bluuebunny/crossref_metadata_2025 huggingface dataset:
Ccdc38is required for sperm flagellum biogenesis and male fertility in mouse
Authors: Zhang Ruidan , Wu Bingbing , Liu Chao , Wang Xiuge , Wang Liying , Xiao Sai , Chen Yinghong , Wei Huafang , Gao Fei , Yuan Li , Li Wei
Published: January 2022

Sperm flagellum is essential for male fertility, defects in flagellum biogenesis are associated with male infertility. Deficiency of CCDC42 is associated with malformation of the mouse sperm flagella. Here, we find that the testis-specific expressed protein CCDC38 (coiled-coil domain containing 38) interacts with CCDC42 and localizes on manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in distorted manchette, multiple morphological abnormalities of the flagella (MMAF) of spermatozoa, and eventually male sterility. Furthermore, we find that CCDC38 interacts with intra-flagellar transport protein 88 (IFT88) as well as the outer dense fibrous 2 (ODF2), and its depletion reduces the transportation of ODF2 to flagellum. Altogether, our results uncover the essential role of CCDC38 during sperm flagellum biogenesis, and suggesting the defects of these genes might be associated with male infertility in human being.

Summary statement

We demonstrated that CCDC38, localizes on manchette and sperm tail, is crucial for male fertility.
Clustering-based COPD Subtypes Have Distinct Longitudinal Outcomes and Multi-omics Biomarkers
Authors: Gregory Andrew , Xu Zhonghui , Pratte Katherine , Lee Sool , Liu Congjian , Chase Robert , Yun Jeong H. , Saferali Aabida , Hersh Craig P. , Bowler Russell P. , Silverman Edwin K. , Castaldi Peter J. , Boueiz Adel
Published: January 2022

Introduction

Chronic obstructive pulmonary disease (COPD) can progress across several domains, complicating the identification of the determinants of disease progression. In our previous work, we applied k-means clustering to spirometric and chest radiologic measures to identify four COPD-related subtypes: “Relatively resistant smokers (RRS)”, “mild upper lobe predominant emphysema (ULE)”, “airway-predominant disease (AD)”, and “severe emphysema (SE)”. In the current study, we examined longitudinal spirometric and radiologic emphysema changes and prospective risks of COPD exacerbations, incident comorbidities, and mortality of these clusters. We also compared their associations to protein and transcriptomic biomarkers.

Methods

We included 8,266 non-Hispanic white and African-American smokers from the COPDGene study. We used linear regression to investigate associations to five-year prospective changes in spirometric and radiologic measures and to plasma protein and blood gene expression levels. We used Cox-proportional hazard modeling to test for associations to prospective exacerbations, comorbidities, and mortality.

Results

The RRS, ULE, AD, and SE clusters represented 39%, 15%, 26%, and 20% of the studied cohort at baseline, respectively. The SE cluster had the greatest 5-year FEV1and emphysema progression, and the highest risks of exacerbations, cardiovascular disease (CVD), and mortality. The AD cluster had the highest diabetes risk. After adjustments, only the ULE and AD clusters had elevated CVD mortality risks, while only the ULE cluster had the highest cancer-related mortality risk. These clusters also demonstrated differential protein and gene expression biomarker associations.

Conclusion

COPD k-means subtypes demonstrate varying rates of disease progression, prospective comorbidities, mortality, and associations to proteomic and transcriptomic biomarkers.

Funding Sources

This work was supported by NHLBI K08 HL141601, K08 HL146972, R01 HL116931, R01 HL124233, R01 HL126596, R01 HL116473, U01 HL089897, R01 HL147326, R01 HL130512, and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Bayer, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
Hypoxia Dynamically Regulates DBC1 Ubiquitination and Stability by SIAH2 and OTUD5 in Breast Cancer Progression
Authors: Liu Qiangqiang , Luo Qian , Feng Jianyu , Zhao Yanping , Liu Linlin , Ma Biao , Cheng Hongcheng , Zhao Tian , Zhang Jiaojiao , Mu Chenglong , Chen Linbo , Lei Hong , Long Yijia , Su Jingyi , Chen Guo , Li Yanjun , Chen Quan , Zhu Yushan
Published: January 2022

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is dynamically regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted the competitive binding of SIAH2 with OTUD5 to DBC1, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway.Siah2knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout ofSiah2/DBC1. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.
HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks
Authors: Charaka Vijaya , Chakraborty Sharmista , Tsai Chi-Lin , Wang Xiaoyan , Pandita Raj K , Tainer John A. , Hunt Clayton R , Pandita Tej K.
Published: January 2022

