bluuebunny/crossref_metadata_2025 huggingface dataset:
NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation‐associated intestinal remodeling
Authors: Szczepanski Holly E. , Flannigan Kyle L. , Mainoli Barbara , Alston Laurie , Baruta Grace M. , Lee Joshua W. , Venu Vivek Krishna Pulakazhi , Shearer Jane , Dufour Antoine , Hirota Simon A.
Published: October 2022

Stricture formation is a common complication of Crohn's disease (CD), driven by enhanced deposition of extracellular matrix (ECM) and expansion of the intestinal smooth muscle layers. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor that exhibits anti‐proliferative effects in smooth muscle cells (SMCs). We hypothesized that NR4A1 regulates intestinal SMC proliferation and muscle thickening in the context of inflammation. Intestinal SMCs isolated from Nr4a1+/+ and Nr4a1−/− littermates were subjected to shotgun proteomic analysis, proliferation, and bioenergetic assays. Proliferation was assessed in the presence and absence of NR4A1 agonists, cytosporone‐B (Csn‐B) and 6‐mercaptopurine (6‐MP). In vivo, we compared colonic smooth muscle thickening in Nr4a1+/+ and Nr4a1−/− mice using the chronic dextran sulfate sodium (DSS) model of colitis. Second, SAMP1/YitFc mice (a model of spontaneous ileitis) were treated with Csn‐B and small intestinal smooth muscle thickening was assessed. SMCs isolated from Nr4a1−/− mice exhibited increased abundance of proteins related to cell proliferation, metabolism, and ECM production, whereas Nr4a1+/+ SMCs highly expressed proteins related to the regulation of the actin cytoskeleton and contractile processes. SMCs isolated from Nr4a1−/− mice exhibited increased proliferation and alterations in cellular metabolism, whereas activation of NR4A1 attenuated proliferation. In vivo, Nr4a1−/− mice exhibited increased colonic smooth muscle thickness following repeated cycles of DSS. Activating NR4A1 with Csn‐B, in the context of established inflammation, reduced ileal smooth muscle thickening in SAMP1/YitFc mice. Targeting NR4A1 may provide a novel approach to regulate intestinal SMC phenotype, limiting excessive proliferation that contributes to stricture development in CD.
Identification of key genes and active anti-inflammatory ingredients in Panax medicinal plants by climate-regulated callus culture combined with gene-component-efficacy gray correlation analysis
Authors: Ai Jiao , Ren Yongshen , Cheng Long , Liu Xinqiao , Li Yanqiu , Jiao Majing , Wang Yingzhou , Deng Xin , Chen Linlin
Published: October 2022

Objective:

We aimed to establish a novel strategy for identifying key genes and active anti-inflammatory ingredients in Panax medicinal plants.

Methods:

First, fresh roots of 2-year-old Panax plants, including P. ginseng C. A. Mey., P. quinquefolium L., P. notoginseng (Burk.) F. H. Chen, P. japonicus C.A.Mey., P. japonicus Mey. var. major (Burk.) C. Y. Wu et K. M. Feng, were selected as explants, and callus formation was induced under three experimental temperatures (17, 24, and 30°C). Second, high-performance liquid chromatography-mass spectrometry was used to analyze the saponin content of the callus. Nitric oxide reduction efficacy was used for “component-efficacy” gray correlation analysis to find the active anti-inflammatory ingredients. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to determine the inflammatory factors and verify the active ingredients’ anti-inflammatory effects. Finally, qRT-PCR was used to detect the expression of key genes in the callus, and “gene-component” gray correlation analysis was used to examine the relationships between the regulatory pathway of the genes and the components.

Results:

Among the three experimental temperatures (17, 24, and 30°C), the lowest temperature (17°C) is the most suitable for generating Panax callus. Lower-latitude native Panax notoginseng is more adaptable under high culture temperatures (24°C and 30°C) than other Panax plants. The ginsenoside contents of the callus of P. notoginseng and P. japonicus were the highest under similar climate conditions (17°C). Major anti-inflammatory components were G-Rh1, G-Rb1, G-Rg3, and G-Rh6/Floral-GKa. CYP76A47 contributed to the accumulation of anti-inflammatory components.

Conclusions:

This study provides a strategy for the gene-component-efficacy correlational study of multi-component, multi-functional, and multi-purpose plants of the same genus.

