bluuebunny/crossref_metadata_2025 huggingface dataset:
Meaningful Recognition for Nurse Managers
Authors: Grant Susan Mitchell
Published: February 2022

Nurse managers have played an instrumental and essential role in the successful delivery of patient care for decades. Often described as the “hardest job in healthcare,” the importance of the nurse manager role is never more apparent during a crisis such as a national nursing shortage or a global pandemic. However, the nurse manager role and its contributions have gone unrecognized. The DAISY Nurse Leader Award is one way healthcare leaders can elevate and recognize nurse manager's contributions.
Comparative Study of Modified Silver Nitrate Staining for the Detection of Helicobacter pylori
Authors: Chu Xiaoying , Xu Jian , Niu Li
Published: February 2022

Background/Aims:

Helicobacter pylori(Hp) infection is associated with a variety of diseases, such as benign lesions, precancerous lesions, and malignant lesions, especially diseases in the digestive system. Most people with Hp infection have mild early symptoms that are not easily noticed. Therefore, the diagnosis and treatment of Hp infection is particularly important. At present, there are many methods to detection Hp infection, but there is a lack of effective detection method with high sensitivity and specificity. On the basis of the existing detection methods, the modified silver nitrate staining method in this study improved the sensitivity and specificity of Hp detection.

Materials and Methods:

We selected gastric antrum and gastric angle mucosal biopsy tissues from 60 inpatients that were archived in the Pathology Department of Zhongnan Hospital of Wuhan University from July to December 2020. An Hp immunohistochemical assay, histochemical assay kit (methylene blue), and modified silver nitrate staining were used to measure the Hp infection positivity rate.

Results:

Comparison of Hp sensitivity and specificity among the 3 methods showed that the modified silver nitrate staining method was the most excellent. The sensitivity of modified silver nitrate staining method was 98.3%, which is statistically significantly higher compared with the other 2 methods.

Conclusion:

The modified silver nitrate staining method for Hp detection is convenient and effective, and could be widely used for clinical Hp detection.
The Many Faces of Serous Neoplasms and Related Lesions of the Female Pelvis: A Review
Authors: Rashid Sameera , Arafah Maria A. , Akhtar Mohammed
Published: February 2022

Ovarian serous tumors and related lesions are one of the most common conditions of the female genital tract. While ovarian high-grade serous carcinoma carries high mortality and adverse prognosis, most other serous lesions have better clinical behavior. In recent years, significant progress has been made in understanding the nature and histogenesis of these lesions that has contributed to better and more precise clinical management. Most of the high-grade serous carcinomas involve the ovaries and/or peritoneum, although in most cases, their origin seems to be in the fallopian tube. This view is supported by the recognition of precursor lesions in the fallopian tube, such as p53 signature and serous tubular in situ carcinoma. This paper presents salient morphologic, immunohistochemical, and molecular data related to serous tumors and related lesions of the female pelvis and discusses the histogenetic interrelationship among these lesions in light of current knowledge.
ALK Immunoexpression is Specific for Inflammatory Myofibroblastic Tumor Among Vulvovaginal Mesenchymal Neoplasms
Authors: Bowman Christopher J. , Medeiros Fabiola , Fadare Oluwole , Sangoi Ankur R. , Horvai Andrew E. , Devine W. Patrick , McCluggage W. Glenn , Rabban Joseph T.
Published: February 2022

Gynecologic tract origin of inflammatory myofibroblastic tumor (IMT), a receptor tyrosine kinase fusion driven tumor with malignant potential, is uncommon and mostly involves the uterine corpus where misclassification as a smooth muscle tumor may occur due to overlapping morphologic features. With rare exception, uterine IMT involves ALK rearrangements and exhibits ALK immunoexpression. Molecularly confirmed vulvovaginal IMT has not been reported, but several low-grade mesenchymal tumors in this region exhibit myxoid stroma and/or inflammatory infiltrates that may resemble IMT. The aims of this study were to define the diagnostic specificity of ALK immunoexpression for IMT among a broad spectrum (107 cases) of vulvovaginal mesenchymal tumors in the differential diagnosis of IMT and to report the clinicopathologic features of vulvovaginal IMT identified in our archives or via retrospective ALK staining of otherwise classified vulvovaginal tumors. Review of archives from 5 different centers revealed a single case of vulvar IMT in a 62-yr-old woman. The 2.5 cm well-circumscribed tumor exhibited the typical microscopic features of IMT, namely a loose fascicular distribution of bland spindle cells within a myxoid stroma, accompanied by an infiltrate of plasma cells, lymphocytes, and eosinophils. The tumor cells exhibited expression for smooth muscle actin, desmin, h-caldesmon, and ALK. Break-apart fluorescence in situ hybridization confirmed the presence of ALK rearrangement. The patient did not receive any treatment and is alive without disease 32 mo later. No evidence of ALK expression was detected in any of the other 107 vulvovaginal tumors, which included 14 aggressive angiomyxomas, 2 superficial angiomyxomas, 12 angiomyofibroblastomas, 8 cellular angiofibromas, 15 smooth muscle neoplasms, 10 peripheral nerve sheath tumors, 20 fibroepithelial polyps, and a variety of other low grade mesenchymal tumors. Although vulvovaginal ALK-rearranged IMT is exceedingly rare, the behavior remains to be fully understood. ALK immunohistochemistry, which appears specific for IMT in this anatomic site, is advised in the evaluation of vulvovaginal mesenchymal tumors exhibiting myxoid stroma and/or an inflammatory infiltrate.
Comparing Autologous to Device-Based Breast Reconstruction
Authors: Huang Hao , Wang Marcos Lu , Ellison Angela , Otterburn David M.
Published: February 2022

Background

Poor breast sensation is common after mastectomy and reconstruction. In this study, we aim to define the temporal pattern of sensory changes after reconstruction and to compare the return in sensation between autologous and device-based reconstruction.

