bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel
Authors: Li Jianlong , Sudiwala Sonia , Berthoin Lionel , Mohabbat Seayar , Gaylord Eliza A. , Sinada Hanan , Cruz Pacheco Noel , Chang Jiun Chiun , Jeon Oju , Lombaert Isabelle M.A. , May Alison J. , Alsberg Eben , Bahney Chelsea S. , Knox Sarah M.
Published: December 2022

Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here, using the adult murine system, we demonstrate that radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist cevimeline. We show that endogenous gland repair coincides with increased nerve activity and acinar cell division that is limited to the first week after radiation, with extensive acinar cell degeneration, dysfunction, and cholinergic denervation occurring thereafter. However, we found that mimicking cholinergic muscarinic input via sustained local delivery of a cevimeline–alginate hydrogel was sufficient to regenerate innervated acini and retain physiological saliva secretion at nonirradiated levels over the long term (>3 months). Thus, we reveal a previously unknown regenerative approach for restoring epithelial organ structure and function that has extensive implications for human patients.
Genomic imprinting-like monoallelic paternal expression determines sex of channel catfish
Authors: Wang Wenwen , Yang Yujia , Tan Suxu , Zhou Tao , Liu Yang , Tian Changxu , Bao Lisui , Xing De , Su Baofeng , Wang Jinhai , Zhang Yu , Liu Shikai , Shi Huitong , Gao Dongya , Dunham Rex , Liu Zhanjiang
Published: December 2022

The X and Y chromosomes of channel catfish have the same gene contents. Here, we report allelic hypermethylation of the X chromosome within the sex determination region (SDR). Accordingly, the X-borne
hydin-1
gene was silenced, whereas the Y-borne
hydin-1
gene was expressed, making monoallelic expression of
hydin-1
responsible for sex determination, much like genomic imprinting. Treatment with a methylation inhibitor, 5-aza-dC, erased the epigenetic marks within the SDR and caused sex reversal of genetic females into phenotypic males. After the treatment,
hydin-1
and six other genes related to cell cycle control and proliferative growth were up-regulated, while three genes related to female sex differentiation were down-regulated in genetic females, providing additional support for epigenetic sex determination in catfish. This mechanism of sex determination provides insights into the plasticity of genetic sex determination in lower vertebrates and its connection with temperature sex determination where DNA methylation is broadly involved.
GABA signaling triggered by TMC-1/Tmc delays neuronal aging by inhibiting the PKC pathway in
C. elegans
Authors: Wu Jieyu , Wang Liuyang , Ervin John F. , Wang Shih-Hsiu J. , Soderblom Erik , Ko Dennis , Yan Dong
Published: December 2022

Aging causes functional decline and degeneration of neurons and is a major risk factor of neurodegenerative diseases. To investigate the molecular mechanisms underlying neuronal aging, we developed a new pipeline for neuronal proteomic profiling in young and aged animals. While the overall translational machinery is down-regulated, certain proteins increase expressions upon aging. Among these aging–up-regulated proteins, the conserved channel protein TMC-1/Tmc has an anti-aging function in all neurons tested, and the neuroprotective function of TMC-1 occurs by regulating GABA signaling. Moreover, our results show that metabotropic GABA receptors and G protein GOA-1/Goα are required for the anti-neuronal aging functions of TMC-1 and GABA, and the activation of GABA receptors prevents neuronal aging by inhibiting the PLCβ-PKC pathway. Last, we show that the TMC-1–GABA–PKC signaling axis suppresses neuronal functional decline caused by a pathogenic form of human Tau protein. Together, our findings reveal the neuroprotective function of the TMC-1–GABA–PKC signaling axis in aging and disease conditions.
Nutrient uptake plasticity in phytoplankton sustains future ocean net primary production
Authors: Kwon Eun Young , Sreeush M. G. , Timmermann Axel , Karl David M. , Church Matthew J. , Lee Sun-Seon , Yamaguchi Ryohei
Published: December 2022

Annually, marine phytoplankton convert approximately 50 billion tons of dissolved inorganic carbon to particulate and dissolved organic carbon, a portion of which is exported to depth via the biological carbon pump. Despite its important roles in regulating atmospheric carbon dioxide via carbon sequestration and in sustaining marine ecosystems, model-projected future changes in marine net primary production are highly uncertain even in the sign of the change. Here, using an Earth system model, we show that frugal utilization of phosphorus by phytoplankton under phosphate-stressed conditions can overcompensate the previously projected 21st century declines due to ocean warming and enhanced stratification. Our results, which are supported by observations from the Hawaii Ocean Time-series program, suggest that nutrient uptake plasticity in the subtropical ocean plays a key role in sustaining phytoplankton productivity and carbon export production in a warmer world.
Ultra-broadband all-optical sampling of optical waveforms
Authors: Zimin Dmitry A. , Yakovlev Vladislav S. , Karpowicz Nicholas
Published: December 2022