Graphical abstract:

http://links.lww.com/AHM/A38
Improved FMEA Methods for Proactive Health Care Risk Assessment of the Effectiveness and Efficiency of COVID-19 Remote Patient Telemonitoring
Authors: Parretti Chiara , Tartaglia Riccardo , La Regina Micaela , Venneri Francesco , Sbrana Giovanni , Mandò Massimo , Barach Paul
Published: October 2022

The COVID-19 pandemic exposed the need to more effectively harness and leverage digital tools and technology for remote patient monitoring (RPM). RPM gained great popularity given the need to provide effective, safe, efficient, and remote patient care. RPM is based on noninvasive digital technologies aimed at improving the safety and efficiency of health care delivery. We report on an RPM program in which 200 COVID-19 patients were followed remotely to evaluate the effectiveness in treating and monitoring patients in home settings. We analyzed the inherent risks using mixed methods, including failure mode and effect analysis, a prospective, team-based risk management methodology structured to identify high-risk process system failures before they occur in telemonitoring of remote patients. The RPM saved lives and improved decision-making during the pandemic and helped prevent the health system’s collapse. The failure mode and effect analysis-based assessment offers important insights and considerations for evaluating future RPM implementation and direction. RPM solutions are technically feasible, staff friendly, and can achieve high adherence rates. Rigorous and ongoing evaluation of devices and platforms is essential to clarifying their value and guiding national health and insurance health coverage decisions and adoption programs.
Expert Panel Consensus on Clinical Assertion Statements Describing Noninvasive Tools for Diagnosing Nonalcoholic Steatohepatitis
Authors: Jacobson Ira M. , Wong Vincent Wai-Sun , Castera Laurent , Anstee Quentin M. , Noureddin Mazen , Cusi Kenneth , Harrison Stephen A. , Bugianesi Elisabetta , Younossi Zobair M.
Published: October 2022

Goals and Background:

A panel of 9 experts in nonalcoholic steatohepatitis gathered to assess multiple components of the diagnostic process.

Materials and Methods:

The Clinical Assertion Statements covered screening of patients with type 2 diabetes for high-risk nonalcoholic fatty liver disease, which—if any—noninvasive tests could determine whether to delay or defer biopsy, whether primary care providers and endocrinologists should routinely calculate Fibrosis-4 (FIB-4) scores in patients with nonalcoholic fatty liver disease or those at risk for it, optimal noninvasive tests to stage fibrosis, the need to consider fibrosis in patients with normal transaminase levels, periodic monitoring for progressive fibrosis, whether patients should undergo biopsy before pharmacotherapy, and the clinical utility of genetic testing.

Results and Conclusions:

Evidence was presented to support or refute each Clinical Assertion Statement; the panel voted on the nature of the evidence, level of support, and level of agreement with each Statement. Panel level of agreement and rationale of each Clinical Assertion Statement are reported here.
Updated management for antibody-mediated rejection: opportunity to prolong kidney allograft survival
Authors: Townamchai Natavudh , Avihingsanon Yingyos
Published: October 2022

Purpose of review

Antibody-mediated rejection (ABMR) is an important barrier to achieve long-term kidney allograft survival. Human leukocyte antibody (HLA)-incompatibility and ABO-incompatibility are the two main mechanisms of ABMR. Nevertheless, the advances in managing ABMR have changed the paradigm for kidney transplantation. This review aimed to emphasize the HLA-incompatibility and ABO-incompatibility kidney transplant and update the management of ABMR.

Recent findings

HLA-incompatibility kidney transplantation is a strong risk factor for ABMR. Donor-specific antibody (DSA) is a surrogate biomarker that prevents long-term allograft survival. The standard treatment for ABMR has unfavorable results. New drugs that target the B cell are a promising approach to treat ABMR. In the past, ABO-incompatibility kidney donor was an absolute contraindication but now, it is widely accepted as an alternative organ resource. The advancement of ABO antibody removal and B-cell depletion therapy has been successfully developed. ABO isoagglutination remains the main biomarker for monitoring ABMR during the transplantation process. C4d staining without inflammation of the kidney allograft is the marker for the accommodation process.

With the shortage of organ donors, transplant experts have expanded the organ resources and learned how to overcome the immunological barriers by using novel biomarkers and developing new treatments that support long-term graft survival.
Redlining has led to increasing rates of nephrolithiasis in minoritized populations: a hypothesis
Authors: Scotland Kymora B. , Cushing Lara , Scales Charles D. , Eisenman David P. , Goldfarb David S.
Published: October 2022

Purpose of review

The persistent rise in kidney stone prevalence in recent decades has prompted much speculation as to the causes. There has been some discussion about the effect of heat on nephrolithiasis. Here, we review recent data and postulate that heat may play a role in stone formation on a large scale and among African-Americans in particular.

Recent findings

African-Americans are the race/ancestry group with faster rates of increasing incidence and prevalence of kidney stones. We make the observation that urban heat islands in the United States have resulted in part from the effects of redlining, a practice of systematic segregation and racism in housing that led to the development of neighborhoods with substantial disparities in environmental conditions.

In this thought experiment, we propose that the disproportionate rise in the prevalence of nephrolithiasis in minoritized populations correlates with increased temperatures specifically in neighborhoods adversely affected by the practice of redlining. We discuss phenomena in support of this hypothesis and ongoing work to test this theory.
The Power of Observation in Advancing Celiac Disease
Authors: Bosch Barbara , Holt Peter R.
Published: October 2022

The link between bread and wheat products and celiac disease was first recognized by Willem Dicke in the 1930s through clinical observations of his child patients. The role of gluten as the toxic factor was then proven by Drs. Dicke, Weijers and Van de Kamer in brilliant and prolonged studies in a small number of children.

