bluuebunny/crossref_metadata_2025 huggingface dataset:
Occult colon cancer with liver abscess and pancreatitis as the first manifestations: A case report
Authors: Yang Shan , Zhao Jin , Liu Qi
Published: January 2023

Introduction:

Klebsiella pneumoniae-induced liver abscess (KP-PLA) is a common type of pyogenic liver abscess, severe acute pancreatitis (SAP) has high mortality, and poor prognosis in advanced colon cancer. There have been no report of SAP complicated with colon cancer after KP-PLA as so far. In this study, we reported a case of SAP secondary to KP-PLA with colon cancer for the first time, so as to provide reference for clinical diagnosis and treatment of these diseases.

Patient concerns and diagnosis:

A 64-year-old woman with a history of diabetes visited our hospital with abdominal pain for 5 + days. He was diagnosed with KP-PLA a month ago, which had not healed when he was admitted. He was diagnosed with SAP, and histological examination of colonic biopsy confirmed the diagnosis of moderately differentiated adenocarcinoma.

Interventions and outcomes:

He was treated with intravenous antibiotics and underwent modified endoscopic mucosal resection under colonoscopy. We conducted a 2-month follow-up, and there was no recurrence of liver abscess and pancreatitis.

Conclusion:

Screening for intestinal tumors is necessary in patients with cryptogenic liver abscess, especially KP-PLA with diabetes.
Serum zinc levels in cancer patients are low and difficult to elevate when complicated by liver cirrhosis: A retrospective study
Authors: Sugimoto Rie , Tanaka Yuki , Senju Takeshi , Morita Yusuke , Lee Lingaku , Hijioka Masayuki , Hisano Terumasa , Furukawa Masayuki
Published: January 2023

In this study, we analyzed blood zinc concentration in patients with various cancer types and the degree of improvement in relation to the underlying disease following treatment with zinc preparations. Serum zinc levels of 530 cancer patients whose blood zinc levels were measured at our hospital from 2016 to 2021 were retrospectively examined in accordance with the primary disease. Changes in zinc levels were analyzed in 155 patients whose zinc levels had been measured on 2 or more occasions in accordance with whether they had received zinc preparations. In addition, the concentration course of zinc before and after zinc formulation administration in 73 patients was examined in accordance with the presence or absence of liver cirrhosis complications. Mean serum zinc levels were below normal in all carcinomas measured, and zinc levels were significantly lower in cirrhosis–hepatocarcinoma cases than in other primary disease cases. Furthermore, serum zinc levels in patients who did not receive zinc preparations decreased significantly over time. In patients who received zinc preparations, the elevated levels of zinc after treatment were significantly lower in patients with cirrhosis than in those without cirrhosis. There was a weak inverse correlation between pre-dose zinc concentration and increased zinc concentration in patients with cirrhosis. In the analysis of covariance, the presence of liver cirrhosis was predominantly correlated with elevated zinc per dose. In summary, serum zinc levels in cancer patients are low and especially low in cancer patients with liver cirrhosis compared with those without cirrhosis after the administration of zinc preparations.
Opioids and constipation therapy in the last week of life: Their impact on patients, caregivers, and the location of death
Authors: Ribeiro Hugo , Magalhães Júlia , Cardoso Tatiana , Chaves-Castro Isabel , Lopes-Mota Carla , Costa Elisabete , Rocha Patrícia , Lopes Luísa , Bouça Ângela , Pereira Cristina , Paulo Andrade José , Dourado Marília
Published: January 2023

The use of opioids to control pain at the end of life may cause constipation, a symptom that can negatively influence the well-being of patients and caregivers. The main aim of this study was to evaluate the impact of constipation on symptomatic control and patients’ overall quality of life at this stage. A particular focus was placed on opioids. We also intended to investigate whether constipation and caregiver fatigue is related to the place of death (hospital vs home). The approach of 121 patients followed in 2021 in their last week of life by a home team specialized in palliative care was analyzed in an observational, retrospective, non-interventional study. The patients were followed up for an average of 39.7 days. A total of 82.6% wished to die at home, which occurred in 74% of the cases. The constipation prevention protocol reduced constipation by 55.1%. It seems that morphine is more related with constipation and tapentadol seems to reduce constipation induced by opioids. Patients tended to die in hospitals when their caregivers were exhausted; however, it was not possible to determine a cutoff point using the Zarit scale, which was used to assess caregiver burden. Constipation in the last week of life does not seem to influence the well-being of patients or their caregivers significantly and the individualization of intensive treatment of constipation is needed. Different opioids have different probabilities of causing adverse effects such as constipation. Future special support mechanisms can be created and activated for the most tired caregivers to avoid exhaustion and promote death at home, if that is the patient’s will.
Pericardial Fat, Socioeconomic Status, and Biological Responses to Acute Mental Stress
Authors: Miller Natalie Ella , Steptoe Andrew
Published: January 2023

Objective

Central adiposity is associated with impaired biological responses to mental stress, and socioeconomic status (SES) might moderate this relationship. However, evidence for associations between pericardial fat, a fat depot implicated in the pathogenesis of cardiovascular disease (CVD), with cardiovascular and inflammatory responses to mental stress is lacking, and moderation by SES is unknown.