Optical-field sampling techniques provide direct access to the electric field of visible and near-infrared light. The existing methods achieve the necessary bandwidth using highly nonlinear light-matter interaction that involves ionization of atoms or generation of charge carriers in solids. We demonstrate an alternative, all-optical approach for measuring electric fields of broadband laser pulses, which offers an advantage in terms of sensitivity and signal-to-noise ratio and extends the detection bandwidth of optical methods to the petahertz domain.
TAp63 determines the fate of oocytes against DNA damage
Authors: Luan Yi , Yu Seok-Yeong , Abazarikia Amirhossein , Dong Rosemary , Kim So-Youn
Published: December 2022

Cyclophosphamide and doxorubicin lead to premature ovarian insufficiency as an off-target effect. However, their oocyte death pathway has been debated. Here, we clarified the precise mechanism of ovarian depletion induced by cyclophosphamide and doxorubicin. Dormant oocytes instead of activated oocytes with high PI3K activity were more sensitive to cyclophosphamide. Checkpoint kinase 2 (CHK2) inhibitor rather than GNF2 protected oocytes from cyclophosphamide and doxorubicin, as cyclophosphamide up-regulated p-CHK2 and depleted primordial follicles in
Abl1
knockout mice. Contrary to previous reports, TAp63 is pivotal in cyclophosphamide and doxorubicin-induced oocyte death. Oocyte-specific
Trp63
knockout mice prevented primordial follicle loss and maintained reproductive function from cyclophosphamide and doxorubicin, indicated by undetectable levels of BAX and cPARP. Here, we demonstrated that TAp63 is fundamental in determining the signaling of oocyte death against DNA damage. This study establishes the role of TAp63 as a target molecule of adjuvant therapies to protect the ovarian reserve from different classes of chemotherapy.
Tandem metalloenzymes gate plant cell entry by pathogenic fungi
Authors: Bissaro Bastien , Kodama Sayo , Nishiuchi Takumi , Díaz-Rovira Anna Maria , Hage Hayat , Ribeaucourt David , Haon Mireille , Grisel Sacha , Simaan A. Jalila , Beisson Fred , Forget Stephanie M. , Brumer Harry , Rosso Marie-Noëlle , Guallar Victor , O’Connell Richard , Lafond Mickaël , Kubo Yasuyuki , Berrin Jean-Guy
Published: December 2022

Global food security is endangered by fungal phytopathogens causing devastating crop production losses. Many of these pathogens use specialized appressoria cells to puncture plant cuticles. Here, we unveil a pair of alcohol oxidase–peroxidase enzymes to be essential for pathogenicity. Using
Colletotrichum orbiculare
, we show that the enzyme pair is cosecreted by the fungus early during plant penetration and that single and double mutants have impaired penetration ability. Molecular modeling, biochemical, and biophysical approaches revealed a fine-tuned interplay between these metalloenzymes, which oxidize plant cuticular long-chain alcohols into aldehydes. We show that the enzyme pair is involved in transcriptional regulation of genes necessary for host penetration. The identification of these infection-specific metalloenzymes opens new avenues on the role of wax-derived compounds and the design of oxidase-specific inhibitors for crop protection.
A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity
Authors: Roehlen Natascha , Saviano Antonio , El Saghire Houssein , Crouchet Emilie , Nehme Zeina , Del Zompo Fabio , Jühling Frank , Oudot Marine A. , Durand Sarah C. , Duong François H. T. , Cherradi Sara , Gonzalez Motos Victor , Almeida Nuno , Ponsolles Clara , Heydmann Laura , Ostyn Tessa , Lallement Antonin , Pessaux Patrick , Felli Emanuele , Cavalli Andrea , Sgrignani Jacopo , Thumann Christine , Koutsopoulos Olga , Fuchs Bryan C. , Hoshida Yujin , Hofmann Maike , Vyberg Mogens , Viuff Birgitte Martine , Galsgaard Elisabeth D. , Elson Greg , Toso Alberto , Meyer Markus , Iacone Roberto , Schweighoffer Tamas , Teixeira Geoffrey , Moll Solange , De Vito Claudio , Roskams Tania , Davidson Irwin , Heide Danijela , Heikenwälder Mathias , Zeisel Mirjam B. , Lupberger Joachim , Mailly Laurent , Schuster Catherine , Baumert Thomas F.
Published: December 2022

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.
Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling
Authors: Rückert Tamina , Andrieux Geoffroy , Boerries Melanie , Hanke-Müller Kathrin , Woessner Nadine M. , Doetsch Stephanie , Schell Christoph , Aumann Konrad , Kolter Julia , Schmitt-Graeff Annette , Schiff Marcel , Braun Lukas M. , Haring Eileen , Kissel Sandra , Siranosian Benjamin A. , Bhatt Ami S. , Nordkild Peter , Wehkamp Jan , Jensen Benjamin A. H. , Minguet Susana , Duyster Justus , Zeiser Robert , Köhler Natalie
Published: December 2022

