bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of CTC guided chemo- or endocrine therapy in ER+ HER2- metastatic breast cancer – results from a randomized controlled multicenter trial
Authors: Berghuis A.M.S. , Koffijberg H. , Pouwels X.G.L.V. , Berger F. , Alix-Panabières C. , Jacot W. , Pierga J.Y. , Bidard F.C. , IJzerman M.J.
Published: October 2023

Patients with metastatic, Estrogen Receptor (ER) positive, HER2-negative, breast cancer, before initiating CDK4/6 inhibitors, receive either single agent endocrine- or chemotherapy based on their clinical risk. In this first-ever trial-based economic evaluation of Circulating Tumor Cells (CTCs), the cost-effectiveness of standardizing the prescription of endocrine- or chemotherapy using a CTC count threshold (with >5 CTCs/7.5mL indicative of unfavorable disease outcomes) was compared to current clinical practice. N=755 ER+ HER2-patients, enrolled in 17 French centres, were randomized to CTC guided or standard of care and were treated according to either through the CTC score or clinical examination. Health state utilities were calculated by mapping the QLQ-C30 to EQ-5D utilities and used to calculate Quality-Adjusted Life Years (QALY) over a 2-year time horizon. Bootstrapping and additional sensitivity analyses were performed to quantify the impact of uncertainty. Health outcomes in both arms were similar, but costs were higher in the CTC guided arm (€19,403) compared to the usual care (€18,254), resulting in an ICER of €104,078/QALY in favor of usual care. However, when the analysis was performed for the clinically high- and low-risk groups separately, CTC enumeration could be a dominant strategy (cost saving) if treatment is de-escalated in clinically high-risk patients as indicated by CTC scores. However, the current analysis was based on the PFS and OS data reported in 2021 and long-term Overall Survival data is collected since then (JCO, 2023 in press). A further analysis of the health economic impact of CTC enumeration in clinically low and high-risk groups is therefore indicated.
Integration of a fasting-mimicking diet program in primary care for type 2 diabetes reduces the need for medication – a 12-month randomised controlled trial
Authors: van den Burg Elske L , Schoonakker Marjolein P , van Peet Petra G , van den Akker – van Marle Elske M , Lamb Hildo J , Longo Valter D , Numans Mattijs E , Pijl Hanno
Published: October 2023

Aims/hypothesis

The aim of this study was to evaluate the impact on metabolic control of the periodic use of a 5-day fasting-mimicking diet (FMD) program as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance.

Methods

In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin only and/or diet alone for glycaemic control were randomised to receive 5-day cycles of FMD monthly as adjunct to regular care by their general practitioner or regular care only. Primary outcomes were changes in glucose-lowering medication and HbA1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA1c levels in individual participants were combined to yield a clinically relevant primary outcome measure (‘glycaemic management’), categorized as improved, stable or deteriorated after one year of follow-up.

Results

100 individuals with type 2 diabetes, age 18-75 years, and BMI > 27 kg/m2, were randomised to the FMD (n=51) or control group (n=49). Eight FMD participants and ten controls were lost to follow-up. In complete case intention-to-treat analyses, the mean medication effect score (MES) significantly declined in patients receiving FMD as compared to controls (FMD −0.2 ± 0.3 vs controls +0.2 ± 0.4, p<0.0001) in the face of similar changes of HbA1c adjusted for MES (FMD −0.4 ± 0.8 % vs controls +0.2 ± 0.8 %, p=0.0021). Glycaemic management improved in 53% of participants using FMD vs 8% of controls, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.0001).

Conclusions/interpretation

Integration of a monthly FMD program in regular primary care for people with type 2 diabetes who use metformin only and/or diet alone for glycaemic control reduces the need for glucose-lowering medication and appears to be safe in routine clinical practice.

Trial registration

ClinicalTrials.gov:NCT03811587
mRNA cap-binding protein eIF4E1 is a novel regulator ofToxoplasma gondiilatency
Authors: Holmes Michael J. , Bastos Matheus S. , Dey Vishakha , Severo Vanessa , Wek Ronald C. , Sullivan William J.
Published: October 2023

The protozoan parasiteToxoplasma gondiicauses serious opportunistic disease due to its ability to persist in patients as latent tissue cysts. The molecular mechanisms coordinating conversion between proliferative parasites (tachyzoites) and dormant cysts (bradyzoites) are not fully understood. We previously showed that phosphorylation of eIF2α accompanies bradyzoite formation, suggesting that this clinically relevant process involves regulation of mRNA translation. In this study, we investigated the composition and role of eIF4F multi-subunit complexes in translational control. Using CLIPseq, we find that the cap-binding subunit, eIF4E1, localizes to the 5’-end of all tachyzoite mRNAs, many of which show evidence of stemming from heterogenous transcriptional start sites. We further show that eIF4E1 operates as the predominant cap-binding protein in two distinct eIF4F complexes. Using genetic and pharmacological approaches, we found that eIF4E1 deficiency triggers efficient spontaneous formation of bradyzoites without stress induction. Consistent with this result, we also show that stress-induced bradyzoites exhibit reduced eIF4E1 expression. Overall, our findings establish a novel role for eIF4F in translational control required for parasite latency and microbial persistence.