Methods

The sample was 473 healthy men and women (mean age = 62.8 years) from the Whitehall II study. Cardiovascular and inflammatory responses to laboratory-induced mental stress, consisting of a 5-minute Stroop task and 5-minute mirror tracing task, were assessed. Pericardial fat volume was measured using electron bean computed tomography and adjusted for body surface area. SES was defined by grade of employment within the British civil service (higher/intermediate/lower).

Results

Pericardial fat was associated with lower heart rate variability, raised heart rate, plasma interleukin-6, fibrinogen, and C-reactive protein at baseline. Furthermore, greater pericardial fat was associated with lower systolic blood pressure reactivity to mental stress, independent of sociodemographics, smoking status, waist-to-hip ratio, and baseline systolic blood pressure. There were no interactions between pericardial fat and SES for any outcome.

Conclusions

Greater pericardial fat was associated with numerous cardiovascular and inflammatory factors implicated in CVD. It was also related to reduced systolic blood pressure reactivity to acute mental stress, independent of central adiposity and baseline systolic blood pressure. This association did not vary by SES. Reduced systolic blood pressure reactivity to mental stress might contribute to the association between greater pericardial fat and CVD.
Low-cost prosthetic feet for underserved populations: A comparison of gait analysis and mechanical stiffness
Authors: Banks Brevin P. , Frei Joshua S. , Spencer Alyssa , Renninger Kaleigh D. , Grover Jordan K. , Abbott Kaitlin , Carlson Benjamin J. , Bruening Dustin A.
Published: January 2023

Background:

Lower-limb loss is an ongoing cause of disability throughout the world. Despite advancements in prosthetic technologies, there are numerous underserved populations in need of effective low-cost prosthetic foot options.

Objective:

To evaluate the biomechanical performance of several low-cost prosthetic feet, using a combination of instrumented gait analysis and mechanical stiffness testing.

Study design:

Randomized crossover with additional case study.

Methods:

We compared the solid-ankle-cushioned-heel (SACH), Jaipur, and Niagara feet with carbon fiber feet. Mechanical stiffness was evaluated using a cantilever-style bending test at 2 angles that was designed to mimic late stance gait loading. Eight below-knee amputees participated in the gait analysis, which focused on foot and ankle motion and energetics.

Results:

Metric analysis showed significant differences among feet in ankle motion and power as well as distal-to-shank power, with SACH showing reduced ankle motion and positive work compared with the other feet. Waveform analysis additionally revealed a compensatory knee flexion moment in SACH and a knee extension moment in Niagara and Jaipur during midstance. In mechanical stiffness testing, SACH had the highest stiffness, with Niagara and carbon fiber roughly similar, and Jaipur the most compliant with the greatest hysteresis.

Conclusions:

There may be an optimal stiffness range for future prosthesis designs that maximizes propulsive energy. This may be achieved by combining some characteristics of Jaipur and Niagara feet in new designs. Ultimately, optimizing stiffness and energetics for gait biomimicry while maintaining cost, availability, and versatility across cultures will alleviate the effects of limb loss among underserved populations.
Comparison of prosthetic mobility and balance in transfemoral amputees with bone-anchored prosthesis vs. socket prosthesis
Authors: Gailey Robert S. , Kristal Anat , Al Muderis Munjed , Lučarević Jennifer , Clemens Sheila , Applegate E. Brooks , Isaacson Brad M. , Pasquina Paul F. , Symsack Allison , Gaunaurd Ignacio A.
Published: January 2023

Background:

The literature comparing bone-anchored prosthesis (BAP) with socket prosthesis (SP) consistently reports improvement in physical health and quality of life using primarily patient-reported outcome measures (PROMs).

Objective:

To determine the differences in mobility and balance using performance-based outcome measures and PROMs in people with transfemoral amputations (TFAs) fitted with BAP vs. SP.

Study design:

Causal comparative.

Methods:

Two groups of people with TFAs were recruited: one using a BAP (N = 11; mean age ± standard deviation, 44 ± 14.9 years; mean residual limb length as a percentage of the intact femur, 68% ± 15.9) and another group using a SP (N = 11; mean age ± standard deviation, 49.6 ± 16.0 years; mean residual limb length as a percentage of the intact femur, 81% ± 13.9), and completed the 10-meter walk test, component timed-up-and-go, Prosthetic Limb Users Survey of Mobility™ 12-item, and Activities-specific Balance Confidence Scale.

Results:

There were no statistically significant differences between the BAP and SP groups in temporal spatial gait parameters and prosthetic mobility as measured by the 10-meter walk test and component timed-up-and-go, yet large effect sizes were found for several variables. In addition, Activities-specific Balance Confidence Scale and Prosthetic Limb Users Survey of Mobility™ scores were not statistically different between the BAP and SP groups, yet a large effect sizes were found for both variables.

Conclusions:

This study found that people with TFA who use a BAP can demonstrate similar temporal spatial gait parameters and prosthetic mobility, as well as self-perceived balance confidence and prosthetic mobility as SP users. Therefore, suggesting that the osseointegration reconstruction surgical procedure provides an alternative option for a specific population with TFA who cannot wear nor have limitations with a SP. Future research with a larger sample and other performance-based outcome measures and PROMs of prosthetic mobility and balance would further determine the differences between the prosthetic options.
Foley Balloon Pull Test of Pelvic Floor Muscle Strength
Authors: Spector Sean , Mama Saifuddin , Andrews Michele , Lipetskaia Lioudmila
Published: January 2023

Importance

Methods for pelvic floor muscle (PFM) strength testing are limited by their subjective nature, prohibitive cost, training burden, or lack of validation.