Methods

Women undergoing mastectomy with immediate reconstruction, with either tissue expander (TE) or neurotized deep inferior epigastric perforator (DIEP) flap, were prospectively identified at their preoperative or postoperative visit at defined time points. Neurosensory testing was performed in 9 breast regions using the AcroVal pressure-specified sensory device to determine 1 point-static cutaneous thresholds. Sensitivity data were averaged between patients at each time point and plotted over time.

Results

Eighty-seven patients (153 breasts) were included in this study, including 41 women (75 breasts) with DIEP flap and 46 women (78 breasts) with TE. The groups were comparable in age, body mass index, breast size, chemotherapy, radiotherapy, and number of revisional breast surgeries (P > 0.05). Compared with preoperative baseline, mean cutaneous thresholds in DIEP flap patients were comparable in most outer breast regions at 18 months postoperatively and in the entire breast, except the inner inferior region, at 3 years (P > 0.05). In contrast, mean cutaneous thresholds in TE patients continued to be significantly worse in the entire breast at 5 years postoperatively compared with baseline (P < 0.05).

Conclusions

Autologous breast reconstruction is superior in sensory recovery. Patients undergoing DIEP flap can expect sensory return to preoperative levels by 3 years, with sensation returning by 18 months in some areas of the breast. Patients undergoing device reconstruction should expect a slower and more unpredictable return in breast sensation.
Out-of-Pocket Costs and Provider Payments in Cleft Lip and Palate Repair
Authors: Rochlin Danielle H. , Ma Lucy W. , Sheckter Clifford C. , Lorenz H. Peter
Published: February 2022

Background

As healthcare spending within the United States grows, payers have attempted to curb spending through higher cost sharing for patients. For families attempting to balance financial obligations with their children's surgical needs, high cost sharing could place families in difficult situations, deciding between life-altering surgery and bankruptcy. We aim to investigate trends in patient cost sharing and provider payments for cleft lip and palate repair.

Methods

The IBM® MarketScan® Commercial Database was queried to extract patients younger than 18 years who underwent primary or secondary cleft lip and/or palate repair from 2007 to 2016. Financial variables included gross payments to the provider (facility and/or physician), net payment as reported by the carrier, coordination of benefits and other savings, and the beneficiary contribution, which consisted of patients' coinsurance, copay, and deductible payments. Linear regression was used to evaluate trends in payments over time. Poisson regression was used to trend the proportion of patients with a nonzero beneficiary contribution. All financial values were adjusted to 2016 dollars per the consumer price index to account for inflation.

Results

The sample included 6268 cleft lip and 9118 cleft palate repair episodes. Total provider payments increased significantly from 2007 to 2016 for patients undergoing cleft lip (median, $2527.33 vs $5116.30, P 0.008) and palate ($1766.13 vs $3511.70, P < 0.001) repair. Beneficiary contribution also increased significantly for both cleft lip ($155.75 vs $193.31, P < 0.001) and palate ($124.37 vs $183.22, P < 0.001) repair, driven by an increase in deductibles (P < 0.002). The proportion of cleft palate patients with a nonzero beneficiary contribution increased yearly by 1.6% (P = 0.002). Higher provider payments and beneficiary contributions were found in the Northeast (P < 0.001) and South (P < 0.011), respectively, for both cleft lip and palate repair.

Conclusions

The US national data demonstrate that for commercially insured patients with cleft lip and/or palate, there has been a trend toward higher patient cost sharing, most pronounced in the South. This suggests that patients are bearing an increased cost burden while provider payments are simultaneously accelerating. Additional studies are needed to understand the impact of increased cost sharing on parents' decision to pursue cleft lip and/or palate repair for their children.
Sensorimotor Outcomes of Upper Extremity End-to-Side Nerve Transfers
Authors: Zeiderman Matthew R. , Fine Jeffrey , Asserson Derek B. , Davé Dattesh R. , Bascone Corey M. , Li Andrew I. , Pereira Clifford T.
Published: February 2022

Background

End-to-side nerve transfer (ETSNT) for treatment of peripheral nerve injuries is controversial given the myriad anatomic locations, injury types, and indications. Efficacy of ETSNT remains debated. We hypothesized differences in age, sex, transfer location, and time to surgery influence outcomes.

