible epithelial cells. This infection-induced fibrin formation is observed in all variants of SARS-CoV-2 infections, and requires thrombin but is independent of tissue factor and other classical plasma coagulation factors. While prothrombin and fibrinogen levels are elevated in acute COVID BALF samples, fibrin clotting occurs only with the presence of viral infected but not uninfected lung epithelial cells. We suggest a viral-induced coagulation mechanism, in which prothrombin is activated by infection-induced transmembrane serine proteases, such as ST14 and TMPRSS11D, on NHBE cells. Our finding reveals the inefficiency of current plasma targeted anticoagulation therapy and suggests the need to develop a viral-induced ARDS animal model for treating respiratory airways with thrombin inhibitors.
Integrated reconstructive spectrometer with programmable photonic circuits
Authors: Yao Chunhui , Xu Kangning , Zhang Wanlu , Chen Minjia , Cheng Qixiang , Penty Richard
Published: October 2023

Optical spectroscopic sensors are a powerful tool to reveal light-matter interactions in many fields. Miniaturizing the currently bulky spectrometers has become imperative for the wide range of applications that demand in situ or even in vitro characterization systems, a field that is growing rapidly. In this paper, we propose a novel integrated reconstructive spectrometer with programmable photonic circuits by simply using a few engineered MZI elements. This design effectively creates an exponentially scalable number of uncorrelated sampling channels over an ultra-broad bandwidth without incurring additional hardware costs, enabling ultra-high resolution down to single-digit picometers. Experimentally, we implement an on-chip spectrometer with a 6-stage cascaded MZI structure and demonstrate <10 pm resolution with >200 nm bandwidth using only 729 sampling channels. This achieves a bandwidth-to-resolution ratio of over 20,000, which is, to our best knowledge, about one order of magnitude greater than any reported miniaturized spectrometers to date.
Dietary D-xylose promotes intestinal health by inducing phage production in Escherichia coli
Authors: Hu Jie , Wu Yifan , Kang Luyuan , Liu Yisi , Ye Hao , Wang Ran , Zhao Jinbiao , Zhang Guolong , Li Xilong , Wang Junjun , Han Dandan
Published: October 2023

Elimination of specific enteropathogenic microorganisms is critical to gut health. However, the complexity of the gut community makes it challenging to target specific bacterial organisms. Accumulating evidence suggests that various foods can change the abundance of intestinal bacteria by modulating prophage induction. By using pathogenic Escherichia coli (E. coli) ATCC 25922 as a model in this research, we explored the potential of dietary modulation of prophage induction and subsequent bacterial survival. Among a panel of sugars tested in vitro, D-xylose was shown to efficiently induce prophages in E. coli ATCC 25922, which depends, in part, upon the production of D-lactic acid. In an enteric mouse model, prophage induction was found to be further enhanced in response to propionic acid. Dietary D-xylose increased the proportion of Clostridia which converted D-lactic acid to propionic acid. Intestinal propionic acid levels were diminished, following either oral gavage with the dehydrogenase gene (ldhA)-deficient E. coli ATCC 25922 or depletion of intestinal Clostridia by administration of streptomycin. D-Xylose metabolism and exposure to propionic acid triggered E. coli ATCC 25922 SOS response that promoted prophage induction. E. coli ATCC 25922 mutant of RecA, a key component of SOS system, exhibited decreased phage production. These findings suggest the potential of using dietary components that can induce prophages as antimicrobial alternatives for disease control and prevention by targeted elimination of harmful gut bacteria.
Effect of mRNA-LNP components of two globally-marketed COVID-19 vaccines on efficacy and stability
Authors: Zhang Lizhou , More Kunal R. , Ojha Amrita , Jackson Cody B. , Quinlan Brian D. , Li Hao , He Wenhui , Farzan Michael , Pardi Norbert , Choe Hyeryun
Published: October 2023

During the COVID-19 pandemic, Pfizer-BioNTech and Moderna successfully developed nucleoside-modified mRNA lipid nanoparticle (LNP) vaccines. SARS-CoV-2 spike protein expressed by those vaccines are identical in amino acid sequence, but several key components are distinct. Here, we compared the effect of ionizable lipids, untranslated regions (UTRs), and nucleotide composition of the two vaccines, focusing on mRNA delivery, antibody generation, and long-term stability. We found that the ionizable lipid, SM-102, in Moderna’s vaccine performs better than ALC-0315 in Pfizer-BioNTech’s vaccine for intramuscular delivery of mRNA and antibody production in mice and long-term stability at 4 °C. Moreover, Pfizer-BioNTech’s 5′ UTR and Moderna’s 3′ UTR outperform their counterparts in their contribution to transgene expression in mice. We further found that varying N1-methylpseudouridine content at the wobble position of mRNA has little effect on vaccine efficacy. These findings may contribute to the further improvement of nucleoside-modified mRNA-LNP vaccines and therapeutics.
The superior healing capacity of MRL tendons is minimally influenced by the systemic environment of the MRL mouse
Authors: Frankewycz Borys , Bell Rebecca , Chatterjee Monideepa , Andarawis-Puri Nelly
Published: October 2023

Murphy Roths Large mice (MRL) exhibit improved tendon healing and are often described as a “super-healer” strain. The underlying mechanisms that drive the superior healing response of MRL remain a controversial subject. We utilized a tendon transplantation model between MRL and “normal-healer” B6-mice to differentiate between the contribution of MRL’s innate tendon and systemic environment to its improved healing capacity. Patellar tendons with a midsubstance punch injury were transplanted back into the same animal (autograft) or into an animal of the other strain (allograft). Findings at 4 weeks showed that the innate MRL tendon environment drives its improved healing capacity as demonstrated by improved stiffness and maximum load in MRL-grafts-in-B6-host-allografts compared to B6-autografts, and higher modulus in MRL-autografts compared to B6-graft-in-MRL-host-allografts. Groups with an MRL component showed an increase in pro-inflammatory cytokines in the 3 days after injury, suggesting an early enhanced inflammatory profile in MRL that ultimately resolves. A preserved range of motion of the knee joint in all MRL animals suggests a systemic “shielding effect” of MRL in regard to joint adhesiveness. Our findings 4-weeks post injury are consistent with previous studies showing tissue-driven improved healing and suggest that the systemic environment contributes to the overall healing process.
Evaluation of and implications for a novel hepatitis C e-consult direct-to-treatment pilot program
Authors: Mohtashemi Neaka Z. , Teng Crystal Y. , Benhammou Jihane , Dong Tien , Goetz Matthew Bidwell , Patel Arpan , Kawamoto Jenna , Bhattacharya Debika
Published: October 2023

A Hepatitis C (HCV) e-Consult Direct-To-Treatment (DTT) program managed by midlevel providers was developed at the Veteran Affairs Greater Los Angeles Healthcare System (VAGLAHS) which provided remote referral and, in some, remote management of HCV. DTT patients were more likely to be initiated on HCV treatment compared to standard of care (SOC), lending support for similar programs of remote engagement in HCV care.