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1 β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1 β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.
Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody
Authors: Baidya Mithu , Chaturvedi Madhu , Dwivedi-Agnihotri Hemlata , Ranjan Ashutosh , Devost Dominic , Namkung Yoon , Stepniewski Tomasz Maciej , Pandey Shubhi , Baruah Minakshi , Panigrahi Bhanupriya , Maharana Jagannath , Banerjee Ramanuj , Selent Jana , Laporte Stephane , Hebert Terence E. , Shukla Arun K.
Published: January 2022

Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs, such as the vasopressin type II receptor (V2R), which exhibit high affinity for βarrs, agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking. We previously found that mutation of a single phosphorylation site in V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes although βarrs are robustly recruited to the plasma membrane. Here, we show that a synthetic intrabody referred to as intrabody30 (Ib30), which selectively recognizes an active-like βarr1 conformation, rescues endosomal translocation of βarr1 for V2RT360A. In addition, Ib30 also rescues agonist-induced ERK1/2 MAP kinase activation for V2RT360A to levels similar to that of the wild-type V2R. Molecular dynamics simulations reveal that Ib30 binding promotes active-like conformation in βarr1 with respect to the inter-domain rotation. Interestingly, we also observe that Ib30 enhances the interaction of βarr1 with β2-adaptin, which provides a mechanistic basis for the ability of Ib30 to promote endosomal trafficking of βarr1. Taken together, our data provide a novel mechanism to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can potentially be integrated in the current paradigm of GPCR-targeted drug discovery.

Significance

The interaction of G protein-coupled receptors (GPCRs) with β-arrestins (βarrs) is a critical step in their regulatory and signaling paradigms. While intrabodies that bind to GPCRs, G proteins and βarrs have been utilized as biosensors and regulators of functional outcomes, allosteric targeting of receptor-transducer complexes to encode gain of function has not been documented so far. Here, we discover that a conformation-specific synthetic intrabody recognizing GPCR-bound βarr1 can allosterically enhance endosomal trafficking of βarr1 and agonist-induced ERK1/2 MAP kinase activation. This intrabody promotes an active-like βarr1 conformation and enhances the interaction of β2-adaptin with βarr1. Our findings establish a conceptual framework to allosterically modulate protein-protein interactions in GPCR signaling cascade to modulate their trafficking and signaling responses.
Can microfinance-backed entrepreneurship be a holistic empowerment tool for women? Empirical evidence from Kashmir Valley, India
Authors: Khan Shagufta Tariq , Bhat Mohd Abass , Sangmi Mohi-Ud-Din
Published: January 2022

Purpose

This study investigates the effectiveness of microfinance-backed entrepreneurship as a mechanism for the holistic empowerment of women.

Design/methodology/approach

This study employs a mixed-method research-design consisting of quasi-experimental design (quantitative approach) involving women, both entrepreneurs (132) and non-entrepreneurs (238), as well as in-depth semi-structured interviews (qualitative approach).

Findings

Quantitative analysis revealed that female entrepreneurs are better off than female non-entrepreneurs in terms of economic, social, political and psychological indicators of empowerment. However, relatively lesser impact was found in terms of political, and to an even smaller extent, social empowerment of women. Analysis of in-depth interviews corroborated these findings confirming that entrepreneurship serves as an effective tool for the holistic empowerment of women. However, non-entrepreneurs also exhibit social empowerment.

Research limitations/implications

Given the restricted geographical ambit of the study, prudence ought to be exercised in drawing inferences applied to alternate contexts. That the vast majority of questionnaire respondents are illiterate presented a notable impediment in the process of collection of accurate responses.

Practical implications

Microfinance intervention ought to be specifically directed to cultivating entrepreneurship among women; in particular, to achieve the full benefits of empowerment, women availing microfinance ought to exert full control over their own business ventures.

Originality/value

In analyzing holistic empowerment through microfinance supported businesses set up by women, the study adds to the existing literature on women entrepreneurship and empowerment.
Applications of blockchain in government education sector: a comprehensive review and future research potentials
Authors: Dash Manoj Kumar , Panda Gayatri , Kumar Anil , Luthra Sunil
Published: January 2022

Purpose

With the time and increase in usage of information technology (IT), blockchain technology is gaining immense attention from researchers, academicians, and practitioners because of its distinctive features such as transference, security and data reliability. The purpose of this study is to endow with a systematic review of literature on blockchain in context to the government education sector in terms of its usage, benefits, obstacles and practical implementation in future areas in education.

Design/methodology/approach

The study adopted a bibliometric visualization tool to classify data in yearly publications, highly cited journals, prominent authors, leading publications in countries and institutions and highly cited papers – the data was extracted from the SCOPUS database by using relevant keywords. Thus, the following research questions were developed: How has blockchain technology been used in the government educational sector? What are the benefits examined in the field of education? What were the problems/obstacles faced using the technology in a government education structure?