Methods

We performed a search of the PubMed database for ETSNT in the upper extremity from 1988 to 2018. Age, sex, transfer location, time to surgery, donor and recipient axons, and strength and sensation outcomes as measured by Medical Research Council scale were extracted from articles. Meaningful recovery was classified as Medical Research Council Grade 3 or greater. Association between meaningful recovery and younger (<25) and older (≥25) patients, injury mechanism, sex, transfer location, donor axons, and recipient axons were calculated using a χ2 or Fisher exact test. A logistic mixed effect model was used with time to surgery, age (categorical), transfer location, and injury type as a fixed effect, and a random paper effect was included to account for correlation among patients from the same paper.

Results

One hundred fifteen patients from 11 studies were included. Neither age (continuous variable, P = 0.68) nor time to surgery (P = 0.28) affected meaningful recovery. Injury mechanism, sex, and younger age (<25 vs ≥25 years) were not associated with meaningful recovery. Within the brachial plexus ETSNT demonstrated median M4 ± 1 postoperative strength, with trunks/cords as the primary axon donor (P = 0.03). The musculocutaneous nerve demonstrated promising but variable results in 31 patients with median strength M3 ± 4. Digital nerves consistently demonstrated meaningful sensory recovery as both donor and recipient axons (15 of 15, 100%). Logistic regression analysis demonstrated that odds of meaningful recovery after ETSNT are significantly greater for transfers within the brachial plexus compared with the distal arm (odds ratio, 41.9; 95% CI, 1.1–1586.7, P = 0.04), but location does not significantly affect meaningful recovery (P = 0.22).

Conclusions

Patients undergoing ETSNT for digital nerve injury demonstrated meaningful recovery. End-to-side nerve transfer seems to be more efficacious when performed within the brachial plexus. This study did not find sex, injury mechanism, or time to surgery to significantly affect meaningful recovery. Additional study is needed to better evaluate the effectiveness of ETSNT in the upper extremity.
Preventing Rectourethral Fistula Recurrence With Gracilis Flap
Authors: Park Keon Min , Rosli Yenny Y. , Simms Allen , Lentz Rachel , Bharadia Deepak R. , Breyer Benjamin , Hoffman William Y.
Published: February 2022

Background

Rectourethral fistula (RUF) is an uncommon serious condition with various etiologies including neoplasm, radiation therapy, and surgery. Treatment for RUF remains problematic with a high recurrence rate. Although studies have suggested the recurrence rate of RUF is lower after surgical repair using a gracilis flap, outcomes have varied and the studies were small and inadequately controlled. Here, we compare outcomes of RUF repair with and without gracilis flap to evaluate its efficacy in preventing fistula recurrence and identify risk factors for recurrence.

Methods

We retrospectively reviewed patients who had undergone surgical repair for RUF between 2007 and 2018 at our institution and had at least 30 days of follow-up. Patient demographics, comorbidities, and surgical outcomes were recorded and compared for patients who had gracilis flap repair and those who did not (controls). Single variable logistic regression analysis was used to identify risk factors for recurrence.

Results

The gracilis group (n = 24) and control group (n = 12) had similar demographics and comorbidities. Fistula recurrence was far less frequent in the gracilis group (8% vs 50%, P = 0.009). There were no significant differences in other outcomes including length of hospitalization and surgical complications. When recurrent RUF was treated with a muscle flap (gracilis or inferior gluteus), 83% of the group had no additional fistula recurrence. In the control group, history of radiation (P = 0.04) and urinary incontinence (P = 0.015) were associated with fistula recurrence.

Conclusions

We recommend using a gracilis flap for RUF repair given its association with lower recurrence without increased surgical complications.
A Systematic Review on the Implementation and Educational Value of Resident Aesthetic Clinics
Authors: Chen Jonlin , Lee Erica , el Eter Leen , Cooney Carisa M. , Broderick Kristen P.
Published: February 2022

Background

Resident aesthetic clinics (RACs) provide plastic surgery residents with hands-on aesthetic surgery training. Although RACs have demonstrated successful surgical outcomes without compromising patient care, few studies have evaluated the efficacy or educational value of RACs to increase resident confidence and competence in procedures. In addition, clinic structures vary widely among institutions, with each clinic offering a unique patient volume, caseload, and degree of resident autonomy that impacts the clinic's educational value. This systematic review identifies existing RAC practices, compares clinic structures, and proposes a curriculum framework to maximize educational value for residents.

Methods

Following PRISMA guidelines, we performed a systematic review of plastic surgery residency training program RACs. We queried PubMed, Embase, and Web of Science from January 2000 to April 2020. Eligible articles were original articles that discussed RAC structure and educational value. Data abstracted included details on clinic structure (eg, volume, location, cost, clinic operations) and trainee-perceived educational value (eg, resident satisfaction, resident confidence in procedures).

Results

Of 1199 identified publications, 10 met the inclusion criteria: 6 single-site studies and 4 national survey studies. Among the single-site studies, annual volumes ranged from 22 to 68 patients/year and 35 to 81 cases/year. Resident aesthetic clinics were all staffed by full-time academic faculty (100%); one-third also were staffed by adjunct faculty and 17% also by community plastic surgeons. Resident involvement varied by hours in clinic and degree of autonomy. The survey studies found that RACs increase resident confidence and competence in performing aesthetic procedures and identified critical challenges to RAC implementation (eg, financial viability, continuity of care) that limited RAC educational value. Based on this review's findings, we propose a 6-step RAC curriculum framework for training programs seeking to establish an RAC and maximize the clinic's educational value.