The Dutch Coeliac Society helped us interview surviving child subjects of these studies.

Vignettes of their lives, difficulties and memories are presented in their own words. These testimonies emphasize the central role clinical observation has had in our understanding of celiac disease pathophysiology.
Metachronous Osteosarcoma, A Differential Diagnosis to be Considered in Children With Osteosarcoma: A Review of Literature and a Case From Our Center
Authors: Gotta Jennifer , Bochennek Konrad , Klingebiel Thomas , Bielack Stefan , Wild Peter J. , Demes Melanie C. , Gradhand Elise
Published: October 2022

Metachronous osteosarcomas (MOS) are currently defined as tumors that arise in a way and site unusual for typical metastasis. In this article, we reviewed the recent literature on the occurrence of metachronous osteosarcoma and presented a case from our center. Our patient, a 10-year-old girl, presented with metachronous osteoblastic osteosarcoma of the left distal femur ∼5 years after the successful treatment for osteosarcoma of the right distal femur. Even after several relapses, complete remission (CR) was achieved after the first osteosarcoma and after the metachronous osteosarcoma. The literature research revealed that metachronous osteosarcoma occurs in 3.4 to 5.4% of osteosarcoma patients. The time interval between the diagnosis of the initial osteosarcoma and the metachronous tumor ranged from 0.2 to 14.3 years (median 2.5 y). MOS appears to have differences in localization and metastatic spread, as well as a different survival pattern compared with primary osteosarcoma and osteosarcoma recurrence. Survival (median 4.3 y, range 0 to 24.6 y) appears to be associated with the time interval to diagnosis of MOS. In particular, early MOS (<24 mo after primary diagnosis) seem to have a poorer prognosis. Therefore, the occurrence of MOS at oncological unusual sites should be considered as a differential diagnosis in osteosarcoma survivors.
The Immunohistochemical Expression of the Von Willebrand Factor: A Potential Tool to Predict Kidney Allograft Outcomes
Authors: Teixeira André Costa , Távora Fábio , Mourão Ester Almeida , Castaldelli Gabriel Bezerra , Evangelista Thiago Belmino Almeida Bernardo , de Matos Esmeraldo Ronaldo , de Sandes-Freitas Tainá Veras
Published: October 2022

Few reports assessed endothelial activation biomarkers in kidney allograft biopsies using immunohistochemistry. This retrospective cohort study evaluated the association between posttransplant outcomes and the immunohistochemistry expression of Caveolin-1, Von Willebrand Factor (Vwf), and T-Cadherin in for-cause biopsies diagnosed as interstitial fibrosis and tubular atrophy of unknown etiology. Samples with antibody-mediated changes were excluded. The patients were followed for 3 years after the biopsy or until graft loss/death. Seventy-one (71) samples from 66 patients were included. Eighteen (25.4%) patients lost their grafts, mainly due to chronic rejection (33.3%). Caveolin-1 and T-Cadherin were not associated with graft loss. Vwf had good accuracy in predicting graft failure (AUC 0.637, 95% CI 0.486 to 0.788 P=0.101). The presence of more than 10% of Vwf positivity in the microvasculature (Vwf >10%) was associated with reduced death-censored graft survival (58.2% vs. 85.4% P=0.006), and this result was also observed in the subgroup presenting mild interstitial fibrosis (ci=1) (65.7% vs. 88.6% P=0.033). The multivariate analysis showed that Vwf >10% was an independent risk factor for graft loss (HR=2.88, 95% CI 1.03 to 8.02 P=0.043). In conclusion, Vwf might be an additional tool to predict allograft outcomes in kidney transplant recipients with interstitial fibrosis and tubular atrophy of unknown etiology, probably reflecting immune endothelial activation.
Point-of-Care Noninvasive Technology for Pediatric Dehydration Assessment
Authors: Sheridan David C. , Kohn-Loncarica Guillermo A. , Nunez Pedro , Hudson Rebekah , Lin Amber , Samatham Ravi , Hansen Matthew L.
Published: October 2022

Objective

Dehydration is a commonly encountered problem worldwide. Current clinical assessment is limited by subjectivity and limited provider training with children. The objective of this study is to investigate a new noninvasive, point-of-care technology that measures capillary refill combined with patient factors to accurately diagnose dehydration.

Methods

This is a prospective observational study at a tertiary care children's hospital in Buenos Aires, Argentina. Patients were eligible if younger than 10 years who presented to the emergency department with vomiting and/or diarrhea whom the triage nurse deems to be potentially dehydrated. Patients had the digital capillary refill device done on presentation in addition to standard of care vital signs and weight. Patients had serial weights measured on hospital scales throughout their stay. The primary outcome was dehydration, which was calculated as a percent change in weight from admission to discharge.