Findings

The findings identify and provide a comprehensive review of the technique regarding the present research stream in terms of highest publication, author, journal, subject-wise and relevance of the technology in government education structure. Thus, the future research potential of the technology in the education sector is much more as it is in the initiation stage. A lot of opportunities and benefits need to be extracted at large.

Research limitations/implications

The present findings of the study provide a base work for government education institutions, policy developers and researchers to investigate other areas where the technology can be implemented. Finally, more technology applications will develop strategies for proper data management and cost-effective decisions.

Originality/value

This study explains the relevance of technology in education through bibliometric visualization. The study adopted the review and significance of blockchain technology in the government education sector by identifying its benefits, current scenario, application and future research potential areas.
Are smart contracts too smart for Supply Chain 4.0? A blockchain framework to mitigate challenges
Authors: Grida Mohamed , Mostafa Noha A.
Published: January 2022

Purpose

Smart contracts are self-executing computer programmes that have the potential to be used in several applications instead of traditional written contracts. With the recent rise of smart systems (e.g. Internet of things) and digital platforms (e.g. blockchain), smart contracts are gaining high interest in both business and academia. In this work, a framework for smart contracts was proposed with using reputation as the system currency, and conducts currency mining through fulfilling the physical commitments that are agreed upon.

Design/methodology/approach

A game theory model is developed to represent the proposed system, and then a system dynamics simulator is used to check the response of the blockchain with different sizes.

Findings

The numerical results showed that the proposed system could identify the takeover attacks and protect the blockchain from being controlled by an outsider. Another important finding is that careful setting of the maximum currency amount can improve the scalability of the blockchain and prevent the currency inflation.

Research limitations/implications

This work is proposed as a conceptual framework for supply chain 4.0. Future work will be dedicated to implement and experiment the proposed framework for other characteristics that may be encountered in the context of supply chain 4.0, such as different suppliers' tiers, different customer typologies and smart logistics applications, which may reveal other challenges and provide additional interesting insights.

Practical implications

By using the proposed framework, smart contracts and blockchains can be implemented to handle many issues in the context of operations and supply chain 4.0, especially in times of turbulence such as the COVID-19 global pandemic crisis.

Originality/value

This work emphasizes that smart contracts are not too smart to be applied in the context of supply chain 4.0. The proposed framework of smart contracts is expected to serve supply chain 4.0 by automating the knowledge work and enabling scenario planning through the game theory model. It will also improve online transparency and order processing in real-time through secured multitier connectivity. This can be applied in global supply chain functions backed with digitization, notably during the time of the pandemic, in which e-commerce and online shopping have changed the rules of the game.
Interplay of coordination, co-creation and community building: examining interprofessional collaboration in workplace development efforts in health care
Authors: Seppänen Laura , Koskela Inka , Heikkilä Heli , Leino-Kilpi Helena , Rautava Päivi , Stolt Minna , Siekkinen Mervi , Valtanen Elisa , Sulosaari Virpi
Published: January 2022

Purpose

Interprofessional collaboration (IPC) is increasingly important in work and workplace learning. The purpose of this paper is to investigate the characteristics of IPC that are relevant for learning and developing at work.

Design/methodology/approach

We examine IPC in the discussion data of health care professionals when designing, implementing and evaluating developmental tasks. Qualitative content analysis is carried out on temporally sequential task trajectories, considering IPC from the perspective of the objects and goals of IPC task activity in developmental efforts.

Findings

The developmentally relevant characteristics of IPC are crystallized in the concepts of coordination, co-creation and community building, which play different, interdependent roles in development efforts. We show their interplay and how they complement each other in practice.

Research limitations/implications

Our findings regarding IPC characteristics are to be interpreted as working hypotheses and resources for further research.

Practical implications

Understanding the dynamics of IPC is useful for renewing work practices. Attention to the interplay and complementarity of IPC characteristics may help in the design and implementation of effective and sustained development efforts.

Originality/value

The dynamics of IPC in developmental settings have not been sufficiently studied. This paper proposes three developmentally relevant and intertwined characteristics of IPC for scholars of workplace learning.
Resolving stress of university teacher: exploring role of workplace spirituality and constructive workplace deviance
Authors: Garg Naval , Kumari Sarika , Punia B.K.
Published: January 2022

Purpose

The study explores the relationship between workplace spirituality and work stress among university teachers. It also investigates the mediating effect of constructive deviance amid the association between workplace spirituality and stress among Indian university teachers.