Conclusions

Resident aesthetic clinics are increasingly important for providing plastic surgery residents with aesthetic training. Patient and case volume, degree of resident autonomy, and clinic attending physicians are critical determinants of the educational value of RACs. We hope our findings can aid plastic surgery training programs in better organizing educational and sustainable RACs.
Optimizing Abdominoplasty Surgical Site Morbidity Profiling Through an Effective and Nationally Validated Risk Scoring System
Authors: Massada Karen E. , Baltodano Pablo A. , Webster Theresa K. , Elmer Nicholas A. , Zhao Huaqing , Lu Xiaoning , Kaplunov Briana S. , Araya Sthefano , Brebion Rohan , Coronado Michael , Patel Sameer A.
Published: February 2022

Background

Abdominoplasty complication rates are among the highest for cosmetic surgery. We sought to create a validated scoring system to predict the likelihood of wound complications after abdominoplasty using a national multi-institutional database.

Methods

Patients who underwent abdominoplasty in the American College of Surgeons National Surgical Quality Improvement Program 2007–2019 database were analyzed for surgical site complications, a composite outcome of wound disruption, and surgical site infections. The cohort was randomly divided into a 60% testing and a 40% validation sample. Multivariable logistic regression analysis was performed to identify independent predictors of complications using the testing sample (n = 11,294). The predictors were weighted according to β coefficients to develop an integer-based clinical risk score. This system was validated using receiver operating characteristic analysis of the validation sample (n = 7528).

Results

A total of 18,822 abdominoplasty procedures were identified. The proportion of patients who developed a composite surgical site complication was 6.8%. Independent risk factors for composite surgical site complication included inpatient procedure (P < 0.01), smoking (P < 0.01), American Society of Anesthesiologists class ≥3 (P < 0.01), and body mass index ≥25.0 and ≤18.0 kg/m2 (P < 0.01). African American race was a protective factor against surgical site complications (P < 0.01). The factors were integrated into a scoring system, ranging from −5 to 42, and the receiver operating characteristic analysis revealed an area under the curve of 0.71.

Conclusions

We present a validated scoring system for postoperative 30-day surgical site morbidity after abdominoplasty. This system will enable surgeons to optimize patient selection to decrease morbidity and unnecessary healthcare expenditure.
Transcription factor retention through multiple polyploidisation steps in wheat
Authors: Evans Catherine EB , Arunkumar Ramesh , Borrill Philippa
Published: February 2022

Whole genome duplication (WGD) is widespread in plant evolutionary history, but the mechanisms of non-random gene loss after WGD are debated. The gene balance hypothesis proposes that dosage-sensitive genes such as regulatory genes are retained in polyploids. To test this hypothesis, we analysed the retention of transcription factors (TFs) in the recent allohexaploid bread wheat(Triticum aestivum).

We annotated TFs in hexaploid, tetraploid and diploid wheats; compared the co-expression of homoeologous TF and non-TF triads; and analysed single nucleotide variation in TFs across cultivars.

We found that, following each of two hybridisation and WGD events, the proportion of TFs in the genome increased. TFs were preferentially retained over other genes as homoeologous groups in tetraploid and hexaploid wheat. Across cultivars, TF triads contain fewer deleterious missense mutations than non-TFs.

TFs are preferentially retained as three functional homoeologs in hexaploid wheat, in support of the gene balance hypothesis. High co-expression between TF homoeologs suggests that neo- and sub-functionalisation are not major drivers of TF retention in this young polyploid. Knocking out one TF homoeolog to alter gene dosage, using TILLING or CRISPR, could be a way to further test the gene balance hypothesis and generate new phenotypes for wheat breeding.
Clinical phenotypes in acute and chronic infarction explained through human ventricular electromechanical modelling and simulations
Authors: Zhou Xin , Wang Zhinuo Jenny , Camps Julia , Tomek Jakub , Santiago Alfonso , Quintanas Adria , Vazquez Mariano , Vaseghi Marmar , Rodriguez Blanca
Published: February 2022

Aims

Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic remodelling, which are reflected as variable phenotypes. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with the post-MI pro-arrhythmic heterogeneities are unknown. We aim to provide a mechanistic explanation of clinical phenotypes in acute and chronic MI, from ionic remodeling to ECG and EF, using human electromechanical modelling and simulation to augment experimental and clinical investigations.

Methods and Results

A human ventricular electromechanical modelling and simulation framework is constructed and validated with rich experimental and clinical datasets. Abnormalities caused by scar and border zone ionic remodeling are introduced in varying degrees as reported in experimental data obtained in acute and chronic infarction. Simulations enabled reproducing and explaining clinical phenotypes post-MI, from ionic remodelling to ECGs and pressure-volume loops. In acute MI, T-wave inversion and Brugada phenocopy were explained by up to 57 ms of local APD prolongation and activation failure due to the inhibition of potassium, sodium and calcium channels in the border zone. In chronic MI, upright tall T-waves highlight large repolarisation dispersion caused by uneven potassium channel expression in border and remote zones, which promoted ectopic propagation at fast pacing. Post-MI ionic remodelling reduced EF by up to 10% through inhibition of calcium transient amplitude due to weaker calcium currents or SERCA activity, but the EF at resting heart rate was not sensitive to the extent of repolarisation heterogeneity and the risk of repolarisation abnormalities at fast pacing.