Objectives

The objectives of this study are to validate a new, inexpensive, and accessible method for PFM strength testing using a 30-mL Foley balloon inserted into the vagina, the Foley Balloon Pull Test (FPT), and to demonstrate external validity by comparing the subjective Oxford Muscle Grading Scale (OMGS) scores to measurements obtained with the FPT. Secondary objectives include demonstrating repeatability and internal validity of the FPT.

Study Design

Participants underwent PFM strength testing with the OMGS on a 0 to 5 scale. A gauge was attached to the Foley balloon to measure the force required to remove the balloon from the vagina. Three measures at rest and 3 measures during maximal muscle contraction were recorded. Cross-sectional data were analyzed.

Results

One hundred one participants were included; there were no adverse events. The ratio of contraction FPT measurements to at-rest measurements revealed moderate linear and rank order correlation with the OMGS (R
2 = 0.54, P < 0.001, and R
2 = 0.58, P < 0.001). The reliability of repeated measurements was highly correlated, with intraclass correlation coefficients >0.95. An FPT ratio of 1.75 discriminated between weak (0–2) and strong (3–5) OMGS scores with an area under the curve of 0.86.

Conclusion

The FPT is an internally reliable, simple, and externally valid method of PFM strength testing.
Cross-Sectional Study of Resident-Reported Surgical Experience in Female Pelvic Medicine and Reconstructive Surgery
Authors: Ward Sarah A. , Mendiola Monica , Royce Celeste S. , Anand Mallika , Gompers Annika , Hacker Michele R. , Winkelman William D.
Published: January 2023

Importance

Comprehensive surgical training is an essential component of obstetrics and gynecology residency, yet subspecialty experience may be declining.

Objective

The objective of this study was to describe trends in reported obstetrics and gynecology resident experience in female pelvic medicine and reconstructive surgery (FPMRS).

Study Design

This study was a retrospective analysis of national case log reports from the Accreditation Council for Graduate Medical Education (ACGME) for obstetrics and gynecology residents.

Results

From 2013 through 2019, ACGME collected data from a median of 241 programs (range, 239–242) with a median of 1,259 residents (range, 1,213–1,286) reporting annually. There was a 26% decrease in resident-reported experience with incontinence and pelvic floor procedures from 74 ± 38 in 2013 to 55 ± 34 in 2019 (P < 0.001). Cystoscopy increased by 19% from 43 ± 25 in 2013 to 51 ± 29 in 2019 (P < 0.001). From 2014 to 2019, vaginal hysterectomy cases decreased by 12% (P < 0.001).

Conclusions

There was a significant decrease in resident-reported FPMRS surgical experience from 2013 to 2019, while cystoscopy numbers increased. After laparoscopic and vaginal hysterectomies were unbundled in 2013, resident vaginal hysterectomy cases decreased from 2014 to 2019. Given that the ACGME Incontinence and Pelvic Floor designation comprises a wide range of procedures, future investigation is needed to elucidate the gaps in FPMRS-specific surgical training during residency and its implication in comprehensive resident surgical training.
Pregnancy and Outcomes After Prolapse Surgery: A Case Series
Authors: Boyd Brittni , Buono Kristen , Novin Atieh , Whitcomb Emily
Published: January 2023

Importance

There are limited data on whether pelvic organ prolapse (POP) surgery is durable after subsequent delivery.

Objectives

The aims of this study were to evaluate the safety and durability of POP surgery after delivery and to describe the medical decision-making and clinical outcomes of patients who gave birth after POP surgery.

Study Design

This study is a retrospective case series of patients who underwent surgery for symptomatic POP between 2007 and 2017, and subsequently had a live birth.

Results

Twenty patients were identified. Seventeen patients underwent posterior colporrhaphy, 10 anterior colporrhaphy, and 5 apical suspensions. The mean interval between POP surgery and the first delivery was 28.6 months. One patient endorsed recurrent POP symptoms before pregnancy, and none of the remaining 19 patients reported recurrent POP symptoms before or during pregnancy. There were no pregnancy complications related to the POP surgery. Nine patients underwent cesarean delivery (CD). Four patients were counseled to have a CD due to their prior POP surgery, 3 patients had an elective primary CD due to the POP surgery, 1 patient chose an elective repeat CD, and 1 patient had a CD due to obstructed labor. Urogynecologists were consulted for delivery recommendations for 6 patients and recommended CD for 3 of them. Eleven patients had spontaneous vaginal delivery. Three patients reported recurrent POP symptoms after delivery.

Conclusions

Our findings corroborate previous case series demonstrating the safety and durability of POP surgery during and after pregnancy. More than 75% of patients gave birth by CD, which was due to physician or patient concerns regarding the prior POP surgery.
Double Pretransplant Positivity for Autoantibodies to LG3 and Angiotensin II Type 1 Receptor Is Associated With Alloimmune Vascular Injury in Kidney Transplant Recipients
Authors: Carroll Robert , Turgeon Julie , Deayton Sue , Emery Tim , Bilogrevic Fiona , Jahan Sadia , Rimbaud Annie Karakeussian , Georges Barbara , Tavares-Brum Alexandre , Hébert Marie-Josée , Cardinal Héloïse
Published: January 2023

Background.