Results

Seventy-six children were enrolled in the study with 56 included in the final analysis. A stepwise forward method selection chose malnutrition, temperature, and systolic blood pressure for the multivariable model. The area under the curve for the final model was fair (0.7431). To further look into the utility of such a device in the home setting where blood pressure is not available often, we reran the model without systolic blood pressure. The area under the curve for the final model was 0.7269.

Conclusions

The digital capillary refill point-of-care device combined with readily available patient-specific factors may improve the ability to detect pediatric dehydration and facilitate earlier treatment or transfer to higher levels of care.
A Surprising Lead Point in an Ileocolic Intussusception
Authors: Scheier Eric , Brenner Galit , Oren Shachar
Published: October 2022

Appendicitis and intussusception are 2 of the most common abdominal emergencies in children and have high rates of morbidity if not treated promptly. However, only rarely do they occur together. We present a case in which clinical suspicion for intussusception was not high. Point-of-care ultrasound (POCUS) was performed in the pediatric emergency department, revealing both ileocolic intussusception and appendicitis. This case reinforces the importance of maintaining a broad differential diagnosis in unclear clinical scenarios and of the potential utility of POCUS. In our case, identification of intussusception on POCUS facilitated expeditious treatment, identification of the lead point, and allowed the treating physicians to prepare for the possibility of surgical management.
One-Year Outcomes of Ear Molding for Infants with Constricted Ear
Authors: Chen Peiwei , Yang Jinsong , Yang Lin , Liu Yujie , Gao Mengdie , Li Sijia , Wang Danni , Zhao Shouqin
Published: October 2022

Background:

Ear molding is a noninvasive treatment that shows promising results for neonatal ear deformations. However, little research has evaluated the 1-year outcomes, especially relapse situations, of ear molding for ear malformations.

Methods:

One-year molding efficacy for constricted ear, which is a common malformation that affects the esthetic appearance of the auricle, was assessed during this single-center, prospective study that conducted over a 3-year period (May 2017 to April 2020). Infants with constricted ears were recruited and treated with the EarWell Infant Corrective System. Constricted ear classification, age at treatment application, duration of treatment, complications, and parent satisfaction were analyzed. Photographic documentation of the ears was performed before treatment, at treatment termination, and 12 months after treatment to evaluate treatment efficacy and relapse.

Results:

Sixty patients with 91 constricted ears were recruited. The EarWell Infant Corrective System was initiated before 2 weeks of age for 75.0% of these patients. Successful correction was achieved in 85.8% of patients. Early molding initiation (<14 days) resulted in a significantly higher success rate (P=0.017). Class 1 and class 2 deformities achieved better outcomes than class 3 deformities (P=0.001). Among the 91 auricles, 37 ears (40.7%) relapsed: 36.3% had mild relapse, 4.4% had moderate relapse, and 0% had severe relapse. The treatment duration for patients with relapse was shorter than for patients without relapse (P=0.035).

Conclusions:

Early ear molding was an effective treatment for constricted ear. Sufficient molding duration and consolidation periods were crucial in maintaining treatment effects.
Prevalence and risk factors of frailty among adults living with HIV aged 70 years or older
Authors: Allavena Clotilde , Blain Hubert , Abulizi Xian , Slama Laurence , Katlama Christine , Delobel Pierre , Rio Vanessa , Cagnot Carole , Raho-Moussa Mariem , Makinson Alain , Meyer Laurence
Published: October 2022

Objectives and design:

Frailty is a phenotype associated with adverse health outcomes in older persons. It has been evaluated mainly in middle-aged persons with HIV (PWH). The French multicenter prospective ANRS EP66 SEPTAVIH study aimed to assess frailty prevalence and risk factors in PWH aged 70 years or older on antiretroviral treatment (ART) for at least 12 months.

Methods:

At baseline, Fried frailty phenotype criteria, sociodemographic data, medical/HIV history, functional status, comorbidities, including impaired cognitive function, depression, history of falls, and co-medications were collected. We measured the prevalence of frailty and compared the characteristics of frail versus prefrail and robust participants using univariate (Kruskal–Wallis tests for continuous variables and Chi2 tests for categorical variables) and multivariate analyses.

Results:

Five hundred and ten PWH, mostly male (81.4%), were included with a median age of 73 years. The median HIV and ART durations were 22.7 years and 15.7 years, respectively. The prevalence of frailty was 13.5%, and of prefrailty 63.3%. In the multivariate analysis, increasing age [odds ratio (OR) 1.79 for each 5-year increment; 95% confidence interval (CI) 1.32–2.41], deprived socioeconomic status (OR 3.17; 95% CI 1.76–5.70), and multimorbidities (three or more) (OR 2.03; 95% CI 1.06–3.90) were associated with frailty.