Conclusions

Multi-scale modelling and simulation coherently integrates experimental and clinical data at subcellular, tissue, and organ scales to unravel electromechanical disease mechanisms in MI. In acute post-MI, ionic remodelling and its effect on refractoriness and propagation failure in the BZ have a strong impact on phenotypic ECG variability, whereas in chronic post-MI, the repolarisation dispersion across the BZ is crucial. T-wave and QT abnormalities are better indicators of repolarisation heterogeneities than EF in post-MI.
Age and spatio-temporal variations in food resources modulate stress-immunity relationships in three populations of wild roe deer
Authors: Carbillet Jeffrey , Hollain Marine , Rey Benjamin , Palme Rupert , Pellerin Maryline , Regis Corinne , Geffré Anne , Duhayer Jeanne , Pardonnet Sylvia , Debias François , Merlet Joël , Lemaître Jean-François , Verheyden Hélène , Gilot-Fromont Emmanuelle
Published: February 2022

Living in variable and unpredictable environments, organisms face recurrent stressful situations. The endocrine stress response, which includes the secretion of glucocorticoids, helps organisms to cope with these perturbations. Although short-term elevations of glucocorticoid levels are often associated with immediate beneficial consequences for individuals, long-term glucocorticoid elevation can compromise key physiological functions such as immunity. While laboratory works highlighted the immunosuppressive effect of long-term elevated glucocorticoids, it remains largely unknown, especially in wild animals, whether this relationship is modulated by individual and environmental characteristics. In this study, we explored the co-variation between baseline cortisol levels, assessed non-invasively using faecal cortisol metabolites (FCMs), and 12 constitutive indices of innate, inflammatory, and adaptive immune functions, in wild roe deer living in three populations with contrasting environmental conditions. Using longitudinal data on 564 individuals, we further investigated whether age and spatio-temporal variations in the quantity and quality of food resources affect the relationship between FCMs and immunity. Negative covariation with glucocorticoids was evident only for innate and inflammatory markers of immunity, while adaptive immunity appeared to be positively or not linked to glucocorticoids. In addition, the negative covariations were generally exacerbated, or revealed, in individuals facing harsh environmental constraints and in old individuals. Therefore, our results highlight the importance of measuring multiple immune markers of immunity in individuals from contrasted environments to unravel the complex relationships between glucocorticoids and immunity in wild animals. Our results also help explain conflicting results found in the literature and could improve our understanding of the long-term consequences of elevated glucocorticoid levels on disease spread and population dynamics.
Locally adaptive temperature response of vegetative growth in Arabidopsis thaliana
Authors: Clauw Pieter , Kerdaffrec Envel , Gunis Joanna , Reichardt Ilka , Nizhynska Viktoria , Koemeda Stefanie , Jez Jakub , Nordborg Magnus
Published: February 2022

We investigated early vegetative growth of natural Arabidopsis thaliana accessions in cold, non-freezing temperatures, similar to temperatures these plants naturally encounter in fall at northern latitudes. We found that accessions from northern latitudes produced larger seedlings than accessions from southern latitudes, partly as a result of larger seed size. However, their subsequent vegetative growth when exposed to colder temperatures was slower. The difference was too large to be explained by random population differentiation, and is thus suggestive of local adaptation, a notion that is further supported by substantial transcriptome and metabolome changes in northern accessions. We hypothesize that the reduced growth of northern accessions is an adaptive response, and a consequence of reallocating resources towards cold acclimation and winter survival.
Arbidol inhibits esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase
Authors: Yang Ning , Lu Xuebo , Jiang Yanan , Zhao Lili , Wang Donghao , Wei Yaxing , Yu Yin , Kim Myoung Ok , Laster Kyle Vaughn , Li Xin , Yuan Baoyin , Dong Zigang , Liu Kangdong
Published: February 2022

Background

Esophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma. Based upon a screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of esophageal squamous cell carcinoma in vitro and in vivo.

Method

We first conducted a series of cell-based assays and found that Arbidol treatment inhibited the proliferation and colony formation ability of ESCC cells and promoted G1 phase cell cycle arrest. Phospho-proteomics experiments and in vitro kinase assays were subsequently performed using cell lysates derived from Arbidol-treated cells in order to identify the underlying growth inhibitory mechanism. Finally, a PDX model was used to verify the inhibitory effect of Arbidol in vivo.

Finding

Arbidol inhibits proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle.

Interpretation

Arbidol is a potential ATR inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of MCM2 at Ser108.