Both angiotensin II receptor autoantibodies (ATRabs) and autoantibodies to LG3 have been linked to kidney graft rejection with alloimmune vascular injury (AVI). We aimed to examine whether positivity for both anti-LG3 and ATRabs is associated with rejection with AVI in kidney transplant recipients.

Methods.

We performed a retrospective cohort study including consecutive kidney transplant recipients between 2013 and 2017 at a single center. The primary outcome was acute rejection with AVI (Banff grade 2 or 3 T-cell-mediated rejection and/or antibody-mediated rejection) in the first 3 mo posttransplant. The secondary outcome was death-censored allograft loss. The independent variables, anti-LG3 and ATRab, were measured pretransplant.

Results.

Among the 328 study participants, 68 experienced acute rejection with AVI and 23 experienced graft loss over a median follow-up of 4.5 y. In a multivariable model, double pretransplant positivity for anti-LG3/ATRab was associated with acute rejection with AVI (odds ratio: 2.73, 95% confidence interval: 1.06-7.05). We did not observe an association between double positivity for anti-LG3/ATRab and death-censored graft loss.

Conclusions.

Double positivity for anti-LG3/ATRabs pretransplant is associated with a higher risk of acute rejection with AVI. Whether therapies that remove antibodies could decrease that risk remains to be studied.

Supplemental Visual Abtract: http://links.lww.com/TXD/A494.
YOKENELLA REGENSBURGEI URINARY TRACT INFECTION IN AN IMMUNOCOMPETENT PATIENT: A CASE REPORT
Authors: V Annie Sheeba , Suji Thangamani , Jayanth Selvin Theodore , Sahni Rani Diana
Published: January 2023

Yokenella regensburgei, belonging to the order Enterobacterales, is a rare and emerging human pathogen reported to cause both superficial and invasive infections. The 13 case reports in literature worldwide highlight blood, bone and wound infections. To our knowledge this is the first case report of Yokenella regensburgei causing UTI in a 69-year old immunocompetent patient which was isolated in 2 separate specimens and identified using MALDI-TOF MS (Bio Mé rieux, Version 3.2, France). It was found to be susceptible to most antimicrobials but resistant to penicillin, amoxicillin-clavulanate, cefoxitin, colistin and chromosomal inducible ampC resistance was demonstrated on disk approximation test and blaYOC-1 Class C beta-lactamase, beta lactamase superfamily and MBL fold metallo-hydrolase genes were found on whole genome sequencing.
Clinical Decision Support with a Comprehensive in-EHR Patient Tracking System Improves Genetic Testing Follow Up
Authors: Campbell Ian M. , Karavite Dean J. , McManus Morgan L. , Cusick Fred C. , Junod David C. , Sheppard Sarah E. , Lourie Eli M. , Shelov Eric D. , Hakonarson Hakon , Luberti Anthony A. , Muthu Naveen , Grundmeier Robert W.
Published: January 2023

Objective

We sought to develop and evaluate an electronic health record (EHR) genetic testing tracking system to address the barriers and limitations of existing spreadsheet-based workarounds.

Materials and Methods

We evaluated the spreadsheet-based system using mixed effects logistic regression to identify factors associated with delayed follow up. These factors informed the design of an EHR-integrated genetic testing tracking system. After deployment we assessed the system in two ways. We analyzed EHR access logs and note data to assess patient outcomes and performed semi-structured interviews with users to identify impact of the system on work.

Results

We found that patient-reported race was a significant predictor of documented genetic testing follow up, indicating a possible inequity in care. We implemented a CDS system including a patient data capture form and management dashboard to facilitate important care tasks. The system significantly speeded review of results and significantly increased documentation of follow-up recommendations. Interviews with system users identified key team members ensuring success and revealed that the system addresses a number of sociotechnical factors that collectively result in safer and more efficient care.

Discussion

Our new tracking system ended decades of workarounds for identifying and communicating test results and improved clinical workflows. Interview participants related that the system decreased cognitive and time burden which allowed them to focus on direct patient interaction.

Conclusion

By assembling a multidisciplinary team, we designed a novel patient tracking system that improves genetic testing follow up. Similar approaches may be effective in other clinical settings.
Incident autoimmune diseases in association with a SARS-CoV-2 infection: A matched cohort study
Authors: Tesch Falko , Ehm Franz , Vivirito Annika , Wende Danny , Batram Manuel , Loser Friedrich , Menzer Simone , Jacob Josephine , Roessler Martin , Seifert Martin , Kind Barbara , König Christina , Schulte Claudia , Buschmann Tilo , Hertle Dagmar , Ballesteros Pedro , Baßler Stefan , Bertele Barbara , Bitterer Thomas , Riederer Cordula , Sobik Franziska , Reitzle Lukas , Scheidt-Nave Christa , Schmitt Jochen
Published: January 2023

Objectives

To investigate whether the risk of developing an incident autoimmune disease is increased in patients with previous COVID-19 disease compared to people without COVID-19.