Conclusion:

A low prevalence of frailty was reported (13.5%) in PWH aged 70 years or older, whereas two-thirds of them were prefrail. Age, low socioeconomic status, and multimorbidities, but no HIV-related factors, were associated with frailty, suggesting the need to target these factors to help promoting successful aging in this population.
Early pneumonia diagnosis decreases ventilator-associated pneumonia rates in trauma population
Authors: Harrell Kevin N. , Lee William B. , Rooks Hunter J. , Briscoe W. Eric , Capote Walter , Dart Benjamin W. , Hunt Darren J. , Maxwell Robert A.
Published: October 2022

BACKGROUND

Ventilator-associated pneumonia (VAP) is a source of morbidity and mortality for trauma patients. Aspiration events are also common because of traumatic brain injury, altered mental status, or facial trauma. In patients requiring mechanical ventilation, early pneumonias (EPs) may be erroneously classified as ventilator associated.

METHODS

A prospective early bronchoscopy protocol was implemented from January 2020 to January 2022. Trauma patients intubated before arrival or within 48 hours of admission underwent bronchoalveolar lavage (BAL) within 24 hours of intubation. Patients with more than 100,000 colony-forming units on BAL were considered to have EP.

RESULTS

A total of 117 patients underwent early BAL. Ninety-three (79.5%) had some growth on BAL with 36 (30.8%) meeting criteria for EP. For the total study population, 29 patients (24.8%) were diagnosed with VAP later in their hospital course, 12 of which had previously been diagnosed with EP. Of EP patients (n = 36), 21 (58.3%) were treated with antibiotics based on clinical signs of infection. Of EP patients who had a later pneumonia diagnosed by BAL (n = 12), seven (58.3%) grew the same organism from their initial BAL. When these patients were excluded from VAP calculation, the rate was reduced by 27.6%. Patients with EP had a higher rate of smoking history (41.7% vs. 19.8%, p < 0.001) compared with patients without EP. There was no difference in median hospital length of stay, intensive care unit length of stay, ventilator days, or mortality between the two cohorts.

CONCLUSION

Early pneumonia is common in trauma patients intubated within the first 48 hours of admission and screening with early BAL identifies patients with aspiration or pretraumatic indicators of pneumonia. Accounting for these patients with early BAL significantly reduces reported VAP rates.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Transplantation of olfactory ensheathing cells decreases local and serological monocyte chemoattractant protein 1 level during the acute phase of rat spinal cord injury
Authors: Wang Yiqun , Gong Minjie , He Xijing , Wu Yutong , Li Yuhuan , Li Jialiang , Wen Zhijing , Wang Yibin , Gu Pengzhen , Li Haopeng
Published: October 2022

Objectives:

Monocyte chemoattractant protein 1 (MCP1) is one of the most upregulated cytokines in the spinal cord and serum throughout acute spinal cord injury (SCI). Olfactory ensheathing cells (OECs) transplantation improves SCI through multiple mechanisms, including immunomodulation. Our study aimed to investigate whether OECs ameliorate acute inflammation after SCI by modulating MCP1 expression.

Methods:

We established a standardized clinically relevant contusion model using the NYU impactor. OECs were administered to the injured spinal cord via microinjection 30 minutes after injury. Rat locomotor functions were assessed by the Basso–Beattie–Bresnahan scale score. Time-course histopathological (H&E and IHC) analyses were performed to record rapid changes in acute inflammation at lesion epicenters. Serum MCP1 level was detected by ELISA assay.

Results:

BBB scores showed improved locomotor functional recoveries in the OECs transplantation group after SCI (P < 0.05). Staining of H&E and CD68 illustrated that OECs transplantation attenuated inflammatory response by reducing lesion areas and infiltrating myeloid cell numbers. We further revealed significantly decreased MCP1 levels in the spinal cord and serum after OECs transplantation (P < 0.05). Noteworthily, distinct expression levels of MCP1 were found in rats undergoing a mild injury (cord impacted from a 10-mm height) compared to the moderate injury (25-mm) group.

Conclusion:

Our study reports that transplantation of OECs promotes locomotor functional recovery after SCI and alleviates acute inflammation by decreasing local and serological MCP1 levels. We provide preliminary evidence that MCP1 might serve as a potential biomarker to reflect the severity of SCI, which is of great interest in future studies.
VEXAS syndrome is characterized by blood and tissues inflammasome pathway activation and monocyte dysregulation
Authors: Kosmider Olivier , Possémé Céline , Templé Marie , Corneau Aurélien , Carbone Francesco , Duroyon Eugénie , Chirayath Twinu-Wilson , Luka Marine , Gobeaux Camille , Lazaro Estibaliz , Outh Roderau , Le Guenno Guillaume , Lifermann François , Berleur Marie , Friedrich Chloé , Lenormand Cédric , Weitten Thierry , Guillotin Vivien , Burroni Barbara , Sohier Pierre , Boussier Jay , Willems Lise , Aractingi Selim , Dionet Léa , Tharaux Pierre-Louis , Vergier Béatrice , Raynaud Pierre , Ea Hang-Korng , Ménager Mickael , Duffy Darragh , Terrier Benjamin
Published: October 2022

Acquired mutations in theUBA1gene, occurring in myeloid cells and resulting in expression of a catalytically impaired isoform of the enzyme E1, were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). The precise physiological and clinical impact of these mutations remains poorly defined.