Funding

This research was supported by the National Natural Science Foundation of China (grant number 81872335), the National Natural Science Youth Foundation (grant number 81902486), and the Natural Science Foundation of Henan (grant number 161100510300).
Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis
Authors: Goelzer Matthew , Howard Sean , Zavala Anamaria , Conway Daniel , Rubin Janet , van Wijnen Andre J , Uzer Gunes
Published: February 2022

Critical to the mechano-regulation of mesenchymal stem cells (MSC), Linker of the Nucleoskeleton and Cytoskeleton (LINC) complex transduces cytoskeletal forces to the nuclei. The LINC complex contains outer nuclear membrane Nesprin proteins that associate with the cytoskeleton and their inner nuclear membrane couplers, Sun proteins. In addition to coupling Nesprin-associated cytoskeletal elements to inner nuclear membrane, Sun proteins also function in regulating nuclear mechanics and chromatin tethering to inner nuclear membrane. This suggests that release of LINC-mediated cytoskeletal connections from cell nuclei may have different effects on chromatin organization and MSC differentiation than those due to ablation of intra-nuclear Sun proteins. To test this hypothesis we compared Sun1/2 depletion with expression of the dominant-negative KASH domain (dnKASH) that inhibits Nesprin-Sun association. In cells cultured under adipogenic conditions, disconnecting LINC from the cytoskeleton through dnKASH expression, increased adipogenic gene expression and fat droplet formation; heterochromatin H3K27 and H3K9 methylation was unaltered. In contrast, Sun1/2 depletion inhibited adipogenic gene expression and fat droplet formation; as well the anti-adipogenic effect of Sun1/2 depletion was accompanied by increased H3K9me3, which was enriched on Adipoq, silencing this fat locus. We conclude that releasing the nucleus from cytoskeletal constraints via dnKASH accelerates adipogenesis while depletion of Sun1/2 increases heterochromatin accrual on adipogenic genes in a fashion independent of LINC complex function. Therefore, while these two approaches both disable LINC functions, their divergent effects on the epigenetic landscape indicate they cannot be used interchangeably to study mechanical regulation of cell differentiation.
Gene Drive Mosquitoes Can Aid Malaria Elimination by Retarding Plasmodium Sporogonic Development
Authors: Hoermann Astrid , Habtewold Tibebu , Selvaraj Prashanth , Del Corsano Giuseppe , Capriotti Paolo , Inghilterra Maria G. , Kebede Temesgen M. , Christophides George K. , Windbichler Nikolai
Published: February 2022

Gene drives hold promise for the genetic control of malaria vectors. The development of vector population modification strategies hinges on the availability of effector mechanisms impeding parasite development in transgenic mosquitoes. We augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptides, Magainin 2 and Melittin. This small genetic modification, capable of efficient non-autonomous gene drive, hampers oocyst development in both Plasmodium falciparum and Plasmodium berghei. It delays the release of infectious sporozoites while it simultaneously reduces the lifespan of homozygous female transgenic mosquitoes. Modeling the spread of this modification using a large-scale agent-based model of malaria epidemiology reveals that it can break the cycle of disease transmission across a range of endemic settings.

One sentence summary

We developed a gene drive effector that retards Plasmodium development in transgenic Anopheles gambiae mosquitoes via the expression of antimicrobial peptides in the midgut and which is predicted to eliminate malaria under a range of transmission scenarios.
Leishmania amazonensisinfection induces PD-L1 expression on dendritic cells in an mTor-dependent manner and impairs Th1 responsesin vitroandin vivo
Authors: Matos Guedes Herbert L. de , Fonseca-Martins Alessandra M. da , Liang Yuejin , Carlsen Eric D. , Henard Calvin A. , Pinchuk Irina V. , Soong Lynn
Published: February 2022

Leishmania amazonensisis one of the etiological agents of diffuse cutaneous leishmaniasis in South America. In murine models of this infection, dysregulated expansion of effector T cells or exhaustion of Th1 responses are known to be related to pathogenesis, while the induction of regulatory T cells (Tregs) promotes lesion resolution. Recent research has identified several important co-stimulator/receptor pairs, including PD-1/PD-L1, for modulating Th1 responses and Treg induction. In this study, we examined the roles of these molecules inL. amazonensis-infected C57BL/6 mice. We found a significant and selective increase in the expression of PD-1 and PD-L1 (20-fold and 5-fold, respectively), in infected footpad tissues, which correlated with an increased percentage of PD-L1+CD11c+dendritic cells (DCs) and PD-1+CD4+T cells in the draining lymph nodes. To evaluate the mechanism of parasite-induced PD-L1 expression, we infected bone marrow-derived DCs (BMDCs) with promastigotes and amastigotesin vitroin the presence of small molecular inhibitors of critical signaling pathways. WhileL. amazonensisinfection decreased PD-L2 expression on the surface of BMDCs, infection-mediated PD-L1 up-regulation was consistently detected, which was dependent on mTOR and partially dependent on STAT3, PI3K, and MAPK. Infected BMDCs also significantly inhibited the expansion of Th1 cells, but were more competent in inducing CD25+FoxP3+Tregsin vitrothan the non-infected BMDCs; such effects were PD-L1-dependent, as BMDCs from PD-L1−/−mice failed to do the same.In vivoexperiments revealed that infected PD-L1−/−mouse tissues showed increased Th1 responses and IFN-γ production, as well as reduced lesion sizes and parasite loads, without affecting Tregs cell expansion. Together, these results support a protective role for PD-1/PD-L1 signaling in regulating local immune responses duringL. amazonensisinfection. This study provides new insights on immune regulation in New World cutaneous leishmaniasis.
Ethnic inequities in multimorbidity among people with psychosis: A retrospective cohort study
Authors: de Freitas Daniela Fonseca , Pritchard Megan , Shetty Hitesh , Khondoker Mizanur , Nazroo James , Hayes Richard D. , Bhui Kamaldeep
Published: February 2022

Background

Research shows persistent ethnic inequities in mental health experiences and outcomes, with a higher incidence of illnesses among minoritised ethnic groups. People with psychosis have a higher risk of multiple long-term conditions (MLTC; multimorbidity). However, there is limited research regarding ethnic inequalities in multimorbidity in people with a schizophrenia spectrum disorder. This study investigates ethnic disparities in physical health multimorbidity in a cohort of people with psychosis.