Method

A cohort was selected from German routine health care data covering 38.9 million individuals. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through December 31, 2020. Patients were matched 1:3 to control patients without COVID-19. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyze the onset of autoimmune diseases during the post-acute period. Incidence rates (IR) per 1000 person-years were calculated for each outcome and patient group. Poisson models were deployed to estimate the incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding diagnosis of COVID-19.

Results

In total, 641,704 patients with COVID-19 were included. Comparing the incidence rates in the COVID-19 (IR=15.05, 95% CI: 14.69-15.42) and matched control groups (IR=10.55, 95% CI: 10.25-10.86), we found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID-19. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID-19 were at a greater risk for incident autoimmune diseases.

Conclusions

SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.
Evidence for Cytokine Dysregulation in Schizophrenia Spectrum Disorders: A Comparison of Cerebrospinal Fluid and Blood Samples
Authors: Gallego Juan A. , McNamara Robert K. , Castaneda Santiago , Jimenez Laura D. , Alvarez-Lesmes Santiago , Blanco Emily A. , Lencz Todd , Malhotra Anil K.
Published: January 2023

Introduction

Abnormalities in immune function have been described in schizophrenia. Cytokines, key signaling molecules of the immune system, have been investigated in peripheral blood samples of patients with schizophrenia though few studies have investigated cytokines in cerebrospinal fluid (CSF). Moreover, very few studies with schizophrenia subjects have investigated the relationships between CSF and blood cytokine levels or investigated sex differences.

Methods

In this cross-sectional study, subjects with schizophrenia spectrum disorder (SSD) diagnosis and healthy volunteers (HV) underwent a lumbar puncture, a blood draw, and psychopathology ratings. CSF and plasma levels of IL-1ß, IL-2, IL-4, IL-6, IL-8 and TNFα were determined by enzyme-linked immunosorbent assay (ELISA) and a high-sensitivity MilliplexTM Multiplex kit. Cytokine levels were square root transformed and compared between both groups using bivariate tests and a multivariate regression analysis. CSF and plasma cytokine levels were compared as were the effects of sex.

Results

Thirty SSD and 23 HV were included in the study. In bivariate analysis, CSF TNFα and IL-4 levels were significantly increased in SSD subjects compared to HV. Multivariate regression analysis also showed increases in TNFα and IL-4 after adjusting for sex, age and body mass index. There were no significant differences in plasma cytokine levels between groups, and there were no correlations between CSF and plasma cytokine levels. CSF levels of TNFα and IL-4 were negatively correlated with speed of processing. Stratified analysis by sex showed significantly increased levels of TNFα and IL-4 in SSD vs. HV in males but not in females, although sample sizes were small after stratification.

Discussion

The present findings provide evidence of dysregulation of TNFα and IL-4 in CSF of schizophrenia and suggest that peripheral cytokine levels are not reflective of CSF levels. We also provide further evidence of the association between cytokine levels and impairment of certain cognitive domains. These results identify elevated CSF TNFα levels as a potential biomarker relevant to the neuropathophysiology of schizophrenia.
SRC-mediated and TKS5-enabled podosome formation is an inherent property of IPF fibroblasts, promoting ECM invasion and pulmonary fibrosis
Authors: Barbayianni Ilianna , Kanellopoulou Paraskevi , Fanidis Dionysios , Ntouskou Eleftheria-Dimitra , Nastos Dimitris , Galaris Apostolos , Harokopos Vaggelis , Hatzis Pantelis , Tsitoura Eliza , Homer Robert , Kaminski Naftali , Antoniou Katerina M. , Crestani Bruno , Tzouvelekis Argyrios , Aidinis Vassilis
Published: January 2023

The activation and accumulation of lung fibroblasts (LFs), resulting in aberrant deposition of collagens and other extracellular matrix (ECM) components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis (IPF), a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of IPF patients and bleomycin (BLM)-treated mice, correlating with increased collagen type I alpha 1 chain (COL1A1) expression. The profibrotic milieu, TGFβ, as well as a stiff Col1a1-rich acellular fibrotic ECM, were found to induceTKS5expression and the formation of prominent podosome rosettes in LFs, culminating in increased ECM invasion. Podosomes were retainedex vivoin the absence of any stimulation, indicating that the formation of TKS5-enabled podosomes is an inherent property of IPF LFs. Remarkably, haploinsufficientTks5+/-mice were relatively resistant to BLM-induced pulmonary fibrosis. Disease protection was largely attributable to diminished podosome formation in LFs and decreased ECM invasion, thus indicating TKS5-enabled and podosome-mediated ECM invasion as a major pathogenic mechanism in pulmonary fibrosis. Expression profiling revealed an ECM-podosome cross talk, and pharmacologic connectivity map analysis suggested several inhibitors that could prevent podosome formation and thus pulmonary fibrosis. Among them, inhibition of src kinase was shown to potently attenuate podosome formation in LFs, ECM invasion, as well as pulmonary fibrosis in post BLM precision cut lung slices, suggesting that pharmacological targeting of TKS5-enabled podosome formation is a very promising therapeutic option in pulmonary fibrosis.
Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma
Authors: Voigt Anita Y. , Walter Andrew , Young Timothy , Graham John P. , Batista Bittencourt Bruna M. , de Mingo Pulido Alvaro , Prieto Karol , Tsai Kenneth Y. , Sundberg John P. , Oh Julia
Published: January 2023