Acute graft-versus-host disease (aGVHD), which is driven by allogeneic T cells, has a high mortality rate and limited treatment options. Human β-defensin 2 (hBD-2) is an endogenous epithelial cell–derived host-defense peptide. In addition to its antimicrobial effects, hBD-2 has immunomodulatory functions thought to be mediated by CCR2 and CCR6 in myeloid cells. In this study, we analyzed the effect of recombinant hBD-2 on aGVHD development. We found that intestinal β-defensin expression was inadequately induced in response to inflammation in two independent cohorts of patients with aGVHD and in a murine aGVHD model. Treatment of mice with hBD-2 reduced GVHD severity and mortality and modulated the intestinal microbiota composition, resulting in reduced neutrophil infiltration in the ileum. Furthermore, hBD-2 treatment decreased proliferation and proinflammatory cytokine production by allogeneic T cells in vivo while preserving the beneficial graft-versus-leukemia effect. Using transcriptome and kinome profiling, we found that hBD-2 directly dampened primary murine and human allogeneic T cell proliferation, activation, and metabolism in a CCR2- and CCR6-independent manner by reducing proximal T cell receptor signaling. Furthermore, hBD-2 treatment diminished alloreactive T cell infiltration and the expression of genes involved in T cell receptor signaling in the ilea of mice with aGVHD. Together, we found that both human and murine aGVHD were characterized by a lack of intestinal β-defensin induction and that recombinant hBD-2 represents a potential therapeutic strategy to counterbalance endogenous hBD-2 deficiency.
Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium
Authors: Finlay John B. , Brann David H. , Abi Hachem Ralph , Jang David W. , Oliva Allison D. , Ko Tiffany , Gupta Rupali , Wellford Sebastian A. , Moseman E. Ashley , Jang Sophie S. , Yan Carol H. , Matsunami Hiroaki , Tsukahara Tatsuya , Datta Sandeep Robert , Goldstein Bradley J.
Published: December 2022

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207
+
dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss.
Pmorf0222
, a Virulence Factor in Pasteurella multocida, Activates Nuclear Factor Kappa B and Mitogen-Activated Protein Kinase via Toll-Like Receptor 1/2
Authors: Xu Tenglin , Zheng Yating , Liu Benjin , Kou Mingxing , Jiang Qian , Liu Jiasen , Kang Hongtao , Yang Mingfa , Guo Dongchun , Qu Liandong
Published: December 2022

Pasteurella multocida
primarily causes hemorrhagic septicemia and pneumonia in poultry and livestock. Identification of the relevant virulence factors is therefore essential for understanding its pathogenicity.
Pmorf0222
, encoding the PM0222 protein, is located on a specific prophage island of the pathogenic strain C48-1 of
P. multocida
.
Antigenic Characterization of Human Monoclonal Antibodies for Therapeutic Use against H7N9 Avian Influenza Virus
Authors: Chang Pengxiang , Lukosaityte Deimante , Sealy Joshua E. , Rijal Pramila , Sadeyen Jean-Remy , Bhat Sushant , Crossley Sylvia , Daines Rebecca , Huang Kuan-Yin A. , Townsend Alain R. , Iqbal Munir
Published: December 2022

Avian influenza virus (AIV) H7N9 continues to circulate and evolve in birds, posing a credible threat to humans. Antiviral drugs have proven useful for the treatment of severe influenza infections in humans; however, concerns have been raised as antiviral-resistant mutants have emerged.
Neural-Cell-Intrinsic NF-κB Signaling Enhances Reovirus Virulence
Authors: Taylor Gwen M. , Pruijssers Andrea J. , Brigleb Pamela H. , Fiske Kay L. , Shang Pengcheng , Urbanek Kelly , Brown Judy J. , Rajasundaram Dhivyaa , Dermody Terence S.
Published: December 2022

Viral encephalitis contributes to illness and death in children and adults worldwide and has limited treatment options. Identifying common host factors upregulated by neurotropic viruses can enhance an understanding of virus-induced neuropathogenesis and aid in development of therapeutics.
My Uncle Charlie
Authors: Desrosiers Ronald C.
Published: December 2022

This is a story about my uncle Charlie, who contracted paralytic polio at an early age, and the remembrances on my career trajectory as a virologist that will never be forgotten.
Watson-Crick Base-Pairing Requirements for ssDNA Recognition and Processing in Replication-Initiating HUH Endonucleases
Authors: Smiley Adam T. , Tompkins Kassidy J. , Pawlak Matthew R. , Krueger August J. , Evans Robert L. , Shi Ke , Aihara Hideki , Gordon Wendy R.
Published: December 2022

Circular Rep-encoding single-stranded DNA (CRESS-DNA) viruses are a ubiquitous group of viruses that infect organisms across all domains of life. These viruses negatively impact both agriculture and human health.
Diversity and Prevalence of Clostridium innocuum in the Human Gut Microbiota
Authors: Bhattacharjee Disha , Flores Clara , Woelfel-Monsivais Christine , Seekatz Anna M.
Published: December 2022

Clostridia
are a group of medically important anaerobes as both commensals and pathogens. Recently, a new class of
Erysipelotrichia
containing a number of reassigned clostridial species has emerged, including
Clostridium innocuum
.
Differential Virulence of Aggregatibacter actinomycetemcomitans Serotypes Explained by Exoproteome Heterogeneity
Authors: Fu Yanyan , Maaβ Sandra , Cavallo Francis M. , de Jong Anne , Raangs Erwin , Westra Johanna , Buist Girbe , Becher Dörte , van Dijl Jan Maarten
Published: December 2022