Methods

In this retrospective cohort study, using the Clinical Records Interactive Search (CRIS) system, we identified service-users of the South London and Maudsley NHS Trust with a schizophrenia spectrum disorder, and then additional diagnoses of diabetes, hypertension, low blood pressure, overweight or obesity, and rheumatoid arthritis. Multinomial logistic regression was then used to investigate ethnic inequities in odds of multimorbidity (psychosis plus one physical health condition), as well as multimorbidity severity (having one or two physical health conditions, or three or more conditions), compared with no additional health conditions (no multimorbidity). The regression models adjusted for age and duration of care and investigated the influence of gender and area-level deprivation.

Results

On a sample of 20,800 service-users with psychosis, aged 13-65, ethnic differences were observed in the odds for multimorbidity. Compared to White British people, higher odds of multimorbidity were found for people of Black African [aOR=1.41, 95%CI (1.23 - 1.56)], Black Caribbean [aOR=1.79, 95%CI (1.58 – 2.03)], and Black British [aOR=1.64, 95%CI (1.49 - 1.81)] ethnicity. Reduced odds were observed among people of Chinese [aOR=0.61, 95%CI (0.43 – 0.88)] and Other ethnicities [aOR=0.67, 95%CI (0.59 – 0.76)]. Increased odds for severe multimorbidity (three or more physical health conditions) were also observed for people of any Black background.

Conclusions

Ethnic inequities are observed for multimorbidity among people with psychosis. Further research is needed to understand the aetiology and impact of these inequities. These findings support the provision of integrated health care interventions and public health preventive policies and actions.
A centimeter-long bacterium with DNA compartmentalized in membrane-bound organelles
Authors: Volland Jean-Marie , Gonzalez-Rizzo Silvina , Gros Olivier , Tyml Tomáš , Ivanova Natalia , Schulz Frederik , Goudeau Danielle , Elisabeth Nathalie H , Nath Nandita , Udwary Daniel , Malmstrom Rex R , Guidi-Rontani Chantal , Bolte-Kluge Susanne , Davies Karen M , Jean Maïtena R , Mansot Jean-Louis , Mouncey Nigel J , Angert Esther , Woyke Tanja , Date Shailesh V
Published: February 2022

Cells of most bacterial species are around 2 µm in length, with some of the largest specimens reaching 750 µm. Using fluorescence, x-ray, and electron microscopy in conjunction with genome sequencing, we characterized Ca. Thiomargarita magnifica, a bacterium with an average cell length greater than 9,000 µm that is visible to the naked eye. We found that these cells grow orders of magnitude over theoretical limits for bacterial cell size through unique biology, display unprecedented polyploidy of more than half a million copies of a very large genome, and undergo a dimorphic life cycle with asymmetric segregation of chromosomes in daughter cells. These features, along with compartmentalization of genomic material and protein synthesis in membrane-bound organelles, indicate gain of complexity in the Thiomargarita lineage, and challenge traditional concepts of bacterial cells.

One Sentence Summary

Ca. T. magnifica are compartmentalized centimeter-long bacteria
FAM21 is critical for TLR2-CLEC4E-mediated dendritic cell function againstCandida albicans
Authors: Kulkarni Rakesh , Kasani Siti Khadijah , Tsai Ching-Yen , Tung Shu-Yun , Yeh Kun-Hai , Yu Chen-Hsin Albert , Chang Wen
Published: February 2022

FAM21 (family with sequence similarity 21) is a component of the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) protein complex that mediates actin polymerization at endosomal membranes to facilitate sorting of cargo-containing vesicles out of endosomes. To study the function of FAM21in vivo, we generated conditional knockout (cKO) mice in the C57BL/6 background in which FAM21 was specifically knocked out of CD11c-positive dendritic cells. Bone marrow-derived dendritic cells (BMDC) from those mice displayed enlarged early endosomes, and altered cell migration and morphology relative to wildtype (WT) cells. FAM21-cKO cells were less competent in phagocytosis and antigen processingin vitro, though antigen presentation was not affected. More importantly, we identified the TLR2/CLEC4E signaling pathway as being downregulated in FAM21-cKO BMDCs when challenged with its specific ligandCandida albicans. Moreover, FAM21-cKO mice were more susceptible toC. albicansinfection than WT mice. Reconstitution of WT BMDCs in FAM21-cKO mice rescued them from lethalC. albicansinfection. Thus, our study highlights the importance of FAM21 in a host immune response against a significant pathogen.
Genome-widein vivoCRISPR screens identify GATOR1 as a potent tumor suppressor in MYC-driven lymphomagenesis
Authors: Potts Margaret A. , Mizutani Shinsuke , Deng Yexuan , Vaidyanathan Srimayee , Ting Keziah E. , Giner Göknur , Sridhar Shruti , Liao Yang , Diepstraten Sarah , Kueh Andrew J. , Pal Martin , Healey Geraldine , Tai Lin , Wang Zilu , König Christina , Kaloni Deeksha , Whelan Lauren , Milevskiy Michael , Coughlan Hannah , Pomilio Giovanna , Wei Andrew H. , Visvader Jane E. , Papenfuss Anthony T. , Wilcox Stephen , Jeyasekharan Anand D. , Shi Wei , Lelliott Emily J. , Kelly Gemma L. , Brown Kristin K. , Strasser Andreas , Herold Marco J.
Published: February 2022