The gut microbiome is increasingly recognized to alter cancer risk, progression, and response to treatments such as immunotherapy, especially in cutaneous melanoma. However, whether the microbiome influences immune checkpoint inhibitor (ICI) immunotherapy response to non-melanoma skin cancer has not yet been defined. As squamous cell carcinomas (SCC) are in closest proximity to the skin microbiome, we hypothesized that the skin microbiome, which regulates cutaneous immunity, might affect SCC-associated anti-PD1 immunotherapy treatment response. We used ultraviolet radiation to induce SCC in SKH1 hairless mice. We then treated the mice with broad-band antibiotics to deplete the microbiome, followed by colonization by candidate skin and gut bacteria or persistent antibiotic treatment, all in parallel with ICI treatment. We longitudinally monitored skin and gut microbiome dynamics by 16S rRNA gene sequencing, and tumor burden by periodic tumor measurements and histologic assessment. Our study revealed that antibiotics-induced abrogation of the microbiome reduced tumor burden, suggesting a functional role of the microbiome in non-melanoma skin cancer therapy response.
Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis
Authors: Bakhshandeh Sadra , Heras Unai , Taïeb Hubert M. , Varadarajan Adithi R. , Lissek Susanna M. , Hücker Sarah M. , Lu Xin , Garske Daniela S. , Young Sarah A. E. , Abaurrea Andrea , Caffarel Maria M , Riestra Ana , Bragado Paloma , Contzen Jörg , Gossen Manfred , Kirsch Stefan , Warfsmann Jens , Honarnejad Kamran , Klein Christoph A. , Cipitria Amaia
Published: January 2023

Resected tumors frequently relapse with distant metastasis, despite systemic treatment. Cellular dormancy has been identified as an important mechanism underlying such drug resistance enabling late relapse. Nonetheless, hurdles associated with detection and isolation of disseminated cancer cells (DCCs) in disease-free patients urge the need forin vitromodels of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D-engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERKlow:P-p38highdormancy signaling ratio, along with Ki67-expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domains 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 downregulation. Thus, our biomaterial-based approach will enable systematic screens for novel compounds suited to eradicate potentially relapsing, dormant cancer cells.

Teaser

Using semi-synthetic bioengineered hydrogels, we reveal a mechanosensitive and drug protective mechanism of dormant cancer cells in tissues
Selective recruitment: Evidence for task-dependent gating of inputs to the cerebellum
Authors: Shahshahani Ladan , King Maedbh , Nettekoven Caroline , Ivry Richard , Diedrichsen Jörn
Published: January 2023

fMRI studies have documented cerebellar activity across a wide array of tasks. However, the functional contribution of the cerebellum within these task domains remains unclear because cerebellar activity is often studied in isolation. This is problematic, as cerebellar fMRI activity may simply reflect the transmission of neocortical activity through fixed connections. Here we present a new approach that addresses this problem. Rather than focus on task-dependent activity changes in the cerebellum alone, we ask if neocortical inputs to the cerebellum are gated in a task-dependent manner. We hypothesize that input is upregulated when the cerebellum functionally contributes to a task. We first validated this approach using a finger movement task, where the integrity of the cerebellum has been shown to be essential for the coordination of rapid alternating movements but not for force generation. While both neocortical and cerebellar activity increased with increasing speed and force, the speed-related changes in the cerebellum were larger than predicted by an optimized cortico-cerebellar connectivity model. We then applied the same approach in a cognitive domain, assessing how the cerebellum supports working memory. Enhanced gating was associated with the encoding of items in working memory, but not with the manipulation or retrieval of the items. Focusing on task-dependent gating of neocortical inputs to the cerebellum offers a promising approach for using fMRI to understand the specific contributions of the cerebellum to cognitive function.
Hacking brain development to test models of sensory coding
Authors: Ahmed Maria , Rajagopalan Adithya E. , Pan Yijie , Li Ye , Williams Donnell L. , Pedersen Erik A. , Thakral Manav , Previero Angelica , Close Kari C. , Christoforou Christina P. , Cai Dawen , Turner Glenn C. , Clowney E. Josephine
Published: January 2023

Animals can discriminate myriad sensory stimuli but can also generalize from learned experience. You can probably distinguish the favorite teas of your colleagues while still recognizing that all tea pales in comparison to coffee. Tradeoffs between detection, discrimination, and generalization are inherent at every layer of sensory processing. During development, specific quantitative parameters are wired into perceptual circuits and set the playing field on which plasticity mechanisms play out. A primary goal of systems neuroscience is to understand how material properties of a circuit define the logical operations— computations--that it makes, and what good these computations are for survival. A cardinal method in biology—and the mechanism of evolution--is to change a unit or variable within a system and ask how this affects organismal function. Here, we make use of our knowledge of developmental wiring mechanisms to modify hard-wired circuit parameters in theDrosophila melanogastermushroom body and assess the functional and behavioral consequences. By altering the number of expansion layer neurons (Kenyon cells) and their dendritic complexity, we find that input number, but not cell number, tunes odor selectivity. Simple odor discrimination performance is maintained when Kenyon cell number is reduced and augmented by Kenyon cell expansion.
Ndel1 modulates dynein activation in two distinct ways
Authors: Garrott Sharon R , Gillies John P , Siva Aravintha , Little Saffron R , El Jbeily Rita , DeSantis Morgan E
Published: January 2023