Periodontitis is an inflammatory disease that causes progressive destruction of alveolar bone and supporting tissues around the teeth, ultimately resulting in tooth loss. The bacterium
Aggregatibacter actinomycetemcomitans
(
Aa
) is a prevalent causative agent of periodontitis, but this oral pathogen is also associated with serious extraoral diseases like rheumatoid arthritis and Alzheimer’s disease.
N
-Myristoyltransferase, a Potential Antifungal Candidate Drug-Target for Aspergillus flavus
Authors: Wang Yu , Lin Ranxun , Liu Mengxin , Wang Sen , Chen Hongyu , Zeng Wanlin , Nie Xinyi , Wang Shihua
Published: December 2022

As an opportunistic pathogen,
A. flavus
causes crop loss due to fungal growth and mycotoxin contamination. Investigating the role of virulence factors during infection and searching for novel drug targets have been popular scientific topics in the field of fungal control. Nmt has become a potential target in some organisms.
Successful airway management of traumatic complete tracheal transection
Authors: Gupta Babita , Bagaria Dinesh , Kumar Atin , Perveen Fahina
Published: December 2022

A man in his 20s sustained complete tracheal transection after being injured by a sandbag pile falling on his neck. An oral endotracheal tube (ETT) was inserted by rapid sequence induction in view of respiratory distress. CT revealed that the ETT did not traverse the distal tracheal segment; however, there were rebreathing bag movements, and normal capnograph and oxygen saturation, which were misleading clinical findings. We describe the successful airway management in this challenging case.
Life-threatening mandibular angle gigantic osteoma presenting with severe dyspnoea
Authors: Gabriele Guido , Chisci Glauco , Cascino Flavia , Gennaro Paolo
Published: December 2022

Osteoma is a benign osteogenic tumour. Solitary osteoma of the jaws usually involves the mandible and commonly remains asymptomatic. Purpose of this article is to report a case of life-threatening gigantic mandibular osteoma in an edentulous woman in her 70s developed in the lingual side of the mandibular angle presenting at emergency department with dyspnoea and discuss the correct management of the patient and the surgical approach for space occupying mass in the pharapharyngeal space.
Rare case of coexisting ovarian Brenner tumour and ovarian stromal hyperplasia presenting with persistent endometrial hyperplasia following treatment with levonorgestrel-intrauterine system
Authors: Mok Zhun Wei , Chin Janice Pui See
Published: December 2022

Endometrial hyperplasia (EH) is a precursor of endometrial cancer. It arises in an environment of unopposed oestrogen. Treatment is based on a combination of weight management, diet and exercise, and the use of progestogens either via a levonogestrel-intrauterine system (LNG-IUS) or orally. The LNG-IUS is the first-line recommendation for EH without atypia. Recurrences are rare, and any recurrences despite prolonged treatment and control of risk factors necessitate a thorough consideration of other oestrogenic sources. This case report presents a rare case of a coexisting ovarian Brenner tumour and ovarian stromal hyperplasia in a menopausal patient in her 50s with recurrent EH despite earlier regression. The above histology may have provided the additional oestrogenic influence. This patient subsequently underwent a definitive hysterectomy and bilateral salpingo-oophorectomy (BSO). It is important to maintain a high index of suspicion for potential oestrogenic influences in cases of refractory EH that are not identifiable on imaging. BSO should be considered at the time of hysterectomy in such cases of unidentified oestrogenic foci.
Quasi-experimental evaluation of a financial incentive for first-dose COVID-19 vaccination among adults aged ≥60 years in South Africa
Authors: Chetty-Makkan Candice Maylene , Thirumurthy Harsha , Bair Elizabeth F , Bokolo Simamkele , Day Candy , Wapenaar Korstiaan , Werner Jesse , Long Lawrence , Maughan-Brown Brendan , Miot Jacqui , Pascoe Sophie J S , Buttenheim Alison M
Published: December 2022

Introduction

COVID-19 vaccination coverage in South Africa (RSA) remains low despite increased access to vaccines. On 1 November 2021, RSA introduced the Vooma Voucher programme which provided a small guaranteed financial incentive, a Vooma Voucher redeemable at grocery stores, for COVID-19 vaccination among older adults, a population most vulnerable to serious illness, hospitalisation and death. However, the association of financial incentives with vaccination coverage remains unclear.

Methods

We evaluated the association of the conditional economic incentive programme with first-dose vaccination rates among adults (aged ≥60 years) through a quasi-experimental cohort study. The Vooma Voucher programme was a nationwide vaccination incentive programme implemented for adults aged ≥60 years from 1 November 2021 to 28 February 2022. We ran ITS models to evaluate the Vooma Voucher programme at national and provincial levels. We used data between 1 October 2021 and 27 November 2021 in models estimated at the daily level. Individuals who received their first vaccine dose received a text message to access a ZAR100 ($~7) voucher that was redeemable at grocery stores.