Significance

Toxoplasma gondiiis an opportunistic pathogen of importance to global human and animal health. There are currently no chemotherapies targeting the encysted form of the parasite. Consequently, a better understanding of the mechanisms controlling encystation are required. Here we show that the mRNA cap-binding protein, eIF4E1, is involved in regulating the encystation process. Encysted parasites reduce eIF4E1 levels and depletion of eIF4E1 decreases the translation of ribosome-associated machinery and drivesToxoplasmaencystation. Together, these data reveal a new layer of mRNA translational control that regulates parasite encystation and latency.
RNA Infrastructure Profiling Illuminates Transcriptome Structure in Crowded Spaces
Authors: Xiao Lu , Fang Linglan , Kool Eric T.
Published: October 2023

RNAs can fold into compact three-dimensional structures, and most RNAs undergo protein interactions in the cell. These compact and occluded environments can block the ability of structure-probing agents to provide useful data about the folding and modification of the underlying RNA. The development of probes that can analyze structure in crowded settings, and differentiate the proximity of interactions, can shed new light on RNA biology. To this end, here we employ 2,-OH-reactive probes that are small enough to access folded RNA structure underlying many close molecular contacts within cells, providing considerably broader coverage for intracellular RNA structural analysis. We compare reverse transcriptase stops in RNA-Seq data from probes of small and standard size to assess RNA-protein proximity and evaluate solvent-exposed tunnels adjacent to RNA. The data are analyzed first with structurally characterized complexes (human 18S and 28S RNA), and then applied transcriptome-wide to polyadenylated transcripts in HEK293 cells. In our transcriptome profile, the smallest probe acetylimidazole (AcIm) yields 80% greater structural coverage than larger conventional reagent NAIN3, providing enhanced structural information in hundreds of transcripts. We further show that acetyl probes provide superior signals for identifying m6A modification sites in transcripts, and provide information regarding methylation sites that are inaccessible to a larger standard probe. RNA infrastructure profiling (RISP) enables enhanced analysis of transcriptome structure, modification, and interactions in living cells, especially in spatially crowded settings.
Predicting global herbicide resistance hotspots using a 30-year-old database and machine-learning techniques
Authors: Brocklehurst Neil , Liu Chun
Published: October 2023

The evolution of herbicide resistance in weeds is a problem affecting both food production and ecosystems. Numerous factors affect selection towards herbicide resistance, making it difficult to anticipate where, under what circumstances, and under what timeframe, herbicide resistance is likely to appear. Using the International Herbicide-Resistant Weed Database to provide data on locations and situations where resistance has occurred, we trained models to predict where resistance is most likely in future. Validation of the global models with historical data found a prediction accuracy of up to 78%, while for well-sampled regions, such as Australia, the model correctly predicted more than 95% of instance of resistance and sensitivity. Applying the models to predict instances of resistance over the next decade, future hotspots were detected in North and South America and Australia. Species such asConyza canadensis,Eleusine indica, andLactuca serriolaare expected to show substantial increases in the number of resistance occurrences. The results highlight the potential of machine-learning approaches in predicting future resistance hotspots and urge more efforts in resistance monitoring and reporting to enable improved predictions. Future work incorporating dimensions such as weed traits, phylogeny, herbicide chemistry, and farming practices could improve the predictive power of the models.
Visualisation of gene expression within the context of tissues: an X-ray computed tomography-based multimodal approach
Authors: Kairišs Kristaps , Sokolova Natalia , Zilova Lucie , Schlagheck Christina , Reinhardt Robert , Baumbach Tilo , Faragó Tomáš , van de Kamp Thomas , Wittbrodt Joachim , Weinhardt Venera
Published: October 2023

The development of an organism is orchestrated by the spatial and temporal expression of genes. Accurate visualisation of gene expression patterns in the context of the surrounding tissues offers a glimpse into the mechanisms that drive morphogenesis. We developed correlative light-sheet fluorescence microscopy and X-ray computed tomography approach to map gene expression patterns to the whole organism’s 3D anatomy at cellular resolution. We show that this multimodal approach is applicable to gene expression visualised by protein-specific antibodies and fluorescence RNAin situhybridisation, offering a detailed understanding of individual phenotypic variations in model organisms. Furthermore, the approach provides a unique possibility to identify tissues together with their 3D cellular and molecular composition in anatomically less-definedin vitromodels, such as organoids. We anticipate that the visual and quantitative insights into the 3D distribution of gene expression within tissue architecture, by the multimodal approach developed here, will be equally valuable for reference atlases of model organisms development, as well as for comprehensive screens and morphogenesis studies ofin vitromodels.
Deep learning-guided selection of antibody therapies with enhanced resistance to current and prospective SARS-CoV-2 Omicron variants
Authors: Frei Lester , Gao Beichen , Han Jiami , Taft Joseph M. , Irvine Edward B. , Weber Cédric R. , Kumar Rachita K. , Eisinger Benedikt N. , Reddy Sai T.
Published: October 2023

