bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining the Association Between Melanomas and Fields of Melanocytic Dysplasia
Authors: Mata Douglas A. , Lian Christine G. , Hafeez Farhaan
Published: January 2023

Some have proposed that melanomas in situ may be associated with fields of melanocytic dysplasia, particularly on sun-damaged skin, whereas others maintain that the atypical junctional melanocytic hyperplasia (MH) at the periphery of melanomas is simply background junctional MH of sun-damaged skin. The biological potential of atypical junctional MH at the periphery of melanomas is uncertain. We examined whether atypical junctional MH was intrinsic to the melanoma itself (ie, melanoma-associated field of melanocytic dysplasia) or was simply the predictable junctional MH associated with long-standing sun exposure. We retrospectively compared 106 cutaneous melanoma excisions without residual tumor with 105 nonmelanoma cutaneous tumor excisions (ie, basal cell or squamous cell carcinomas) without residual tumor. MH with atypia occurred significantly more frequently in melanoma than in nonmelanoma cutaneous tumor excisions (55.7% vs. 24.8%, P < 0.001). Solar elastosis occurred significantly less frequently in melanoma than in nonmelanoma cutaneous tumor excisions; 33.0% of melanoma excisions and 8.6% of nonmelanoma excision samples exhibited no solar elastosis, respectively (P < 0.001). After controlling for solar elastosis using multivariable linear regression, the association between MH with atypia and melanoma excisions remained significant (P < 0.001). Our results, therefore, demonstrate that melanomas were associated with atypical junctional MH that could not solely be accounted for by the extent of sun damage as measured by solar elastosis.
Primary Cutaneous Ewing Sarcoma of the Scalp With Metastasis to the Lung: An Unusual Manifestation During Pregnancy
Authors: Regmi Aayushma , Raouf Maryam , Mudaliar Kumaran M. , Speiser Jodi J. , Ananthanarayanan Vijayalakshmi
Published: January 2023

A 32-year-old G2P1L1 (5 months pregnant) woman presented with a 3-month history of a slow-growing cystic lesion on her scalp vertex. Similar lesions in the exact location were excised twice in the past with a diagnosis of trichilemmal carcinoma (TC). A biopsy of the scalp lesion showed morphology and immunoprofile consistent with previously diagnosed TC. Staging PET/CT demonstrated a 4.7 cm right upper lobe lung, and a subsequent lung biopsy showed a small, round blue-cell tumor with necrosis, morphologically identical to the prior biopsies from the scalp. Considering the unusual clinical course of TC, a lung biopsy was sent for next-generation sequencing that showed EWSR1-FLI1 (type1) fusion. Additionally, CD99 immunostaining revealed uniform cytoplasmic and membranous staining in the tumor cells. The previous scalp excision specimen was also sent for mutation analysis, which showed EWSR1-FLI1 fusion. In conjunction with clinical history and histological and molecular findings, a definitive diagnosis of primary cutaneous Ewing sarcoma (PCES) with local recurrence and metastasis to the lung was made. We present a case of PCES, which was previously misdiagnosed and treated as TC. This case emphasizes the importance of CD99 in the initial screening of cutaneous small round blue-cell tumors to avoid misdiagnosis from other morphological overlaps. Also, despite its rarity, PCES should be included in the differential diagnosis of small, round, blue cell tumors at cutaneous sites. Our case also exemplifies common biases in medical decision-making, including premature closure and anchoring bias which can result in misdiagnosis or diagnostic delay and associated delay in appropriate management.
Staged Excision of Lentigo Maligna of the Head and Neck: Assessing Surgical Excision Margins With Melan A, SOX10, and PRAME Immunohistochemistry
Authors: de Wet Johann , Plessis Pieter J. du , Schneider Johann W.
Published: January 2023

Background:

Staged excision has emerged as a superior treatment option for lentigo maligna (LM) of the head and neck when compared with conventional wide local excision. Assessing surgical excision margins for remaining LM poses a diagnostic challenge.