Results

The Vooma Voucher programme was associated with a 7.15%–12.01% increase in daily first-dose vaccinations in November 2021 compared with late October 2021. Overall, the incentive accounted for 6476–10 874 additional first vaccine doses from 1 November to 27 November 2021, or 8.31%–13.95% of all doses administered to those aged ≥60 years during that period. This result is robust to the inclusion of controls for the number of active vaccine delivery sites and for the nationwide Vooma vaccination weekend initiative (12 November to 14 November), both of which also increased vaccinations through expanded access to vaccines and demand creation activities.

Conclusions

Financial incentives for COVID-19 vaccination led to a modest increase in first-dose vaccinations among older adults in RSA. Financial incentives and expanded access to vaccines may result in higher vaccination coverage.

Trial registration number (SANCTR)

DOH-27-012022-9116.
Must countries shoulder the burden of mesothelioma to ban asbestos? A global assessment
Authors: Chimed-Ochir Odgerel , Rath Emma M , Kubo Tatsuhiko , Yumiya Yui , Lin Ro-Ting , Furuya Sugio , Brislane Kim , Klebe Sonja , Nowak Anna K , Kang Seong-Kyu , Takahashi Ken
Published: December 2022

Introduction

Mesothelioma is a key asbestos-related disease (ARD) but can be difficult to diagnose. Countries presumably ban asbestos to reduce future ARD burdens, but it is unknown if countries ban asbestos as a consequence of ARD burdens. We assessed if and to what extent mesothelioma burden has an impact on a country banning asbestos and obtaining targets for preventative strategies.

Methods

We analysed the status of asbestos ban and mesothelioma burden during 1990–2019 in 198 countries. We assessed mesothelioma burden by age-adjusted mortality rates (MRs) estimated by the Global Burden of Disease Study (GBD) and mesothelioma identification by the WHO mortality database. For GBD-estimated mesothelioma MR, the pre-ban period in the asbestos-banned countries was compared with the 1990–2019 period in the not-banned countries. For mesothelioma identification, the 1990–2019 period was applied to both banned and not-banned countries.

Results

The association of mesothelioma MR with ban status increased as the ban year approached. Logistic regression analyses showed that the odds of a country banning asbestos increased 14.1-fold (95% CI 5.3 to 37.9) for mesothelioma identification combined with a 26% (12% to 42%) increase per unit increase of mesothelioma MR (one death per million per year) during the period 1–5 year before ban (model p<0.0001).

Conclusion

Mesothelioma burden had an impact on, and together with its identification, explained the banning of asbestos in many countries. Asbestos-banned countries likely learnt lessons from their historical policies of using asbestos because mesothelioma burden and identification follow historical asbestos use. Prevention targets for ARD elimination should combine asbestos ban with mesothelioma identification.
Pulmonary hypertension with a precapillary component in heart failure with preserved ejection fraction
Authors: Sera Fusako , Ohtani Tomohito , Tamaki Shunsuke , Yano Masamichi , Hayashi Takaharu , Nakagawa Akito , Nakagawa Yusuke , Nakatani Daisaku , Yamada Takahisa , Yasumura Yoshio , Hikoso Shungo , Yamauchi-Takihara Keiko , Sakata Yasushi
Published: December 2022

Objectives

Heart failure with preserved ejection fraction (HFpEF) is often complicated by pulmonary hypertension (PH), which is mainly characterised by postcapillary PH and occasionally accompanied by a precapillary component of PH. Haemodynamic changes in worsening heart failure (HF) can modify the characteristics of PH. However, the clinical features of PH after HF treatment in HFpEF remain unclear. We investigated the prevalence and clinical significance of the precapillary component of PH after HF treatment in HFpEF, using data from the Prospective Multicentre Observational Study of Patients with HFpEF (PURSUIT-HFpEF).

Methods

From the PURSUIT-HFpEF registry, 219 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into four groups according to the 2015 and 2018 PH definitions: non-PH, isolated postcapillary pulmonary hypertension (Ipc-PH), precapillary PH and combined postcapillary and precapillary pulmonary hypertension (Cpc-PH). The latter two were combined as PH with the precapillary component.

Results

Using the 2015 definition, we found that the prevalence of PH after HF treatment was 27% (Ipc-PH: 20%, precapillary PH: 3%, Cpc-PH: 4%). Applying the 2018 definition resulted in a doubled frequency of precapillary PH (6%). PH with a precapillary component according to the 2015 definition was associated with poor clinical outcomes and characterised by small left ventricular dimension and high early diastolic mitral inflow velocity/early diastolic mitral annular tissue velocity.

Conclusion

After initial HF treatment, 7% of hospitalised patients with HFpEF had precapillary component of PH according to the 2015 definition. Echocardiographic parameters of the left ventricle can contribute to the risk stratification of patients with HFpEF with a precapillary component of PH.
Variability in perceived burden and health trajectories among older caregivers: a population-based study in Sweden
Authors: Kirvalidze Mariam , Beridze Giorgi , Wimo Anders , Morin Lucas , Calderón-Larrañaga Amaia
Published: December 2022

Background

The negative effects of informal caregiving are determined by the characteristics of the caregiver-care receiver dyad and the context of care. In this study, we aimed to identify which subgroups of older informal caregivers (1) experience the greatest subjective burden and (2) incur a faster decline in objective health status.