Most COVID-19 antibody therapies rely on binding the SARS-CoV-2 receptor binding domain (RBD). However, heavily mutated variants such as Omicron and its sublineages, which are characterized by an ever increasing number of mutations in the RBD, have rendered prior antibody therapies ineffective, leaving no clinically approved antibody treatments for SARS-CoV-2. Therefore, the capacity of therapeutic antibody candidates to bind and neutralize current and prospective SARS-CoV-2 variants is a critical factor for drug development. Here, we present a deep learning-guided approach to identify antibodies with enhanced resistance to SARS-CoV-2 evolution. We apply deep mutational learning (DML), a machine learning-guided protein engineering method to interrogate a massive sequence space of combinatorial RBD mutations and predict their impact on angiotensin-converting enzyme 2 (ACE2) binding and antibody escape. A high mutational distance library was constructed based on the full-length RBD of Omicron BA.1, which was experimentally screened for binding to the ACE2 receptor or neutralizing antibodies, followed by deep sequencing. The resulting data was used to train ensemble deep learning models that could accurately predict binding or escape for a panel of therapeutic antibody candidates targeting diverse RBD epitopes. Furthermore, antibody breadth was assessed by predicting binding or escape to synthetic lineages that represent millions of sequences generated usingin silicoevolution, revealing combinations with complementary and enhanced resistance to viral evolution. This deep learning approach may enable the design of next-generation antibody therapies that remain effective against future SARS-CoV-2 variants.
A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions
Authors: Dankwa Sedem , Kosman Christina , Dennis Maria , Giorgi Elena E. , Vuong Kenneth , Pahountis Ioanna , Garza Ashley , McCarthy Janice , Mayer Bryan T. , Ngo Julia T. , Enemuo Chiamaka A. , Carnathan Diane G. , Stanfield-Oakley Sherry , Berendam Stella J. , Weinbaum Carolyn , Engelman Kathleen , Magnani Diogo M. , Chan Cliburn , Ferrari Guido , Silvestri Guido , Amara Rama R. , Chahroudi Ann , Permar Sallie R. , Fouda Genevieve G. , Goswami Ria
Published: October 2023

To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple bNAb combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robustin vitroneutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy (PE) of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has a predicted PE≥90% against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.
Forming limit diagram and optimization of process parameters in SPIF of Inconel 625 aviation-grade superalloy
Authors: Bishnoi Pawan , Chandna Pankaj
Published: October 2023

Purpose

This paper aims to optimize the single-point incremental forming process variables for realizing higher formability in Inconel 625 components and to plot the forming limit diagram for Inconel 625 aviation-grade superalloy.

Design/methodology/approach

The formability of Inconel 625 components has been measured in terms of major strain, minor strain and minimum sheet thickness. Response surface methodology with desirability function analysis has been used to achieve maximum formability. The finite element analysis has been conducted at optimal parametric setting.

Findings

The derived forming limit diagram proves that the maximum forming limit for Inconel 625 is 57.5° at the optimal parametric setting, achieved with desirability of 0.995. The outcomes of finite element analysis conducted at optimal parametric setting show excellent agreement with confirmation experiment results.

Practical implications

Inconel 625 superalloy is frequently used in aircraft and other high-performance applications for its superior strength.

Originality/value

It has been suggested that to enhance formability, higher tool rotation speed, minimum step-size, larger tooltip diameter and higher wall angle must be used. Wall angle is the governing parameter among all the parameters.
Macy’s, Inc.: “Polaris” turnaround strategy and the road ahead
Authors: Bodhanwala Shernaz , Bodhanwala Ruzbeh
Published: October 2023

Research methodology

The case is written based on publicly available data from primary sources such as the company’s annual reports, company website and the company’s presentations, as well as from secondary sources comprising newspaper articles, research papers, research magazines, magazine articles, industry reports, research reports, etc. as indicated in the references. The company’s financials and peer data are sourced from the Thomson Reuters Eikon database.

Case overview/synopsis

The case examines the financial position of Macy’s, Inc., America’s largest and one of the oldest premier departmental stores, with a consolidated annual turnover of US$18,097m in the fiscal year 2020/2021 (FY, 2021). Over the previous few years, the company had been struggling with decreasing market share and profitability mainly due to increasing competition from online retailers and deep discounters, which was affecting the company’s share price. With the appointment of a new chief executive officer (CEO) in fiscal year (FY) 2017, Macy’s, Inc. undertook several changes to revive its financial health and improve its market share. However, it still registered heavy losses of US$3,944m in the FY 2020/2021, the company’s first time in the past decade. With many retailers filing for bankruptcy, was there more that Macy’s could do to improve the company’s position and regain lost investor confidence? Will its entry into emerging markets play a crucial role in its turnaround?

Complexity academic level

The case can be used in undergraduate and postgraduate courses such as accounting for managers, financial statement analysis, management accounting, introduction to accounting and advanced financial statement analysis. The case can also be effectively used to understand the primary fundamental analysis of the company that involves understanding the company’s positioning and strengths, weaknesses, opportunities and threats analysis. The case would also help business management and entrepreneurship students to get a preliminary idea about the change management process. Finally, the case can be used to familiarize students with using Microsoft Excel to build financial analysis worksheets.

Supplementary Material

Teaching notes are available for educators only.
Transportation Justice and Health
Authors: HANSMANN KELLIA J. , RAZON NA'AMAH
Published: October 2023

Policy Points

The health care sector is increasingly investing in social conditions, including availability of safe, reliable, and adequate transportation, that contribute to improving health.