Design/methodology/approach

The association between spirituality and stress is studied using correlation and multiple regression. The mediating effect of constructive deviance is examined using the Sobel test and bootstrapping estimates using Hayes' PROCESS macro. The hierarchical regression is used to report direct and indirect effects.

Findings

Findings reveal a significant negative association between the six dimensions of workplace spirituality and stress. The results also concluded the mediation effect of constructive deviance, which means workplace spirituality promotes constructive deviance that influences educators' stress levels.

Originality/value

The study is based on primary data collected by the author. It is one of the first explorations of the mediating effect of constructive deviance in the relationship of six dimensions of workplace spirituality and work stress among teachers.
The alarming rise in risk factors for hypertensive disorders of pregnancy
Authors: van Oostwaard Miriam F.
Published: January 2022

Linked article: This is a mini commentary on Timothy Wen et al. To view this article visit https://doi.org/10.1111/1471-0528.17038
Did the Dodd–Frank Whistleblower Provision Deter Accounting Fraud?
Authors: BERGER PHILIP G. , LEE HEEMIN
Published: January 2022

We examine the deterrence effect of the Dodd–Frank whistleblower provision on accounting fraud. To facilitate causal inference, we use state False Claims Acts (FCAs), under which whistleblowing about accounting fraud at a firm invested in by a state's pension fund can result in monetary rewards from that state's government. We divide our sample into firms exposed and not exposed to whistleblowing risk from a state FCA during the 2008–2010 period that preceded the 2011 SEC implementation of the Dodd–Frank whistleblowing provision. We hypothesize that firms already exposed to a state FCA whistleblower law are less affected by the Dodd–Frank whistleblower provision. Using the companies exposed to a state FCA as control firms in our Dodd–Frank tests, the remaining firms constitute the treatment sample. We find that exposure to Dodd–Frank reduces the likelihood of accounting fraud of treatment firms by 12%–22% relative to control firms, but do not find that it affects audit fees.
Morphology of the mammary gland in romanian buffalo
Authors: Tătaru Mariana , Stan Florin , Martonoș Cristian Olimpiu , Gal Adrian , Mârza Sorin Marian , Purdoiu Robert Cristian , Lăcătuș Radu , Damian Aurel , Șonea Cosmin , Mireșan Vioara , Papuc Ionel
Published: January 2022

The gross morphology of the mammary gland in buffalo is the foundation that is necessary for the process to improve the species for agricultural use. This study determined the mammary gland's anatomical, histological and imaging structure in the Romanian buffalo. The research material was represented by ten udders, five udders from adult buffaloes and five udders from young females slaughtered in the abattoir. The udders were collected immediately after slaughtering the animals, then transported to USAMV Cluj‐Napoca, Romania, examined macroscopically, histologically and through imagistic methods. The morphological examination tracked the topography, external conformation, vascularization and innervation of the mammary gland in the buffalo. The histological examination highlighted differences between the ductoacinary structures of the mammary gland parenchyma in adult buffaloes compared with young females. The imaging examination showed the detachment of the middle mammary artery and the arterial anastomoses established between the mammary arteries on the left side of the udder and those on the right side and between the arteries of the quarters on the same side. This research can be theoretical and practical support to other studies in establishing the most accurate diagnosis and therapeutic protocol in various clinical pathologies of the udder in buffalo.
Does deep neuromuscular blockade provide improved outcomes in low pressure laparoscopic colorectal surgery? A single blinded randomized pilot study
Authors: Lowen Darren John , Hodgson Russell , Tacey Mark , Barclay Karen L.
Published: January 2022

Background

Low intra‐abdominal pressure during laparoscopic colorectal surgery may improve outcomes and reduce hospital stay, in addition to Enhanced Recovery After Surgery (ERAS) protocols. There is concern that low pressure reduces laparoscopic vision and may increase surgical complications. Deep neuromuscular blockade may abrogate any reduction in vision of low‐pressure pneumoperitoneum. However, antagonism of deep neuromuscular blockade at completion of surgery necessitates the use of sugammadex, which is prohibitively expensive, if there are no surgical benefits and warrants further study.

Methods

A single institution, single blinded randomized controlled pilot study was performed comparing deep to moderate neuromuscular blockade in major laparoscopic colorectal surgery.

Results

Thirty‐eight patients were randomized to deep or moderate neuromuscular blockade. There were no statistically significant differences between groups, when comparing key patient demographics, or surgeon satisfaction with view, which required increased pressure or further relaxation demands. The deep blockade group had increased QoR15 scores and a decrease in pain, C‐Reactive Protein (CRP) measurements and operating times, although were non‐significant. The moderate group had slightly higher incidents of Medical Emergency Team (MET) calls and more severe complications, although were non‐significant.