Here, we studied a unique prospective cohort of individuals with severe autoinflammatory disease with (VEXAS) or without (VEXAS-like)UBA1somatic mutations and compared with low-risk myelodysplastic syndromes (MDS) and aged gender-matched healthy controls. We performed an integrated immune analysis including multiparameter phenotyping of peripheral blood leukocytes, cytokines profiling, bulk and single-cell gene expression analyses and skin tissue imaging mass cytometry.

Focusing on myeloid cells, we show that monocytes fromUBA1-mutated individuals were quantitatively and qualitatively impaired and displayed features of exhaustion with aberrant expression of chemokine receptors. Within affected tissues, pathological skin biopsies from VEXAS patients showed an abundant enrichment of CD16+CD163+monocytes adjacent to blood vessels and M1 macrophages, possibly promoting local inflammation in part through STAT3 activation. In peripheral blood from VEXAS patients, we identified a significant increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirmed the role of circulating cells in the IL-1β and IL-18 dysregulation in VEXAS patients and revealed a significant enrichment of TNF-α and NFκB signaling pathways that could mediate cell death and inflammation. Single-cell analysis confirmed the inflammatory state of monocytes from VEXAS patients and allowed us to identify specific molecular pathways that could explain monocytopenia, especially the activation of PANoptosis and a deficiency in the TYROBP/DAP12 axis and β-catenin signaling pathway. Together, these findings on monocytes from patients withUBA1mutations provide important insights into the molecular mechanisms involving the mature myeloid commitment in VEXAS syndrome and suggest that the control of the undescribed inflammasome activation and PANoptosis could be novel therapeutic targets in this condition.

GRAPHICAL ABSTRACT
Deacidification of distal lysosomes by neuronal aging drives synapse loss
Authors: Burrinha Tatiana , Cunha César , Almeida Cláudia Guimas
Published: October 2022

Previously, we found that age-dependent beta-amyloid accumulation is not enough to cause synaptic decline. Here, we characterized endolysosomes (late-endosomes and lysosomes) in aged neurons and the aged brain, which might drive synaptic decline since lysosomes are a cellular aging target and relevant for synapses. Neuronal aging induces enlarged endolysosome accumulation in the aged neurons and brain, especially distally, related to the increased anterograde movement. Aged lysosomes abound in neurites but are less degradative due to deacidification despite cathepsin D buildup, leading to late-endosome accumulation. Increasing the acidification of aged lysosomes by ML-SA1 treatment increased degradation and reverted synaptic decline, while lysosome alkalinization by chloroquine treatment mimicked age-dependent lysosome dysfunction and synaptic decline. We identify the deacidification of distal lysosomes as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address lysosomal defects might be able to delay age-related synaptic decline.

Highlights

Enlarged endolysosomes accumulate close to synapses in aged neurons and aged brain

Late-endosomes accumulate with neuronal aging

Aged lysosomes are less acidic and degradative despite accumulating Cathepsin D

Increasing acidification of aged lysosomes improves synapses, while deacidification recapitulates age-dependent synapse loss

We identify the downregulation of the lysosome degradative activity via deacidification as a neuronal aging mechanism contributing to aging-dependent synapse loss.

Graphical abstract
COVID-19 Vaccine Effectiveness against Symptomatic and Asymptomatic SARS-CoV-2 Infections with the Delta Variant among a Cohort of Children Aged ≥ 12 Years and Adults in Utah
Authors: Mohanty Sarita , Dawood Fatimah S. , Stanford Joseph B. , Duque Jazmin , Stockwell Melissa S. , Veguilla Vic , Porucznik Christina A.
Published: October 2022

We conducted weekly surveillance for SARS-CoV-2 infection among a sample of households with ≥1 child aged 0-17 years from selected Utah counties. A Cox proportional hazards model approach was used to calculate infection hazard rate and vaccine effectiveness. Findings show that the recommended primary series of COVID-19 vaccine was effective against circulating variants during a Delta-predominant wave in Utah.
Trans-ancestry meta-analysis of genome wide association studies of inhibitory control
Authors: Arnatkeviciute Aurina , Lemire Mathieu , Morrison Claire , Mooney Michael , Ryabinin Peter , Roslin Nicole , Nikolas Molly , Coxon James , Tiego Jeggan , Hawi Ziarih , Fornito Alex , Henrik Walter , Martinot Jean-Luc , Paillère Martinot Marie-Laure , Artiges Eric , Garavan Hugh , Nigg Joel , Friedman Naomi , Burton Christie , Schachar Russell , Crosbie Jennifer , Bellgrove Mark A.
Published: October 2022

Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N=14,877) using behavioural traits derived from the stop-signal task, namely – go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. The polygenic risk for ADHD was significantly associated with GoRT SD further supporting its suggested utility as an endophenotype for ADHD. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.
Early immunomodulatory program triggered by pro-tolerogenicBifidobacterium pseudolongumdrives cardiac transplant outcomes
Authors: Gavzy Samuel J , Kensiski Allison , Saxena Vikas , Lakhan Ram , Hittle Lauren , Wu Long , Iyyathurai Jegan , Dhakal Hima , Lee Zachariah L , Li Lushen , Lee Young S , Zhang Tianshu , Lwin Hnin W , Shirkey Marina W , Paluskievicz Christina M , Piao Wenji , Mongodin Emmanuel F , Ma Bing , Bromberg Jonathan S
Published: October 2022

Background

Despite ongoing improvements in regimens to prevent allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes.

Methods

In this study, we further detailed the multifaceted immunomodulatory properties of pro-tolerogenic and pro-inflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation.

Results

In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed thatBifidobacterium pseudolongum (Bifido)induced an early anti-inflammatory phenotype within 7 days, whileDesulfovibrio desulfuricans (Desulfo)resulted in a pro-inflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed,in vitroresults showed thatBifidoandDesulfoacted directly on primary innate immune cells. However, by 40 days after treatment, these two bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation withBifidotreatment.

Conclusions

These dynamic effects suggest a critical role for early microbiota-triggered immunological events such as innate immune cell engagement, T cell differentiation, and LN architectural changes in the subsequent modulation of pro-tolerant versus pro-inflammatory immune responses in organ transplant recipients.
Mitochondrial complex I controls blood brain barrier permeability
Authors: Davis Gavin M. , Juere Estelle , Hayes Jerrard M. , Davey Gavin P.
Published: October 2022

Mitochondrial electron transport chain (ETC) complexes are key mediators of energy metabolism in astrocytes and neurons, with subsequent effects on memory, behaviour and neurodegeneration. Mitochondrial dysfunction and increased blood brain barrier (BBB) permeability are known pathologies in Parkinson’s and Alzheimer’s diseases. However, knowledge of how ETC activities regulate metabolic flux and influence permeability in the BBB is lacking. Using metabolic flux control analysis we show that complex I is a critical control point for oxidative flux and permeability in brain microvascular endothelial cells derived from human induced pluripotent stem cells. Inhibition of complex I activity immediately reduced the transendothelial electrical resistance (TEER) by 60%, leading to an increase in protein transport across the BBB. These events were accompanied by a transient reduction in ATP that was recovered, along with TEER values, over an extended time period. Furthermore, while inhibition of downstream complexes III or IV decreased oxygen respiration rates, no effects on BBB permeability were identified, due to compensatory glycolytic flux and maintenance of ATP synthesis. These data show that mitochondrial complex I is critical for maintaining energy production in endothelial cells and transiently controls BBB permeability, which may contribute to brain disorders where complex I dysfunction is a hallmark.
Dysfunctional neuro-muscular mechanisms explain gradual gait changes in prodromal spastic paraplegia
Authors: Laßmann Christian , Ilg Winfried , Rattay Tim W. , Schöls Ludger , Giese Martin , Haeufle Daniel F.B.
Published: October 2022

In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperreflexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes – depicted by digital gait recording – are related to disease severity in prodromal and early-to-moderate manifest SPG4 subjects. We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperreflexia and muscle weakness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 subjects. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor reflex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. By increasing hyperreflexia of plantarflexor and dorsiflexor muscles, we found gradual muscular and kinematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 subjects. Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 subjects by gradual alterations of sensory-motor reflex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions.
Investigating the cause of a 2021 winter wave of COVID-19 in a border region in Eastern Germany: a mixed-methods study, August to November 2021
Authors: Yi Buqing , Laubner Alexa , Stadtmüller Marlena , Patrasová Eva , Šimůnková Lenka , Rost Fabian , Winkler Sylke , Reinhardt Susanne , Dahl Andreas , Dalpke Alexander H.
Published: October 2022

In winter 2020 and 2021 many countries worldwide experienced a COVID-19 pandemic wave which led to severe burdens on healthcare systems and huge economic losses. Yet, it remains unclear how the winter waves started and many debates are ongoing about actions necessary to prevent future winter waves. In this study we deciphered the dynamic course of a winter wave in 2021 in Saxony, a state in Eastern Germany neighboring Czech Republic and Poland. The information we achieved might help future pandemic prevention.

The dynamic course of the 2021 winter wave in Saxony was investigated through integration of multiple virus genomic epidemiology approaches and functional evaluations of locally circulating variants. Through international collaborations, we performed genomic epidemiology analysis on a weekly base with samples from Saxony and also from one neighbor region in the Czech Republic. Phylogeny analyses were used to track transmission chains, monitor virus genetic changes and identify emerging variants. Phylodynamic approaches have been applied to track the dynamic changes of transmission clusters. For identified local variants of interest, active viruses were isolated and functional evaluations were performed.