Methods

From a total of 3363 older participants in the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), we identified 629 informal caregivers (19.2%, mean age 69.9 years). Limitations to life and perceived burden were self-reported, and objective health status was quantified using the comprehensive clinical and functional Health Assessment Tool (HAT) score (range: 0–10). Ordered logistic regressions and linear mixed models were used to estimate the associations between caregiving-related exposures and subjective outcomes (cross-sectionally) and objective health trajectories (over 12 years), respectively.

Results

Having a dual role (providing and receiving care simultaneously), caring for a spouse, living in the same household as the care receiver and spending more hours on caregiving were associated with more limitations and burden. In addition, having a dual role (β=−0.12, 95% CI −0.23 to −0.02) and caring for a spouse (β=−0.08, 95% CI −0.14 to −0.02) were associated with a faster HAT score decline. Being female and having a poor social network were associated with an exacerbation of the health decline.

Conclusions

Both the heterogeneity among caregivers and the related contextual factors should be accounted for by policymakers as well as in future research investigating the health impact of informal caregiving.
Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer
Authors: Qiao Meng , Zhou Fei , Liu Xinyu , Jiang Tao , Wang Haowei , Jia Yijun , Li Xuefei , Zhao Chao , Cheng Lei , Chen Xiaoxia , Ren Shengxiang , Liu Hongcheng , Zhou Caicun
Published: December 2022

Background

Anti-PD-1(L1) therapies are less efficacious in patients withEGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.

Methods

The characteristics of T cells inEGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples.In vitrorestimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenicEGFRL858Rmouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanismin vivo.

Results

EGFR-mutated tumors showed a lack of CD8+T cell infiltration and impaired CD8+T cell cytotoxic function. The incompetent CD8+T cells inEGFR-mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8+T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited inEGFR-mutated tumors. IL-10 induced hallmarks of CD8+T cells immunity in CD39-dependent manner. Using autochthonousEGFRL858R-driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects inEGFR-mutated lung tumors.

Conclusions

Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8+T cells, fewer phenotypically cytotoxic and exhausted CD39+CD8+T cells inEGFR-mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment inEGFR-mutated tumors.
Activated B cells suppress T-cell function through metabolic competition
Authors: Imahashi Nobuhiko , Basar Rafet , Huang Yuefan , Wang Fang , Baran Natalia , Banerjee Pinaki Prosad , Lu Junjun , Nunez Cortes Ana Karen , Uprety Nadima , Ensley Emily , Muniz-Feliciano Luis , Laskowski Tamara J , Moyes Judy S , Daher May , Mendt Mayela , Kerbauy Lucila N , Shanley Mayra , Li Li , Lim Francesca Lorraine Wei Inng , Shaim Hila , Li Ye , Konopleva Marina , Green Michael , Wargo Jennifer , Shpall Elizabeth J , Chen Ken , Rezvani Katayoun
Published: December 2022

Background

B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood.

Methods

We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing.

Results

Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell–cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy.

Conclusions

We have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.
Tumor-associated neutrophils and macrophages exacerbate antidrug IgG-mediated anaphylactic reaction against an immune checkpoint inhibitor
Authors: Arai Takahiro , Kokubo Tomomi , Tang Ruiheng , Abo Hirohito , Terui Ayu , Hirakawa Jotaro , Akita Hidetaka , Kawashima Hiroto , Hisaka Akihiro , Hatakeyama Hiroto
Published: December 2022

Background

With the increased use of immune checkpoint inhibitors (ICIs), side effects and toxicity are a great concern. Anaphylaxis has been identified as a potential adverse event induced by ICIs. Anaphylaxis is a life-threatening medical emergency. However, the mechanisms and factors that can potentially influence the incidence and severity of anaphylaxis in patients with cancer remain unclear.

Methods

Healthy, murine colon 26, CT26, breast 4T1, EMT6, and renal RENCA tumor-bearing mice were treated with an anti-PD-L1 antibody (clone 10F.9G2). Symptoms of anaphylaxis were evaluated along with body temperature and mortality. The amounts of antidrug antibody and platelet-activating factor (PAF) in the blood were quantified via ELISA and liquid chromatography-mass spectrometry (LC-MS/MS). Immune cells were analyzed and isolated using a flow cytometer and magnetic-activated cell sorting, respectively.

Results

Repeated administration of the anti-PD-L1 antibody 10F.9G2 to tumor-bearing mice caused fatal anaphylaxis, depending on the type of tumor model. After administration, antidrug immunoglobulin G (IgG), but not IgE antibodies, were produced, and PAF was released as a chemical mediator during anaphylaxis, indicating that anaphylaxis was caused by an IgG-dependent pathway. Anaphylaxis induced by 10F.9G2 was treated with a PAF receptor antagonist. We identified that neutrophils and macrophages were PAF-producing effector cells during anaphylaxis, and the tumor-bearing models with increased numbers of neutrophils and macrophages showed lethal anaphylaxis after treatment with 10F.9G2. Depletion of both neutrophils and macrophages using clodronate liposomes prevented anaphylaxis in tumor-bearing mice.