Conclusions

Low intra‐abdominal pressure in laparoscopic colorectal surgery is feasible and allows adequate surgical visualization, regardless of the degree of neuromuscular blockade. Potential benefits of deep neuromuscular blockade may include improved pain and quality of recovery and a possible reduction of complications; however a larger cohort is required to confirm this. Future ERAS protocols may consider deep neuromuscular blockade with low intra‐abdominal pressure to further benefit patients.
Designer organs: The future of personalized transplantation
Authors: Buchwald Julianna E. , Martins Paulo N.
Published: January 2022

Organ transplantation is the definitive treatment for end‐stage solid organ diseases, yet biological and logistical barriers reduce the rate of successful organ transplants. As such, there is a need for gene therapy and gene modulation strategies in the organ transplantation setting to prevent rejection, expand the donor pool of available organs, and attenuate ischemia‐reperfusion damage. As we are entering an era of “precision medicine,” the organ transplant field is becoming equipped with the tools necessary to personalize and optimize organs designed specifically to withstand injurious pathways that occur during transplantation, such that the concept of “designer organs” will be a reality in the near future. In this review, we highlight the recent progress using gene knockout and knock‐in strategies used mainly in the context of xenotransplantation. We also discuss advancements in CRISPR‐Cas9 gene editing and RNA interference in relation to organ transplantation. Lastly, we discuss the exciting future implications of customized gene therapy in the transplantation setting, and its ability to potentially create a future where organs intended for transplant are personalized to maximize both graft and patient survival.
How do I know how I am doing? Use of different types of comparison in judgment of well‐being in patients seeking psychological treatment and healthy controls
Authors: Morina Nexhmedin , Meyer Thomas , Sickinghe Marthe
Published: January 2022

Judgment of well‐being is formed on the spot, and we know little about its foundations. We aimed at examining the role of comparison standards in informing evaluations of well‐being in a clinical and a nonclinical sample. In a semi‐structured face‐to‐face interview, individuals seeking psychological treatment and healthy control individuals rated how they have been feeling in general and relative to specific comparison standards and were each time invited to substantiate their ratings. Independent coders assessed number, type, direction, and specificity of reported comparisons. When asked to explain why they chose a particular rating of their well‐being, 93% of clinical participants and 61% of nonclinical participants spontaneously reported some type of comparison standard. Both groups reported highest well‐being ratings relative to social and past temporal comparisons and lowest relative to prospective temporal comparison. Furthermore, clinical participants engaged in more upward than downward comparisons, whereas this was not the case for healthy control participants. Our findings suggest that evaluations of well‐being are informed by different comparison types and that individuals with clinical complaints use more comparisons when evaluating their well‐being. The results encourage further investigation of comparative thinking as an underlying mechanism of judgment of well‐being and ill‐being.
Randomised clinical trial: a phase 1b study of GB004, an oral HIF‐1α stabiliser, for treatment of ulcerative colitis
Authors: Danese Silvio , Levesque Barrett G. , Feagan Brian G. , Jucov Alina , Bhandari Bal Raj , Pai Rish K. , Taylor Meadows Kristen , Kirby Brian J. , Bruey Jean‐Marie , Olson Allan , Osterhout Robin , Van Biene Courtney , Ford Julia , Aranda Richard , Raghupathi Kartik , Sandborn William J.
Published: January 2022

Background

Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut‐targeted stabiliser of hypoxia‐inducible factor‐1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut.

Aims

To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC.

Methods

This double‐blind, placebo‐controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3‐12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5‐aminosalicylates, corticosteroids or immunosuppressants.

Results

Thirty‐four patients were randomised. GB004 120 mg for 28 days was generally well‐tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment‐related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo.

Conclusion

Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.
Stratigraphic record of continental breakup, offshore NW Australia
Authors: Reeve Matthew T. , Magee Craig , Jackson Christopher A.‐L. , Bell Rebecca E. , Bastow Ian D.
Published: January 2022