In this paper, we suggest ways to advance the impact of transportation interventions and highlight the limitations of how health services researchers and practitioners currently conceptualize and use transportation.

Incorporating a transportation justice framework offers an opportunity to address transportation and mobility needs more comprehensively and equitably within health care research, delivery, and policy.
Clinical and medico‐legal considerations in endodontics
Authors: Johnstone M , Evans M
Published: October 2023

Endodontic treatment can be challenging for a number of reasons, including the microscopic nature of the clinical environment, reliance on tactile sensation and lack of direct visualization of the work being performed. Commonly, endodontic patients present with pain and distress, which can exacerbate an already difficult clinical situation. Complications may might arise prior to, or during treatment, despite practising with the utmost care and skill. Preventing and managing these complications can take considerable time and energy, and oftentimes assistance from or referral to more experienced colleagues is required. The aim of this review is to discuss medico‐legal considerations in endodontics, with clinical correlations and a focus on the Australian legal landscape. [Correction added on 18 October 2023, after first online publication: The abstract was amended from a structured to an unstructured abstract.]
Confronted by Insurmountable Opportunities: Geography in Society at the AAG's Centennial*
Authors: Richardson Douglas , Solis Patricia
Published: October 2023

Geographers at the AAG's centennial are challenged with exceptional opportunities to create a more central place for geography in society and in the university. Realizing these opportunities requires identifying and leveraging key emerging trends in the formation and uses of geographic knowledge. Better integration of geography's profound technological innovations with its core traditions also is necessary to strengthen the discipline's research capacity, and to more effectively engage with and contribute to the needs of society. Trends toward multidisciplinary research and integrative science, and the heightened need for geographic understanding in today's world, hold further promise for advancing the discipline while sustaining its historic strengths and diversity.
A note on the largest sum‐free sets of integers
Authors: Jing Yifan , Wu Shukun
Published: October 2023

Given a set of positive integers, an old question in additive combinatorics asks that whether contains a sum‐free subset of size at least for some increasing unbounded function . The question is generally attacked in the literature by considering another conjecture, which asserts that as , . This conjecture, if true, would also imply that a similar phenomenon occurs for ‐sum‐free sets for every . In this note, we prove the latter result directly. The new ingredient of our proof is a structural analysis on the host set , which might be of independent interest.
How Eco-Spatial Edutourism Support Sustainability in Coastal Areas in South Malang, Indonesia?
Authors: Sumarmi Sumarmi , Tanjung Ardiyanto , Putra Alfyananda Kurnia , Zubaidah Siti , Shrestha Rajendra P , Suprianto Agung
Published: October 2023

This study aimed to determine the effect of edutourism based on eco-spatial to support sustainability in coastal areas in South Malang, East Java, Indonesia. The qualitative research design is conducted at Kondang Merak Beach, Pesanggrahan Beach, Bajulmati Beach, CMC (Clungup Mangrove Conservation) Tiga Warna, Tamban Beach, and Perawan Beach, which located in South Malang Regency, East Java, Indonesia. Data were taken using participant observation, documentation, and in-depth interviews. Data analysis used qualitative analysis from Miles and Huberman, consisting of three stages, reduction, data presentation, and conclusions. The result found that each beach has unique qualities depending on the surrounding  environment and can be developed into an edutourism destination. Edutourism has benefited environmental sustainability, showed in the condition of natural resources in maintained tourist attractions (mangroves, coral reefs, pine shrimp, sea pandanus, turtles, and crabs), and maintained cleanliness at tourist areas.
Effects of Manufacturing Tolerances on Double-Wall Effusion Cooling
Authors: van de Noort Michael , Ireland Peter T. , Telisinghe Janendra C.
Published: October 2023

As aeroengine designers seek to raise turbine entry temperatures for greater thermal efficiencies, novel cooling schemes are required to ensure that components can survive in increasingly hotter environments. By utilizing a combination of impingement cooling, pin-fin cooling, and effusion cooling, double-wall effusion cooling is well equipped to achieve the high metal cooling effectiveness required for such challenges while keeping coolant consumption at an acceptably low level. However, this high performance can drop off within the variability of common manufacturing tolerances, which can also expose cooling schemes to issues such as hot gas ingestion. This paper uses an experimentally validated low-order flow network model (LOM) to assess the cooling performance of a double-wall effusion cooling scheme employed in a high-pressure turbine nozzle guide vane, subject to the variability of geometric parameters set by their manufacturing tolerances. The relative significance of each geometric parameter is examined by varying it individually and comparing the effects on the cooling performance. A Monte Carlo analysis is then conducted to assess the likelihood of performance variation for a baseline design. Finally, multiple optimization studies are conducted for the cooling scheme, with the simultaneous objectives of reducing coolant usage and maximizing the design tolerances to reduce manufacturing cost, all while maintaining acceptable metal cooling effectiveness and backflow margins.
Stannane in extreme ultraviolet lithography and vacuum technology: Synthesis and characterization
Authors: Garza Raquel , Bartlett Nathan , Crouse Jameson , Herschberg Andrew , Mohan Sankaran R. , Amzad Hossain Md. , Ruzic David N.
Published: October 2023