Genomic epidemiology studies revealed multiple long-lasting community transmission clusters acting as the major driving forces for the winter wave 2021. Analysis of the dynamic courses of two representative long-lasting community transmission clusters indicated similar dynamic changes. In the first 6-8 weeks, the relevant variant was mainly circulating in a small region among young and middle-aged people; after eight weeks, the ratio of people aged above 60 years in the infected population markedly increased, and the virus got more widely spread to distant regions. On the other hand, the transmission cluster caused by a locally occurring variant showed a different transmission pattern. It got geographically widely distributed within six weeks, with many people aged above 60 years being infected since the beginning of the cluster, indicating a higher risk for escalating healthcare burdens. This variant displayed a relative growth advantage compared to co-circulating Delta sub-lineages. Functional analyses revealed a replication advantage, but no advantage in immune evasion ability.

This study indicated that long-lasting community transmission clusters starting between August and October caused by imported variants as well as locally occurring variants all contributed to the development of the 2021 winter wave in Saxony. In particular, the cluster derived from a locally occurring variant with certain growth advantage might have stressed local healthcare systems.
Serological Cross-Reactivity Between Spotted Fever and Typhus Groups of Rickettsia Infection in Japan
Authors: Aita Tetsuro , Sando Eiichiro , Katoh Shungo , Hamaguchi Sugihiro , Fujita Hiromi , Kurita Noriaki
Published: October 2022

We examined the frequency of cross-reactions toRickettsia typhiin patients with Japanese spotted fever and found that approximately 20% of cases were positive. Comparison of antibody titers revealed the difficulty in identifying some positive cases. The frequency of misclassification in serodiagnosis was found to be limited.
Single-cell analysis reveals inter- and intratumour heterogeneity in metastatic breast cancer
Authors: Hamelin Baptiste , Obradović Milan , Sethi Atul , Kloc Michal , Muenst Simone , Beisel Christian , Eschbach Katja , Kohler Hubertus , Soysal Savas , Vetter Marcus , Weber Walter P. , Stadler Michael B. , Bentires-Alj Mohamed
Published: October 2022

Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set Enrichment Analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top Differentially Expressed Genes (DEGs) between these cell states revealed a common set of partial EMT Transcriptions Factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer.
Spatiotemporal dynamics of RAD51C between the Golgi and nucleus regulates homologous recombination and genomic stability
Authors: Galea George , Kuodyte Karolina , Khan Muzamil M. , Thul Peter , Neumann Beate , Lundberg Emma , Pepperkok Rainer
Published: October 2022

Abstract

Intra-organelle communication is essential for cellular homeostasis, but the coordination between nuclear processes and cytoplasmic compartments remains poorly understood. Here, we uncover a novel spatiotemporal regulatory pathway linking the Golgi complex to the nucleus upon DNA damage. We show key DNA repair proteins, including RAD51C, dynamically shuttle between these organelles in response to distinct types of DNA damage. Mechanistic analysis reveals that RAD51C is anchored at the Golgi by Giantin. Disrupting this interaction leads to premature RAD51C nuclear localization, impaired homologous recombination signaling, genomic instability, and increased cell proliferation. Our findings establish Golgi-nuclear communication as a critical regulator of DNA repair, offering new insights into genomic integrity maintenance with profound implications for cancer and aging-related genomic instability.
Metabolic clogging of mannose triggers genomic instability via dNTP loss in human cancer cells
Authors: Harada Yoichiro , Mizote Yu , Suzuki Takehiro , Nishida Mikako , Hiratsuka Toru , Ueda Ayaka , Imagawa Yusuke , Maeda Kento , Ohkawa Yuki , Murai Junko , Freeze Hudson H. , Miyoshi Eiji , Higashiyama Shigeki , Udono Heiichiro , Dohmae Naoshi , Tahara Hideaki , Taniguchi Naoyuki
Published: October 2022

Mannose has anti-cancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its anti-cancer activity, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphates (dNTPs). This metabolic remodeling impaired dormant origin firing required to rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition ofde novodNTP biosynthesis was sufficient to retard cell cycle progression, sensitize cells to cisplatin, and inhibit dormant origin firing, suggesting dNTP loss-induced genomic instability as a central mechanism for the anti-cancer activity of mannose.
Electrophysiological Measurements of Compound Action Potential Responses from the Antennal Nerve in Response to Stimulation
Authors: Su Matthew P. , Albert Joerg T.
Published: October 2022

Electrophysiological recordings taken from the antennal nerve can provide essential information on the general auditory condition of the mosquito tested. Furthermore, electrophysiological recordings provide detailed information on what types of stimulation induce the largest nerve responses. When these are used in conjunction with a vibrometer to measure the corresponding movement of the antennal ear during stimulation, a comprehensive overview of hearing function can be obtained. This protocol can be applied to male and female adults from any mosquito strain and can be scaled relative to available resources.