Continental breakup involves a transition from rapid, fault‐controlled syn‐rift subsidence to relatively slow, post‐breakup subsidence induced by lithospheric cooling. Yet the stratigraphic record of many rifted margins contain syn‐breakup unconformities, indicating that episodes of uplift and erosion interrupt this transition. This uplift has been linked to mantle upwelling, depth‐dependent extension and/or isostatic rebound. Deciphering the breakup processes recorded by these unconformities and their related rock record is challenging because uplift‐associated erosion commonly removes the strata that help constrain the onset and duration of uplift. We examine three major breakup‐related unconformities and the intervening rock record in the Lower Cretaceous succession of the Gascoyne and Cuvier margins, offshore NW Australia, using seismic reflection and borehole data. These data show the breakup unconformities are disconformable (non‐erosive) in places and angular (erosive) in others. Our recalibration of palynomorph ages from rocks underlying and overlying the unconformities shows: (i) the lowermost unconformity developed between 134.98–133.74 Ma (Intra‐Valanginian), probably during the localisation of magma intrusion within continental crust and consequent formation of continent–ocean transition zones (COTZ); (ii) the middle unconformity formed between ca. 134 and 133 Ma (Top Valanginian), possibly coincident with breakup of continental crust and generation of new magmatic (but not oceanic) crust within the COTZs; and (iii) the uppermost unconformity likely developed between ca. 132.5 and 131 Ma (i.e. Intra‐Hauterivian), coincident with full continental lithospheric breakup and the onset of seafloor spreading. During unconformity development, uplift was focussed along the continental rift flanks, likely reflecting flexural bending of the crust and landward flow of lower crust and/or lithospheric mantle from beneath areas of localised extension towards the continent (i.e. depth‐dependent extension). Our work supports the growing consensus that the ‘breakup unconformity’ is not always a single stratigraphic surface marking the onset of seafloor spreading; multiple unconformities may form and reflect a complex history of uplift and subsidence during continent–ocean transition.
A persistent plaque on the back of the hand
Authors: Cameron S. , Ramakrishnan R. , Patel N. P.
Published: January 2022

We report the case of a 75-year-old woman presenting with acrodermatitis chronica atrophicans affecting the right hand dorsum, developing after an insect bite sustained in Greece. Diagnosis was confirmed by serology, PCR and histopathological findings. The plaque resolved following a 3-week course of oral doxycycline.

Click https://www.wileyhealthlearning.com/#/online-courses/4ebea04b-e4de-49d3-9bbb-0d3355007e92 for the corresponding questions to this CME article.
A disciplinary divide in the framing of urbanization’s environmental impacts
Authors: Armstrong John H. , Nisi Anna C. , Millard‐Ball Adam
Published: January 2022

We identify a disciplinary divide in how the environmental impacts of urbanization are presented in ecology and urban planning journals. We analyzed the sentiments expressed in 202,900 journal articles and found that articles in ecology journals discuss urbanization three times more negatively relative to urban planning journals. Articles in both disciplines identified the negative local impacts of urban growth on biodiversity, habitat, and other ecological outcomes. However, urban planning research also considered the positive global‐scale benefits of cities in enabling more efficient settlement patterns that reduce greenhouse gas emissions and energy consumption. These diverging perspectives are likely due to the different scales and scopes of the two disciplines, but also because of different counterfactuals: the alternative to urbanization might be car‐dependent exurbs, or simply no new development within the focal study area. Interdisciplinary collaborations may provide a path to reconcile the different perspectives and boost sustainability.
The metabolic triad of non‐alcoholic fatty liver disease, visceral adiposity and type 2 diabetes: Implications for treatment
Authors: Cariou Bertrand
Published: January 2022

Non‐alcoholic fatty liver disease (NAFLD) is associated with visceral obesity, insulin resistance, type 2 diabetes (T2D) and has been often considered as the hepatic expression of the metabolic syndrome (MetS). Epidemiological studies highlight a bidirectional relationship of NAFLD with T2D in which NAFLD increases the risk of incident T2D and T2D increases the risk of severe non‐alcoholic steatohepatitis (NASH) and liver fibrosis. Regarding the molecular determinants of NAFLD, we specifically focused in this review on adipocyte dysfunction as a key molecular link between visceral adipose tissue, MetS and NAFLD. Notably, the subcutaneous white adipose tissue expandability appears a critical adaptive buffering mechanism to prevent lipotoxicity and its related metabolic complications, such as NAFLD and T2D. There is a clinical challenge to consider therapeutic strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis. Strategies that promote significant and sustained weight loss (~10% of total body weight) such as metabolic and bariatric surgery or incretin‐based therapies (GLP‐1 receptor agonists or dual GLP‐1/GIP or GLP‐1/glucagon receptor co‐agonists) are among the most efficient ones. In addition, insulin sensitizers such as PPARγ (pioglitazone) and pan‐PPARs agonists (lanifibranor) have shown some beneficial effects on both NASH and liver fibrosis. Since NASH is a complex and multifactorial disease, it is conceivable that targeting different pathways, not only insulin resistance but also inflammation and fibrotic processes, is required to achieve NASH resolution.
Peri‐operative changes in diastolic function and outcomes in congenital aortic valve surgery
Authors: Pesce Meredith , LaPar Damien , Kalfa David , Bacha Emile , Freud Lindsay
Published: January 2022

Background

The ratio of early diastolic mitral inflow velocity (E) to early diastolic mitral annular tissue velocity (e’), or E/e’, is an echocardiographic measure of left ventricular filling pressure. Peri‐operative changes in E/e’ and association with outcomes have been demonstrated in adults undergoing surgery for aortic stenosis (AS). We sought to explore changes in E/e’ and other diastolic indices in the setting of congenital AS surgery and to assess for association with post‐operative outcomes among children and young adults.