Dynein is the primary minus-end-directed microtubule motor [1]. To achieve activation, dynein binds to the dynactin complex and an adaptor to form the “activated dynein complex” [2, 3]. The protein Lis1 aids activation by binding to dynein and promoting its association with dynactin and adaptor [4, 5]. Ndel1 and its orthologue Nde1 are dynein and Lis1 binding proteins that help control where dynein localizes within the cell [6]. Cell-based assays suggest that Ndel1/Nde1 also work with Lis1 to promote dynein activation, although the underlying mechanism is unclear [6]. Using purified proteins and quantitative binding assays, we found that Ndel1’s C-terminal region contributes to binding to dynein and negatively regulates binding to Lis1. Using single-molecule imaging and protein biochemistry, we observed that Ndel1 inhibits dynein activation in two distinct ways. First, Ndel1 disfavors the formation of the activated dynein complex. We found that phosphomimetic mutations in Ndel1’s C-terminal domain increase its ability to inhibit dynein-dynactin-adaptor complex formation. Second, we observed that Ndel1 interacts with dynein and Lis1 simultaneously and sequesters Lis1 away from its dynein binding site. In doing this, Ndel1 prevents Lis1-mediated dynein activation. Our work suggests thatin vitro, Ndel1 is a negative regulator of dynein activation, which contrasts with cellular studies where Ndel1 promotes dynein activity. To reconcile our findings with previous work, we posit that Ndel1 functions to scaffold dynein and Lis1 together while keeping dynein in an inhibited state. We speculate that Ndel1 release can be triggered in cellular settings to allow for timed dynein activation.
The memory of pathogenic IgE is contained within CD23+IgG1+memory B cells poised to switch to IgE in food allergy
Authors: Ota Miyo , Hoehn Kenneth B. , Ota Takayuki , Aranda Carlos J. , Friedman Sara , Braga Weslley F. , Malbari Alefiyah , Kleinstein Steven H. , Sicherer Scott H. , Curotto de Lafaille Maria A.
Published: January 2023

Food allergy is caused by allergen-specific IgE antibodies but little is known about the B cell memory of persistent IgE responses. Here we describe in human pediatric peanut allergy CD23+IgG1+memory B cells arising in type 2 responses that contain peanut specific clones and generate IgE cells on activation. These ‘type2-marked’ IgG1+memory B cells differentially express IL-4/IL-13 regulated genesFCER2/CD23, IL4R, and germlineIGHEand carry highly mutated B cell receptors (BCRs). Further, high affinity memory B cells specific for the main peanut allergen Ara h 2 mapped to the population of ‘type2-marked’ IgG1+memory B cells and included convergent BCRs across different individuals. Our findings indicate that CD23+IgG1+memory B cells transcribing germlineIGHEare a unique memory population containing precursors of pathogenic IgE.

One-Sentence Summary

We describe a unique population of IgG+memory B cells poised to switch to IgE that contains high affinity allergen-specific clones in peanut allergy.
Evolutionary loss of the ß1-adrenergic receptor in salmonids
Authors: Joyce William
Published: January 2023

Whole-genome duplications (WGDs) have been at the heart of the diversification of ß-adrenergic receptors (ß-ARs) in vertebrates. Non-teleost jawed vertebrates typically possess three ß-AR genes:adrb1(ß1-AR),adrb2(ß2-AR), andadrb3(ß3-AR), originating from the ancient 2R (two rounds) WGDs. Teleost fishes, owing to the teleost-specific WGD, have five ancestraladrbparalogs (adrb1, adrb2a, adrb2b, adrb3aandadrb3b). Salmonids are particularly intriguing from an evolutionary perspective as they experienced an additional WGD after separating from other teleosts. Moreover, adrenergic regulation in salmonids, especially rainbow trout, has been intensively studied for decades. However, the repertoire ofadrbgenes in salmonids has not been yet characterized. An exhaustive genome survey of diverse salmonids, spanning five genera, complemented by phylogenetic sequence analysis, revealed each species has sevenadrbparalogs: twoadrb2a, twoadrb2b, twoadrb3aand oneadrb3b. Surprisingly, salmonids emerge as the first known jawed vertebrate lineage to lackadrb1. adrb1is nevertheless highly expressed in the hearts of non-salmonid teleosts, indicating that the wealth of data on adrenergic regulation in salmonids should be generalised to other teleost fishes with caution. It is hypothesised that the loss ofadrb1could have been viable because of the evolutionary radiation ofadrb2andadrb3genes attributable to the salmonid WGD.
Genomic targets of HOP2 are enriched for features found at recombination hotspots
Authors: Daradur Jenya , Kesserwan Mohamad , Freese Nowlan H. , Loraine Ann E. , Riggs C. Daniel
Published: January 2023