In extreme ultraviolet (EUV) lithography, tin droplets evaporate and subsequently coat various surfaces including the collector mirrors. To clean off the tin, a hydrogen plasma is often used, but as a result, an unstable by-product, stannane (SnH4) is formed. The physicochemical characteristics of this gas, its formation in a plasma process, and its interaction with various materials have not been explored and understood completely. Here, the electron ionization mass spectrum of SnH4 is presented. All ten natural abundance isotopes were observed experimentally for each fragment, i.e., Sn+, SnH+, SnH2+, and SnH3+. Density functional electronic structure theory was used to calculate the optimized ground state geometries of these gas phase species and their relative stabilities and helped explain the absence of SnH4+ in the observed signals. The density of the liquid, its cracking pattern, and the surface morphology of its deposits were examined. The surface of the deposited tin film resulting from the decomposition and subsequent oxidation was characterized by x-ray photoelectron spectroscopy. The main species found at the surface were metallic tin and tin (II) oxide (SnO). The detailed characterization of stannane should help correctly identify it in EUV lithographic processes and develop approaches in the future to mitigate its decomposition and redeposition on the collector mirrors or vacuum chamber walls.
Phase composition of polycrystalline HfNx (0.45 ≤ x ≤ 1.60) and effects of low-energy ion irradiation on microstructure, texture, and physical properties
Authors: Seo Hwan-Seok , Lee Taeyoon , Kim Hyungjun , Petrov Ivan , Greene J. E.
Published: October 2023

We have investigated the phase composition of HfNx as a function of x and the effects of low-energy ion irradiation on the microstructure and physical properties of polycrystalline layers grown on SiO2 at 350 °C by ultrahigh vacuum reactive dc magnetron sputtering of Hf in mixed N2/Ar discharges. X-ray diffraction and Rutherford backscattering spectrometry results show that the phases obtained in polycrystalline HfNx layers with increasing x are hcp-structure α-Hf:N (x ≲ 0.6); multiphase mixtures consisting of α-Hf, NaCl-structure δ-HfN, rhombohedral ɛ-Hf3N2, and/or ζ-Hf4N3 (0.6 ≲ x ≲ 0.9); δ-HfN single phase (0.9 ≲ x ≲ 1.3); and mixtures of δ-HfN and higher nitrides (x ≳ 1.3). HfNx layers with 0.9 ≲ x ≲ 1.2 grown under mild ion irradiation (incident ion energy Ei ≃ 7 eV and ion-to-Hf flux ratios Ji/JHf = 1−3) are underdense with mixed orientation, low in-plane stress, and rough surface morphology due to limited adatom mobilities resulting in kinetic roughening and atomic shadowing during film growth. However, the use of intense ion irradiation (Ei = 25 eV and Ji/JHf = 4−20) results in HfNx layers, which are fully dense with strongly 111-oriented texture, compressive in-plane stress, and smooth surfaces due to ion irradiation enhanced adatom surface mobilities. In addition, the latter films have lower resistivity and higher hardness. For stoichiometric δ-HfN layers, ρ decreases from 69.7 to 35.2 μΩ cm and H increases from 22.1 to 27.4 GPa, with increasing ion-irradiation intensity. However, for HfNx layers with 1.2 ≲ x ≲ 1.6, the correspondingly higher steady state atomic N surface coverages during deposition alter growth kinetics in favor of 001 texture with a fully dense structure and compressive in-plane stress.
TRIM55 promotes noncanonical NF-κB signaling and B cell–mediated immune responses by coordinating p100 ubiquitination and processing
Authors: Lin Liangbin , Yu Hui , Li Li , Yang Wenyong , Chen Xueying , Gong Yanqiu , Lei Qingqiang , Li Zhonghan , Zhou Zhaocai , Dai Lunzhi , Zhang Huiyuan , Hu Hongbo
Published: October 2023

The ubiquitination-dependent processing of NF-κB2 (also known as p100) is a critical step in the activation of the noncanonical NF-κB pathway. We investigated the molecular mechanisms regulating this process and showed that TRIM55 was the E3 ubiquitin ligase that mediated the ubiquitination of p100 and coordinated its processing. TRIM55 deficiency impaired noncanonical NF-κB activation and B cell function. Mice with a B cell–specific
Trim55
deficiency exhibited reduced germinal center formation and antibody production. These mice showed less severe symptoms than those of control mice upon the induction of a systemic lupus–like disease, suggesting B cell–intrinsic functions of TRIM55 in humoral immune responses and autoimmunity. Mechanistically, the ubiquitination of p100 mediated by TRIM55 was crucial for p100 processing by VCP, an ATPase that mediates ubiquitin-dependent protein degradation by the proteasome. Furthermore, we found that TRIM55 facilitated the interaction between TRIM21 and VCP as well as TRIM21-mediated K63-ubiquitination of VCP, both of which were indispensable for the formation of the VCP-UFD1-NPL4 complex and p100 processing. Together, our results reveal a mechanism by which TRIM55 fine-tunes p100 processing and regulates B cell–dependent immune responses in vivo, highlighting TRIM55 as a potential therapeutic target for lupus-like disease.
Membrane-proximal motifs encode differences in signaling strength between type I and III interferon receptors
Authors: Mesev Emily V. , Lin Aaron E. , Guare Emma G. , Heller Brigitte L. , Douam Florian , Adamson Britt , Toettcher Jared E. , Ploss Alexander
Published: October 2023