Methods

A retrospective, single‐center study was performed among patients 6 months to 30 years of age who underwent congenital AS surgery from 2006 to 2018. Tissue Doppler indices were collected from pre‐ and post‐operative echocardiograms. Post‐operative outcomes were reviewed.

Results

Sixty‐six subjects with subvalvar (45%), valvar (47%), and supravalvar (8%) AS underwent surgery at a median age of 9.5 years (IQR: 4.0–14.8). Pre‐operatively, the lateral E/e’ ratio was 8.6 (6.7–11.0); 33% had E/e’≥10. Post‐operatively, the lateral e’ decreased to 9.9 cm/s (8.0–11.4), the E/e’ ratio increased to 10.4 (8.3–13.1); and 53% had E/e’≥10 (p‐values < 0.0001, 0.0072, and < 0.001, respectively). Pre‐operative lateral e’ correlated modestly with duration of intubation (ρ = −0.24, p‐value 0.048) and post‐operative lateral e’ correlated modestly with duration of intubation and length of hospital stay (ρ = −0.28 and −0.26, p‐values = 0.02 and 0.04, respectively).

Conclusions

Children and young adults who underwent congenital AS surgery had echocardiographic evidence of diastolic dysfunction pre‐operatively that worsened post‐operatively. Lateral e’ may be a sensitive indicator of impaired ventricular relaxation in these patients and may impact duration of intubation and hospital stay.
Influence of different diameter reductions in the labial neck region on the stress distribution around custom‐made root‐analogue implants
Authors: Lin Chunping , Hu Hongcheng , Zhu Junxin , Rong Qiguo , Tang Zhihui
Published: January 2022

This study was designed to investigate the influence of diameter reductions on the stress distribution around root‐analogue implants via 3D finite element analysis. Four root‐analogue implant models with different diameter reductions (0, 1, 2, or 3 mm), a traditional threaded implant and congruent bone models were created through reverse engineering. A 100‐N force was applied parallel with and in a 45° angle to the implant axis, respectively. The stress concentration in the labial neck area around implants with 1–2 mm diameter reduction was lower than seen with no reduction. When the implant diameter was reduced by 3 mm, there were obvious stress concentrations in both implant and bone (the maximum stress was 206  and 111 MPa, respectively). In other groups, the maximum stress was 65.1 MPa in the bone and 108 MPa in the implant. Additionally, the stress concentration in the bone around the root‐analogue implant when the implant diameter was reduced by 0–2 mm (maximum stress of 65.1 MPa) was obviously smaller than that around the traditional implant (maximum stress 130.4 MPa). Reducing the diameter of maxillary central incisor root‐analogue implants by up to 2 mm next to the labial cortical bone could help disperse stress.
“It kinda breaks my heart”: LGBTQ young adults' responses to family rejection
Authors: DeChants Jonah P. , Shelton Jama , Anyon Yolanda (Yoli) , Bender Kimberly
Published: January 2022

Objective

This study examines the realities of LGBTQ young adults experiencing family rejection, specifically illuminating forms of heterosexist and cisgenderist family rejection and their impact on LGBTQ young adults.

Background

Extant research indicates family rejection is a driving factor in the overrepresentation of LGBTQ young adults among young adults experiencing homelessness.

Method

This study analyzed two waves of interviews with 15 LGBTQ young adults. It addressed two research questions: (a) What kinds of heterosexist and cisgenderist rejection do LGBTQ young adults experience from their parents or guardians? and (b) How do LGBTQ young adults react to and experience that rejection?

Results

Participants reported multiple forms of heterosexist and cisgenderist rejection from their families, including increased heterosexism and cisgenderism in the home after coming out, increased arguments and conflict after coming out, abuse and neglect, silence and avoidance, control and isolation, and revoking young people's access to housing. Participants' responses to these forms of rejection included pain, disconnection from their families, feeling stifled in the home, and the desire to resist.

Conclusion

These findings illuminate specific forms and manifestations of heterosexist and cisgenderist family rejection and their impact on LGBTQ young adults.