Conclusions

Thus, increased numbers of neutrophils and macrophages associated with cancer progression may be risk factors for anaphylaxis. These findings may provide useful insights into the mechanism of anaphylaxis following the administration of immune checkpoint inhibitors in human subjects.
Expanded terminal sedation in end-of-life care
Authors: Gilbertson Laura , Savulescu Julian , Oakley Justin , Wilkinson Dominic
Published: December 2022

Despite advances in palliative care, some patients still suffer significantly at the end of life. Terminal Sedation (TS) refers to the use of sedatives in dying patients until the point of death. The following limits are commonly applied: (1) symptoms should be refractory, (2) sedatives should be administered proportionally to symptoms and (3) the patient should be imminently dying. The term ‘Expanded TS’ (ETS) can be used to describe the use of sedation at the end of life outside one or more of these limits.

In this paper, we explore and defend ETS, focusing on jurisdictions where assisted dying is lawful. We argue that ETS is morally permissible: (1) in cases of non-refractory suffering where earlier treatments are likely to fail, (2) where gradual sedation is likely to be ineffective or where unconsciousness is a clinically desirable outcome, (3) where the patient meets all criteria for assisted dying or (4) where the patient has greater than 2 weeks to live, is suffering intolerably, and sedation is considered to be the next best treatment option for their suffering.

While remaining two distinct practices, there is scope for some convergence between the criteria for assisted dying and the criteria for ETS. Dying patients who are currently ineligible for TS, or even assisted dying, should not be left to suffer. ETS provides one means to bridge this gap.
Co-use of cannabis and prescription opioids in adults in the USA: a population-based, cross-sectional analysis of the NHANES from 2009 to 2018
Authors: Diep Calvin , Goel Akash , Wijeysundera Duminda N , Clarke Hance , Ladha Karim S
Published: December 2022

Introduction

Cannabis and cannabinoids continue to gain popularity as adjuncts or alternatives to opioids in pain management, with evolving evidence of effectiveness. The relationship between cannabis and opioid use has previously been investigated in smaller cohorts or ecological samples, but not yet in a nationally representative sample.

Methods

A cross-sectional analysis of adults in the USA was undertaken using National Health and Nutrition Examination Survey (NHANES) data from 2009 to 2018. The primary exposure was self-reported use of at least one opioid-containing prescription medication in the 30 days prior to survey administration. The outcome of interest was self-reported cannabis use in the same period. Multivariable logistic regression was used to adjust for sociodemographic and health-related covariates, and NHANES survey sample weights were included in modeling. Prescription opioid users were then subclassified as short-term users (<90 days) or chronic users (≥90 days) in secondary analysis.

Results

A total 10,928 survey respondents were included in analyses, representing 110 million adults in the USA aged 18–59. In this weighted cohort, 5.6%±0.4% reported a recent opioid prescription. Among prescription opioid users, 18.4%±3.1% reported recent cannabis use, not significantly different from 17.7%±0.7% among non-users (OR 1.05, 95% CI 0.81 to 1.36, p=0.714). After adjustment for covariates, opioid users were significantly less likely to have recently used cannabis (adjusted OR, aOR 0.70, 95% CI 0.51 to 0.97, p=0.032). When opioid users were subclassified by duration of prescription, there was no detectable difference in recent cannabis use between chronic opioid users and short-term opioid users (aOR 1.11, 95% CI 0.70 to 1.78, p=0.649).

Conclusion

Recent prescription opioid use was associated with decreased odds of cannabis use in this cross-sectional analysis of a nationally representative cohort. These findings suggest that use of cannabis or prescription opioids may not independently promote use of the other.
Bipolar radiofrequency ablation of the superomedial (SM), superolateral (SL) and inferomedial (IM) genicular nerves for chronic osteoarthritis knee pain: a randomized double-blind placebo-controlled trial with 12-month follow-up
Authors: Malaithong Wanwipha , Tontisirin Nuj , Seangrung Rattaphol , Wongsak Siwadol , Cohen Steven P
Published: December 2022

Background

Variability in anatomy in the knees supports the use of aggressive lesioning techniques such as bipolar-radiofrequency ablation (RFA) to treat knee osteoarthritis (KOA). There are no randomized controlled trials evaluating the efficacy of bipolar-RFA.

Methods

Sixty-four patients with KOA who experienced >50% pain relief from prognostic superomedial, superolateral and inferomedial genicular nerve blocks were randomly assigned to receive either genicular nerve local anesthetic and steroid injections with sham-RFA or local anesthetic and steroid plus bipolar-RFA. Participants and outcome adjudicators were blinded to allocation. The primary outcome was Visual Analog Scale pain score 12 months postprocedure. Secondary outcome measures included Western Ontario and McMaster Universities Arthritis (WOMAC) and Patient Global Improvement-Indexes (PGI-I).

Results

Both groups experienced significant reductions in pain, with no significant differences observed at 12 months (reduction from 5.7±1.9 to 3.2±2.6 in the RFA-group vs from 5.0±1.4 to 2.6±2.4 in the control-group (p=0.40)) or any other time point. No significant changes were observed between groups for WOMAC and PGI-I at the primary endpoint, with only the control group experiencing a significant improvement in function at 12-month follow-up (mean reduction from 91.2±38.2 to 67.1±51.9 in the RFA-group (p=0.06) vs from 95.8±41.1 to 60.6±42.8 in the control group (p=0.001); p=0.85 between groups).