Interferons (IFNs) play crucial roles in antiviral defenses. Despite using the same Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) signaling cascade, type I and III IFN receptors differ in the magnitude and dynamics of their signaling in terms of STAT phosphorylation, gene transcription, and antiviral responses. These differences are not due to ligand-binding affinity and receptor abundance. Here, we investigated the ability of the intracellular domains (ICDs) of IFN receptors to differentiate between type I and III IFN signaling. We engineered synthetic, heterodimeric type I and III IFN receptors that were stably expressed at similar amounts in human cells and responded to a common ligand. We found that our synthetic type I IFN receptors stimulated STAT phosphorylation and gene expression to greater extents than did the corresponding type III IFN receptors. Furthermore, we identified short “box motifs” within ICDs that bind to JAK1 that were sufficient to encode differences between the type I and III IFN receptors. Together, our results indicate that specific regions within the ICDs of IFN receptor subunits encode different downstream signaling strengths that enable type I and III IFN receptors to produce distinct signaling outcomes.
Neural control of gut repair
Authors: VanHook Annalisa M.
Published: October 2023

Intestinal injury induces the outgrowth of adrenergic neurons that stimulate a proregenerative pathway.
Redundant and scattered genetic determinants for coumarin biodegradation in
Pseudomonas
sp. strain NyZ480
Authors: Gu Yichao , Li Tao , Zhou Ning-Yi
Published: October 2023

Coumarin (COU) is both a naturally derived phytotoxin and a synthetic pollutant which causes hepatotoxicity in susceptible humans. Microbes have potentials in COU biodegradation; however, its underlying genetic determinants remain unknown.
Pseudomonas
sp. strain NyZ480, a robust COU degrader, has been isolated and proven to grow on COU as its sole carbon source. In this study, five homologs of xenobiotic reductase A scattered throughout the chromosome of strain NyZ480 were identified, which catalyzed the conversion of COU to dihydrocoumarin (DHC)
in vitro
. Phylogenetic analysis indicated that these COU reductases belong to different subgroups of the old yellow enzyme family. Moreover, two hydrolases (CouB1 and CouB2) homologous to the 3,4-dihydrocoumarin hydrolase in the fluorene degradation were found to accelerate the generation of melilotic acid (MA) from DHC. CouC, a new member from the group A flavin monooxygenase, was heterologously expressed and purified, catalyzing the hydroxylation of MA to produce 3-(2,3-dihydroxyphenyl)propionate (DHPP). Gene deletion and complementation of
couC
indicated that
couC
played an essential role in the COU catabolism in strain NyZ480, considering that the genes involved in the downstream catabolism of DHPP have been characterized (Y. Xu and N. Y. Zhou, Appl Environ Microbiol 86:e02385-19, 2020) and homologous catabolic cluster exists in strain NyZ480. This study elucidated the genetic determinants for complete degradation of COU by
Pseudomonas
sp. strain NyZ480.

IMPORTANCE

Coumarin (COU) is a phytochemical widely distributed in the plant kingdom and also artificially produced as an ingredient for personal care products. Hence, the environmental occurrence of COU has been reported in different places. Toxicologically, COU was proven hepatotoxic to individuals with mutations in the CYP2A6 gene and listed as a group 3 carcinogen by the International Agency for Research on Cancer and thus has raised increasing concerns. Until now, different physicochemical methods have been developed for the removal of COU, whereas their practical applications were hampered due to high cost and the risk of secondary contamination. In this study, genetic evidence and biochemical characterization of the COU degradation by
Pseudomonas
sp. strain NyZ480 are presented. With the gene and strain resources provided here, better managements of the hazards that humans face from COU could be achieved, and the possible microbiota-plant interaction mediated by the COU-utilizing rhizobacteria could also be investigated.
Porcine deltacoronavirus accessory protein NS6 harnesses VPS35-mediated retrograde trafficking to facilitate efficient viral infection
Authors: Fang Puxian , Zhang Huichang , Cheng Ting , Ding Tong , Xia SiJin , Xiao Wenwen , Li Zhuang , Xiao Shaobo , Fang Liurong
Published: October 2023

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus with the potential to infect humans. Accessory protein NS6, encoded by PDCoV, is a key factor required for optimal viral replication. However, the precise mechanism(s) used by PDCoV NS6 to function remains largely unclear. The retromer is an evolutionarily highly conserved protein complex that plays an important role in normal cellular biological processes and viral replication. In this study, we identified VPS35, a subunit of the retromer complex, as a potential NS6-interacting protein via immunoprecipitation and mass spectrometry analysis in the context of PDCoV infection. Furthermore, we confirmed the interaction of VPS35 with NS6 by co-immunoprecipitation in both an overexpression system and PDCoV-infected cells. Knockdown of VPS35 by specific small interfering RNA inhibited wild-type PDCoV infection but did not suppress the infection of recombinant PDCoVs with an NS6 deletion, demonstrating that the VPS35-NS6 interaction is required for the proviral function of VPS35. We further demonstrated that the lysosomal pathway and Golgi trafficking are required for efficient PDCoV infection and that depletion of VPS35 prevented retrograde transport of PDCoV NS6 from endosomes to the Golgi, resulting in its lysosomal degradation and the inhibition of viral production. Taken together, our findings are the first to identify VPS35 as a critical host factor required for PDCoV to establish productive infection, revealing a novel evasion mechanism of PDCoV.