Implications

Implications for research include further exploration of how family rejection manifests in the families of LGBTQ young adults. Implications for clinical practice include developing tailored outreach and services for young adults experiencing family rejection and housing instability.
Surface strengthening of building tiles by ion exchange with adding molten salt of KOH
Authors: Xu Wei , Li Kai , Li Yueming , Sun Yi , Bao Yiwang , Wan Detian , Tan Xiang , Hao Dong
Published: January 2022

The surface strengthening by ion exchange technology was used to improve the strength of thin building tiles. The effects of exchange time, exchange temperature, and content of KOH additive on strengthening of building tiles were investigated by analyzing the flexural strength and distribution of K+ in the samples. The results showed that the addition of .3 mol% KOH to the molten salt of industrial KNO3 at 450°C for 5 h resulted in a maximum flexural strength of 86.53 MPa, which was 50.3% higher than that of the sample without ion exchange and 8.9% higher than without KOH addition. After ion exchange, the concentration of K+ ion in cross‐section of the sample decreased with increasing distance from the sample surface, and the diffusion coefficient changed with the change of the content of KOH additive in the molten salt, increasing the diffusion coefficient of K+ ion from .93 × 10−15 to 1.8 × 10–15 m2/s by adding .3 mol% KOH.
Left ventricular contractile reserve as a determinant of adverse clinical outcomes: a systematic review
Authors: Thein Paul M. , Mirzaee Sam , Cameron James D. , Nasis Arthur
Published: January 2022

An abnormal left ventricular contractile reserve is often seen in patients undergoing stress echocardiogram and may indicate the presence of obstructive coronary artery disease. The techniques and indexes used to identify abnormal left ventricular contractile response and its prognostic value in the absence of known causes has not been well studied. To describe the characteristics and clinical outcomes associated with an abnormal left ventricular contractile response, we performed a systematic review that identified 27 eligible studies. A diverse range of indices were utilised to measure left ventricular contractile reserve, most commonly Δleft ventricular ejection fraction in 11 studies. Dobutamine stress echocardiogram was the most commonly performed modality (19 studies) followed by exercise stress echocardiogram (4 studies), dipyridamole stress echocardiogram (2 studies), invasive hemodynamic measurement (1 study) and dobutamine stress magnetic resonance imaging (1 study). All but one study demonstrated a significant association between the absence of left ventricular contractile reserve and increased rate of cardiovascular events, cardiac death and all‐cause mortality.
Optimal admission control under premature discharge decisions for operational effectiveness
Authors: Yang Feifei , Jiang Yanping , Tang Zhenpeng
Published: January 2022

The shortage of inpatient beds causes surgery cancellations, treatment delays, and inappropriate ward arrangements. That is why studying how to make admission decisions on the wards of crowded units under premature discharge decisions is essential. In this study, we set up an infinite‐horizon total discounted cost Markov decision process model to minimize the total expected cost to the hospital. By analyzing the structural properties of the optimal value function, we find that there is an optimal admission control policy of the threshold type for low‐acuity emergency patients (type‐2). Numerical experiments are done to examine how optimal dynamic policy depends on key system parameters. Furthermore, we evaluate the performance of the optimal dynamic policy with a benchmark policy without premature discharge decisions. The results indicate that the optimal admission control policy helps hospitals in maintaining low costs and enables patients with high‐acuity diseases to enter primary wards more quickly.
MicroRNA‐381 in human cancer: Its involvement in tumour biology and clinical applications potential
Authors: Sha Huanhuan , Gan Yujie , Xu Feng , Zhu Yue , Zou Renrui , Peng Weiwei , Wu Zhiya , Ma Rong , Wu Jianzhong , Feng Jifeng
Published: January 2022

MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression at the post‐transcriptional level. MiRNAs are involved in the development and progression of a wide range of cancers. Among such cancer‐associated miRNAs, miR‐381 has been a major focus of research. The expression pattern and role of miR‐381 vary among different cancer types. MiR‐381 modulates various cellular behaviours in cancer, including proliferation, apoptosis, cell cycle progression, migration and invasion. MiR‐381 is also involved in angiogenesis and lymphangiogenesis, as well as in the resistance to chemotherapy and radiotherapy. MiR‐381 itself is regulated by several factors, such as long noncoding RNAs, circular RNAs and cytokines. Aberrant expression of miR‐381 in blood samples indicates that it can be used as a diagnostic marker in cancer. Tissue miR‐381 expression may serve as a prognostic factor for the clinicopathological characteristics of cancers and survival of patients. Metformin and icaritin regulate miR‐381 expression and present anticancer properties. This review comprehensively summarizes the effect of miR‐381 on tumour biological behaviours, as well as the clinical application potential of miR‐381 for the treatment of cancer.