Conclusion

Our failure to find efficacy for genicular nerve RFA, coupled with evidence showing that a plenitude of nerves supply the knee joint and preliminary studies indicating superiority of lesioning strategies targeting more than three nerves, suggest controlled trials using more aggressive lesioning strategies are warranted.

Trial registration number

TCTR20170130003.
Addendum: A dispersive analysis of $$\varvec{\eta '\rightarrow \pi ^+\pi ^-\gamma }$$ and $$\varvec{\eta '\rightarrow \ell ^+\ell ^-\gamma }$$
Authors: Holz Simon , Hanhart Christoph , Hoferichter Martin , Kubis Bastian
Published: December 2022

In this addendum to Ref. [1] we show that the mismatch between the $$\rho $$
ρ
–$$\omega $$
ω
mixing parameter $$\epsilon _{\rho \omega }$$

ϵ

ρ
ω

as extracted from $$\eta '\rightarrow \pi ^+\pi ^-\gamma $$

η
′

→

π
+

π
-

γ

and $$e^+e^-\rightarrow \pi ^+\pi ^-$$

e
+

e
-

→

π
+

π
-

can be resolved by including higher orders in the expansion in $$e^2$$

e
2

in the description of the $$\eta '\rightarrow \pi ^+\pi ^-\gamma $$

η
′

→

π
+

π
-

γ

decay. We repeat the analysis in this extended framework and update the numerical results accordingly.
Performance of the SABRE detector module in a purely passive shielding
Authors: Calaprice F. , Benziger J. B. , Copello S. , Dafinei I. , D’Angelo D. , D’Imperio G. , Di Carlo G. , Diemoz M. , Di Giacinto A. , Di Ludovico A. , Ianna M. , Ianni A. , Mariani A. , Milana S. , Orlandi D. , Pettinacci V. , Pietrofaccia L. , Rahatlou S. , Suerfu B. , Tomei C. , Vignoli C. , Zani A.
Published: December 2022

We present here a characterization of the low background NaI(Tl) crystal NaI-33 based on a period of almost one year of data taking (891 kg$$\times $$
×
days exposure) in a detector configuration with no use of organic scintillator veto. This remarkably radio-pure crystal already showed a low background in the SABRE Proof-of-Principle (PoP) detector, in the low energy region of interest (1–6 keV) for the search of dark matter interaction via the annual modulation signature. As the vetoable background components, such as $$^{40}$$

40

K, are here sub-dominant, we reassembled the PoP setup with a fully passive shielding. We upgraded the selection of events based on a Boosted Decision Tree algorithm that rejects most of the PMT-induced noise while retaining scintillation signals with > 90% efficiency in 1–6 keV. We find an average background of 1.39 ± 0.02 counts/day/kg/keV in the region of interest and a spectrum consistent with data previously acquired in the PoP setup, where the external veto background suppression was in place. Our background model indicates that the dominant background component is due to decays of $$^{210}$$

210

Pb, only partly residing in the crystal itself. The other location of $$^{210}$$

210

Pb is the reflector foil that wraps the crystal. We now proceed to design the experimental setup for the physics phase of the SABRE North detector, based on an array of similar crystals, using a low radioactivity PTFE reflector and further improving the passive shielding strategy, in compliance with the new safety and environmental requirements of Laboratori Nazionali del Gran Sasso.
Shadow, lensing, quasinormal modes, greybody bounds and neutrino propagation by dyonic ModMax black holes
Authors: Pantig Reggie C. , Mastrototaro Leonardo , Lambiase Gaetano , Övgün Ali
Published: December 2022

Motivated by recent work on the Modified Maxwell (ModMax) black holes [Phys Lett B 10.1016/j.physletb.2020.136011], which are invariant in duality rotations and conformal transformations founded in [Phys Rev D 10.1103/PhysRevD.102.121703], we probe its effects on the shadow cast, weak field gravitational lensing, and neutrino propagation in its vicinity. Using the EHT data for the shadow diameter of Sgr. A* and M87*, and LIGO/VIRGO experiments for the dyonic ModMax black hole perturbations, we find constraints for ModMax parameters such as $$Q_\text {m}$$

Q
m

and the screening factor $$\gamma $$
γ
. We also analyze how the shadow radius behaves as perceived by a static observer and one that is comoving with the cosmic expansion. The effect of the ModMax parameters is constant for a static observer, and we found That it varies when the observer is comoving with cosmic expansion. We also analyzed its effect on the weak deflection angle by exploiting the Gauss–Bonnet theorem and its application to Einstein ring formation. We also consider the finite distance effect and massive particle deflection. Our results indicate that the far approximation of massive particle gives the largest deflection angle and amplifies the effect of $$Q_\text {m}$$

Q
m

and $$\gamma $$
γ
. Then we also calculate the quasinormal modes and greybody bounds which encode unique characteristic features of the dyonic ModMax black hole. With the advent of improving space technology, we reported that it is possible to detect the deviation caused through the shadow cast, Einstein rings, quasinormal modes, and neutrino oscillations.