IMPORTANCE

Retrograde transport has been reported to be closely associated with normal cellular biological processes and viral replication. As an emerging enteropathogenic coronavirus with zoonotic potential, porcine deltacoronavirus (PDCoV) has attracted considerable attention. However, whether retrograde transport is associated with PDCoV infection remains unclear. Our present study demonstrates that retromer protein VPS35 acts as a critical host factor that is required for PDCoV infection. Mechanically, VPS35 interacts with PDCoV NS6, mediating the retrograde transport of NS6 from endosomes to the Golgi and preventing it from lysosomal degradation. Recombinant PDCoVs with an NS6 deletion display resistance to VPS35 deficiency. Our work reveals a novel evasion mechanism of PDCoV that involves the manipulation of the retrograde transport pathway by VPS35, providing new insight into the mechanism of PDCoV infection.
The Trans-Baikal Parametric Borehole: First Evidence of the Deep Structure of the Borshchovochnyi Metamorphic Core Complex
Authors: Petrov O. V. , Kashubin S. N. , Gladkochub D. P. , Donskaya T. V. , Morozov A. F. , Kudryavtsev I. V. , Milshtein E. D. , Gorbachev V. I. , Narkisova V. V.
Published: October 2023

The Trans-Baikal parametric borehole drilled out a metamorphic core complex in the reference geological and geophysical profile within the Central Asian fold belt, south of the Mongol–Okhotsk suture zone. In the section of the borehole drilled to a depth of 2600 m, a set of geophysical, geological, and laboratory–analytical studies made it possible to identify three main structural elements of metamorphic core complexes: the upper plate, detachment, and the lower plate. The upper plate (slightly metamorphosed rocks) is represented by a serpentinite mélange separated from the underlying rocks of the lower plate by a zone of chlorite breccias (detachment). The lower plate as a part of the crystalline basement complex comprises rocks of granite–schist and granite–plagiogneiss subcomplexes. The granite–schist subcomplex is composed of mafic and intermediate schist with amphibolites and quartzites. Biotite granite is widespread in the section as layered veins with synkinematic signs. According to the preliminary estimates, the age of biotite granite is about 130 Ma. Schist is characterized by a mylonite structure at intervals of interbedding with biotite granite veins. In accordance with the geophysical survey data on the borehole and the petrophysical characteristics of cored rocks, the mylonite zone is the provenance of a series of inclined reflectors in the seismic RSS–CDP section, which can be traced to a depth of at least 10 km. The granite–plagiogneiss subcomplex is represented by plagiogneiss, leucogranite, and gneissic granite. In the Trans-Baikal parametric borehole, a detailed section of the Borshchovochnyi metamorphic core complex, fully characterized by core samples, was obtained. It should be considered as a reference for studying these structures. The investigation of this section will make it possible later to answer many questions about the formation and evolution of the Central Asian fold belt.
Large unruptured tubal pregnancy mimicking abdominal pregnancy
Authors: Traisrisilp Kuntharee , Sethasathien Sethawat
Published: October 2023

Ectopic pregnancy accounts for 1–2% of all pregnancies. Ultrasound is the primary diagnostic tool to locate pregnancy outside the uterus and identify complications such as haemoperitoneum. In inconclusive cases, MRI is an adjunctive imaging modality offering more precise tissue differentiation and helpful to location identification. Presented is an unusual case of tubal pregnancy. The patient in her 30s, who was 14 weeks into her first pregnancy, had a suspected abdominal pregnancy. Both transabdominal ultrasound and an MRI indicated an ectopic pregnancy, likely originating from the right fallopian tube. A successful laparotomy and right salpingectomy were performed without complications. Rarely, as in this case, large unruptured and advanced tubal pregnancies can mimic an abdominal pregnancy, underscoring the importance of disease recognition and familiarity with uncommon image findings. An accurate diagnosis of pregnancy location is crucial for effective case management.
Successful implementation of virtual care to overcome the challenges of managing gestational diabetes during the COVID-19 pandemic: a quality improvement project
Authors: Khurana Reena , Tong Jeffery , Burrows Jason , Stafford Sara , Singh Avash , Jain Akshay , Severin Naomi , Kissock Jagoda , Pisani Serena , Eng Janice
Published: October 2023