HOP2 is a conserved protein that plays a positive role in homologous chromosome pairing and a separable role in preventing illegitimate connections between nonhomologous chromosome regions during meiosis. We employed ChIP-seq to discover that Arabidopsis HOP2 binds along the length of all chromosomes, except for centromeric and nucleolar organizer regions, and no binding sites were detected in the organelle genomes. A large number of reads were assigned to the HOP2 locus itself, yet TAIL-PCR and SNP analysis of the aligned sequences indicate that many of these reads originate from the transforming T-DNA, supporting the role of HOP2 in preventing nonhomologous exchanges. The 292 ChIP-seq peaks are largely found in promoter regions and downstream from genes, paralleling the distribution of recombination hotspots, and motif analysis revealed that there are several conserved sequences that are also enriched at crossover sites. We conducted coimmunoprecipitation of HOP2 followed by LC-MS/MS and found enrichment for several proteins, including some histone variants and modifications that are also known to be associated with recombination hotspots. We propose that HOP2 may be directed to chromatin motifs near double strand breaks, where homology checks are proposed to occur.
Rescue of normal excitability in LGI1-deficient epileptic neurons
Authors: Extrémet Johanna , Ramirez-Franco Jorge , Fronzaroli-Molinieres Laure , Boumedine-Guignon Norah , Ankri Norbert , Far Oussama El , José Garrido Juan , Debanne Dominique , Russier Michaël
Published: January 2023

Leucine-rich Glioma Inactivated 1 (LGI1) is a glycoprotein secreted by neurons, the deletion of which leads to Autosomal Dominant Lateral Temporal Lobe Epilepsy. Recently, we showed that LGI1 deficiency in a mouse model (KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release. However, the precise conditions for rescuing normal excitability in KO-Lgi1 neurons have still not been reported. Here we show that the selective expression of LGI1 in KO-Lgi1 neurons with the use of single-cell electroporation reduces intrinsic excitability, and restores both the Kv1.1 mediated D-type current and Kv1.1 immunostaining at the AIS. In addition, we show that the homeostatic shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons electroporated with the Lgi1 gene. Furthermore, we reveal a spatial gradient of both intrinsic excitability and Kv1.1 immunostaining that is centred on the electroporated neuron. We conclude that expression of LGI1 restores normal excitability through the expression of functional Kv1 channels at the AIS.
Synthetic genetic circuits to uncover and enforce the OCT4 trajectories of successful reprogramming of human fibroblasts
Authors: Ilia Katherine , Shakiba Nika , Bingham Trevor , Jones Ross D. , Kaminski Michael M. , Aravera Eliezer , Bruno Simone , Palacios Sebastian , Weiss Ron , Collins James J. , Del Vecchio Domitilla , Schlaeger Thorsten M.
Published: January 2023

Reprogramming human fibroblasts to induced pluripotent stem cells (iPSCs) is inefficient, with heterogeneity among transcription factor (TF) trajectories driving divergent cell states. Nevertheless, the impact of TF dynamics on reprogramming efficiency remains uncharted. Here, we identify the successful reprogramming trajectories of the core pluripotency TF, OCT4, and design a genetic controller that enforces such trajectories with high precision. By combining a genetic circuit that generates a wide range of OCT4 trajectories with live-cell imaging, we track OCT4 trajectories with clonal resolution and find that a distinct constant OCT4 trajectory is required for colony formation. We then develop a synthetic genetic circuit that yields a tight OCT4 distribution around the identified trajectory and outperforms in terms of reprogramming efficiency other circuits that less accurately regulate OCT4. Our synthetic biology approach is generalizable for identifying and enforcing TF dynamics for cell fate programming applications.

One-sentence summary

Genetic controllers and live-cell imaging offer a versatile strategy for probing the role of transcription factor dynamics in cell fate transitions.
Ensemble Processing and Synthetic Image Generation for Abnormally Shaped Nuclei Segmentation
Authors: Han Yue , Lei Yang , Shkolnikov Viktor , Xin Daisy , Auduong Alicia , Barcelo Steven , Allebach Jan , Delp Edward J.
Published: January 2023

Abnormalities in biological cell nuclei morphology are correlated with cell cycle stages, disease states, and various external stimuli. There have been many deep learning approaches that have described nuclei segmentation and analysis of nuclear morphology. One problem with many deep learning methods is acquiring large amounts of annotated nuclei data, which is generally expensive to obtain. In this paper, we propose a system to segment abnormally shaped nuclei with a limited amount of training data. We first generate specific shapes of synthetic nuclei groundtruth. We randomly sample these synthetic groundtruth images into training sets to train several Mask R-CNNs. We design an ensemble strategy to combine or fuse segmentation results from the Mask R-CNNs. We also design an oval nuclei removal by StarDist to reduce the false positives and improve the overall segmentation performance. Our experiments indicate that our method outperforms other methods in segmenting abnormally shaped nuclei.
Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages
Authors: Zarrow Jonah E. , Alli-Oluwafuyi Abdul-Musawwir , Youwakim Cristina M. , Kim Kwangho , Jenkins Andrew N. , Suero Isabelle C. , Jones Margaret R. , Mashhadi Zahra , Mackie Kenneth P. , Waterson Alex G. , Doran Amanda C. , Sulikowski Gary A. , Davies Sean S.
Published: January 2023

N-acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzesN-acyl-phosphatidylethanolamine (NAPEs) to formN-acyl-ethanolamides (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance,NAPEPLDexpression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators (VU534 and VU533) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced inNapepld-/-BMDM or after Nape-pld inhibition. Together these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.