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC (which is abnormally highly expressed in ∼70% of human cancers) we have used a genome-wide CRISPR knockout screen inEµ-Myc;Cas9transgenic hematopoietic stem and progenitor cellsin vivo. We discovered that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerated c-MYC-driven lymphoma development in mice. Low expression of the GATOR1 complex genes correlated with poor survival outcomes for human patients with high MYC- expressing cancers. Murine lymphomas lacking GATOR1 were highly sensitive to mTOR inhibitors as a single agent therapy, bothin vitroandin vivo. These findings identify inhibition of mTORC1 as a potent tumor suppressive mechanism in c-MYC-driven lymphomagenesis and suggest a new avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition.

Key Points

In vivoCRISPR/Cas9 whole genome knockout screens identified the GATOR1 complex as a potent suppressor of c-MYC-driven lymphomagenesis.

GATOR1 deficiency in MYC-driven lymphomas confers sensitivity to mTOR inhibition, suggesting a novel therapeutic approach.
Autophagy promotes programmed cell death and corpse clearance in specific cell types of the Arabidopsis root cap
Authors: Feng Qiangnan , De Rycke Riet , Dagdas Yasin , Nowack Moritz K.
Published: February 2022

Autophagy is a conserved quality control pathway that mediates the degradation of unnecessary or dysfunctional cellular components by targeting them to the lysosomes or central vacuoles. Autophagy has been implicated in the regulation or execution of regulated cell death processes in a wide range of eukaryotes. However, its function in developmentally controlled programmed cell death (dPCD) in plants remains little studied and controversial. Here, we investigated the role of autophagy in dPCD using the Arabidopsis root cap as an accessible and genetically tractable model system. We show that autophagic flux is induced prior to dPCD execution in both root cap tissues, the columella and the lateral root cap (LRC), and impaired in autophagy-deficient mutants. These mutants show a strongly delayed cell death and an absence of corpse clearance in the columella during and after their shedding into the rhizosphere. However, autophagy deficiency does not affect dPCD execution or corpse clearance in LRC cells at the distal end of the root cap. Our results demonstrate that autophagy promotes dPCD in a highly cell-type specific manner, and present the root cap as a powerful model system to study organ-specific autophagy in vivo.
Tensor decomposition reveals coordinated multicellular patterns of transcriptional variation that distinguish and stratify disease individuals
Authors: Mitchel Jonathan , Gordon M. Grace , Perez Richard K. , Biederstedt Evan , Bueno Raymund , Ye Chun Jimmie , Kharchenko Peter V.
Published: February 2022

Tissue- and organism-level biological processes often involve coordinated action of multiple distinct cell types. Current computational methods for the analysis of single-cell RNA-sequencing (scRNA-seq) data, however, are not designed to capture co-variation of cell states across samples, in part due to the low number of biological samples in most scRNA-seq datasets. Recent advances in sample multiplexing have enabled population-scale scRNA-seq measurements of tens to hundreds of samples. To take advantage of such datasets, here we introduce a computational approach called single-cell Interpretable Tensor Decomposition (scITD). This method extracts “multicellular gene expression patterns” that capture how sample-specific expression states of a cell type are correlated with the expression states of other cell types. Such multicellular patterns can reveal molecular mechanisms underlying coordinated changes of different cell types within the tissue, and can be used to stratify individuals in a clinically-relevant and reproducible manner. We first validated the performance of scITD usingin vitroexperimental data and simulations. We then applied scITD to scRNA-seq data on peripheral blood mononuclear cells (PBMCs) from 115 patients with systemic lupus erythematosus and 56 healthy controls. We recapitulated a well-established pan-cell-type signature of interferon-signaling that was associated with the presence of anti-dsDNA autoantibodies and a disease activity index. We further identified a novel multicellular pattern linked to nephritis, which was characterized by an expansion of activated memory B cells along with helper T cell activation. Our approach also sheds light on ligand-receptor interactions potentially mediating these multicellular patterns. As validation, we demonstrated that these expression patterns also stratified donors from a pediatric SLE dataset by the same phenotypic attributes. Lastly, we found the interferon multicellular pattern and others to be conserved in a COVID-19 dataset, pointing to the presence of both general and disease-specific patterns of inter-individual immune variation. Overall, scITD is a flexible method for exploring co-variation of cell states in multi-sample single-cell datasets, which can yield new insights into complex non-cell-autonomous dependencies that define and stratify disease.