At the start of the COVID-19 pandemic, the Jim Pattison Diabetes and Pregnancy (JP DAP) clinic quickly switched from in-person to virtual care for patients with gestational diabetes (GDM) to reduce the risk of viral transmission. Poor glycaemic control in pregnancies increases the risk of maternal–fetal complications and thus women with GDM require education, frequent follow-up and treatment to reduce these risks. Delays in care could potentially result in increased maternal–fetal complications. We conducted a prospective, single-centre quality improvement (QI) study of women with GDM who attended the JP DAP clinic and delivered between 1 September 2019 and 31 March 2021. 2123 singleton pregnancies between 1 September 2019 and 31 March 2021 with GDM were analysed for this study. The time of referral to see the endocrinologist was lower than baseline in the first wave but rose significantly in the second wave. No-shows for appointments increased in the first wave but were lower than baseline after the implementation of time slots. There was no special cause variation for maternal–fetal complications pre pandemic, first wave or during the second wave. A patient satisfaction survey reported that 93% of respondents strongly agreed or agreed with the statement ‘I was satisfied with the care provided to me over the telephone appointments’. The GDM education package, online educational videos in Hindi and English and the glucometer smartphone application helped to maintain the time of referral to first endocrinologist appointment in the first wave and therefore were considered an effective substitute for in-person education. Despite the delays in care seen in the second wave, there was no increase in maternal-fetal complications. Our clinic plans to continue using virtual tools for the foreseeable future.
RNA-binding protein NOVA1 promotes acute T-lymphocyte leukemia progression by stabilizing USP44 mRNA
Authors: Zhang Bin , Sun Ruowen , Gu Min , Jiang Zehui , Wang Ye , Zhang Linlin , Liu Xiaoyang , Chi Zuofei
Published: October 2023

Acute T-lymphocyte leukemia (T-ALL) is a malignant tumor disease. RNA-binding protein neotumor ventral antigen-1 (NOVA1) is highly expressed in bone marrow mononuclear cells of T-ALL patients, while the role of NOVA1 in T-ALL progression remains unknown. The gain- and loss-of-function studies for NOVA1 were performed in Jurkat and CCRF-CEM cells. NOVA1 overexpression promoted cell proliferation and cell cycle progression. NOVA1 knockdown increased the apoptosis rate of T-ALL cells. Ubiquitin-specific protease 44 (USP44), a nuclear protein with deubiquitinase catalytic activity, has been reported to play an oncogene role in human T-cell leukemia. USP44 expression was positively associated with NOVA1, and RNA immunoprecipitation assay verified the binding of NOVA1 to the mRNA of USP44. USP44 knockdown partially abolished NOVA1-induced cell proliferation and inhibition of apoptosis. The in vivo xenograft experiment was performed by injection of T-ALL tumor cells into the tail vein of NOD/SCID mice. The knockdown of NOVA1 had lower tumorigenicity. NOVA1 knockdown alleviated pathological changes in lung and spleen tissues, and increased the overall survival period and the weight of T-ALL mice. Thus, NOVA1 acts as an accelerator in T-ALL, and its function might be achieved by binding to and stabilizing USP44 mRNA.
Virulence-associated genes and antimicrobial resistance patterns in bacteria isolated from pregnant and nonpregnant women with urinary tract infections: the risk of neonatal sepsis
Authors: Angulo-Zamudio Uriel A. , Flores-Villaseñor Hector , Leon-Sicairos Nidia , Zazueta-Armenta Dina , Martínez-Villa Francisco A. , Tapia-Pastrana Gabriela , Angulo-Rocha Jorge , Murillo-Llanes Joel , Barajas-Olivas Mario Francisco , Canizalez-Roman Adrian
Published: October 2023

Uropathogenic Escherichia coli (UPEC) is classified as the major causative agent of urinary tract infections (UTIs). UPEC virulence and antibiotic resistance can lead to complications in pregnant women and (or) newborns. Therefore, the aim of this study was to determine the etiological agents of UTIs, as well as to identify genes related to virulence factors in bacteria isolated from pregnant and nonpregnant women. A total of 4506 urine samples were collected from pregnant and nonpregnant women. Urine cultures were performed, and PCR was used to identify phylogroups and virulence-related genes. Antibiotic resistance profiles were determined. The incidence of UTIs was 6.9% (pregnant women, n = 206 and nonpregnant women, n = 57), and UPEC belonging to phylogroup A was the most prevalent. The presence of genes related to capsular protection, adhesins, iron acquisition, and serum protection in UPEC was associated with not being pregnant, while the presence of genes related to adhesins was associated with pregnancy. Bacteria isolated from nonpregnant women were more resistant to antibiotics; 36.5% were multidrug resistant, and 34.9% were extensively drug resistant. Finally, UTIs were associated with neonatal sepsis risk, particularly in pregnant women who underwent cesarean section while having a UTI caused by E. coli. In conclusion, UPEC isolated from nonpregnant women carried more virulence factors than those isolated from pregnant women, and maternal UTIs were associated with neonatal sepsis risk.
Cosmological standard timers from unstable primordial relics
Authors: Cai Yi-Fu , Chen Chao , Ding Qianhang , Wang Yi
Published: October 2023

In this article we study a hypothetical possibility of tracking the evolution of our Universe by introducing a series of the so-called standard timers. Any unstable primordial relics generated in the very early Universe may serve as the standard timers, as they can evolve through the whole cosmological background until their end while their certain time-varying properties could be a possible timer by recording the amount of physical time elapsed since the very early moments. Accordingly, if one could observe these quantities at different redshifts, then a redshift-time relation of the cosmic history can be attained. To illustrate such a hypothetical possibility, we consider the primordial black hole bubbles as a concrete example and analyze the mass function inside a redshifted bubble by investigating the inverse problem of Hawking radiation. To complete the analyses theoretically, the mass distribution can serve as a calibration of the standard timers.