Objectives:

To determine whether immunohistochemical (IHC) staining with SOX10 and preferentially expressed antigen in melanoma (PRAME) aids in diagnosing LM on excision margins compared with conventional hematoxylin and eosin and Melan A IHC staining.

Methods:

This study included cases of LM of the head and neck treated with staged excision. Histological findings were reviewed according to standard criteria for the diagnosis of LM and compared with the results after IHC staining for Melan A, SOX10, and PRAME.

Results:

The cohort consisted of 35 sections. Based on hematoxylin and eosin and Melan A IHC staining, 23 sections were diagnosed as LM by the initial pathologist. Further staining with SOX10 IHC showed only 8 to be consistent with a diagnosis of LM and 9 revealing features of actinic melanocyte hyperplasia. PRAME was positive in 5 of the 8 cases of LM and negative in all 9 cases of actinic melanocyte hyperplasia (P = 0.009). The presence of melanocyte nests (P = 0.29) and pagetoid spread (P = 0.003) was the most reliable histological findings distinguishing LM from its mimics.

Conclusion:

SOX10 is a more specific and sensitive marker for melanocytes when assessing for LM on excision margins compared with Melan A. The addition of PRAME can be useful to confirm or exclude the diagnosis in challenging cases.
The impact of multidrug-resistant microorganisms on critically ill patients with cirrhosis in the intensive care unit: a cohort study
Authors: Kim Minjee , Cardoso Filipe S. , Pawlowski Anna , Wunderink Richard , Ladner Daniela P. , Abraldes Juan G. , Karvellas Constantine J.
Published: January 2023

The impact of multidrug-resistant (MDR) colonization and MDR infection in critically ill cirrhosis patients remains unclear. We assessed the association of MDR colonization and MDR infection with these patients’ survival. Observational cohort study including adult cirrhosis patients admitted to 5 intensive care units at Northwestern Memorial Hospital (Chicago, Illinois, USA) on January 1, 2010, to December 31, 2017. Patients admitted for elective liver transplant or with previous liver transplant were excluded. Patients were screened for MDR colonization on intensive care unit admission. Infection diagnoses during the intensive care unit stay were considered. The primary endpoint was hospital transplant-free survival. Among 600 patients included, 362 (60%) were men and median (interquartile range) age was 58.0 (49.0, 64.0) years. Median (interquartile range) Model for End-stage Liver Disease, Sequential Organ Failure Assessment, and Chronic Liver Failure—Acute-on-Chronic Liver Failure scores on intensive care unit day 1 were 28.0 (20.0, 36.0), 9.0 (6.0, 13.0), and 55.0 (48.0, 64.0), respectively. Overall, 76 (13%) patients were transplanted and 443 (74%) survived the hospital stay. Infections were diagnosed in 347 (58%) patients: pneumonia in 197 (33%), urinary tract infection in 119 (20%), peritonitis in 93 (16%), bloodstream infection in 99 (16%), Clostridium difficile colitis in 9 (2%), and catheter tip infection in 7 (1%). MDR colonization and MDR infection were identified in 200 (33%) and 69 (12%) patients, respectively. MDR colonization was associated with MDR infection (p < 0.001). MDR colonization or MDR infection was associated with higher number and duration of antibiotics (p < 0.001). Following adjustment for covariables (age, sex, etiology, portal hypertension, and Sequential Organ Failure Assessment score), MDR colonization [OR (95% CI), 0.64 (0.43, 0.95)] or MDR infection [adjusted OR (95% CI), 0.22 (0.12, 0.40)] were independently associated with lower transplant-free survival. Among critically ill cirrhosis patients, MDR colonization or MDR infection portended a worse prognosis.
The evolving role of liver sinusoidal endothelial cells in liver health and disease
Authors: McConnell Matthew J. , Kostallari Enis , Ibrahim Samar H. , Iwakiri Yasuko
Published: January 2023

LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.
Mechanisms of drug resistance in HCC
Authors: Ladd Alexandra D. , Duarte Sergio , Sahin Ilyas , Zarrinpar Ali
Published: January 2023

HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
Complete Femoral Osteonecrosis in the Setting of Myelodysplastic Syndrome
Authors: Kargar Samani Isaac , Akachar Yassin , Krug Bruno
Published: January 2023

A 76-year-old man was diagnosed with a hematological neoplasm combining myelodysplastic and myeloproliferative characteristics back in July 2021. Five months after the diagnosis, his condition got more severe when the blasts rose up to 14%, so he was started on hypomethylating agent–based therapy. A few weeks later, the patient was hospitalized after developing fever and a pain in the right thigh. To exclude any source of occult infection, an 18F-FDG PET/CT was performed. FDG PET/CT showed a complete lack of metabolism in the right femur. An MRI and a biopsy confirmed the suspected diagnosis of osteonecrosis.
MACROPHAGE SWITCHING: POLARIZATION AND MOBILIZATION AFTER TRAUMA
Authors: Hoteit Lara , Loughran Patricia , Haldeman Shannon , Reiser Danielle , Alsaadi Nijmeh , Andraska Elizabeth , Bonaroti Jillian , Srinivasan Amudan , Williamson Kelly M. , Alvikas Jurgis , Steinman Richard , Keegan Joshua , Lederer James A. , Scott Melanie , Neal Matthew D. , Seshadri Anupamaa
Published: January 2023

Introduction: Trauma alters the immune response in numerous ways, affecting both the innate and adaptive responses. Macrophages play an important role in inflammation and wound healing following injury. We hypothesize that macrophages mobilize from the circulation to the site of injury and secondary sites after trauma, with a transition from proinflammatory (M1) shortly after trauma to anti-inflammatory (M2) at later time points. Methods: C57Bl6 mice (n = 6/group) underwent a polytrauma model using cardiac puncture/hemorrhage, pseudofemoral fracture, and liver crush injury. The animals were killed at several time points: uninjured, 24 h, and 7 days. Peripheral blood mononuclear cells, spleen, liver nonparenchymal cells, and lung were harvested, processed, and stained for flow cytometry. Macrophages were identified as CD68+; M1 macrophages were identified as iNOS+; M2 macrophages as arginase 1+. Results: We saw a slight presence of M1 macrophages at baseline in peripheral blood mononuclear cells (6.6%), with no significant change at 24 h and 7 days after polytrauma. In contrast, the spleen has a larger population of M1 macrophages at baseline (27.7%), with levels decreasing at 24 h and 7 days after trauma (20.6% and 12.6%, respectively). A similar trend is seen in the lung where at baseline 14.9% of CD68+ macrophages are M1, with subsequent continual decrease reaching 8.7% at 24 h and 4.4% at 7 days after polytrauma. M1 macrophages in the liver represent 14.3% of CD68+ population in the liver nonparenchymal cells at baseline. This percentage increases to 20.8% after trauma and decreases at 7 days after polytrauma (13.4%). There are few M2 macrophages in circulating peripheral blood mononuclear cells and in spleen at baseline and after trauma. The percentage of M2 macrophages in the lungs remains constant after trauma (7.2% at 24 h and 9.2% at 7 days). In contrast, a large proportion of M2 macrophages are seen in the liver at baseline (36.0%). This percentage trends upward and reaches 45.6% acutely after trauma and drops to 21.4% at 7 days. The phenotypic changes in macrophages seen in the lungs did not correlate with a functional change in the ability of the macrophages to perform oxidative burst, with an increase from 2.0% at baseline to 22.1% at 7 days after polytrauma (P = 0.0258). Conclusion: Macrophage phenotypic changes after polytrauma are noted, especially with a decrease in the lung M1 phenotype and a short-term increase in the M2 phenotype in the liver. However, macrophage function as measured by oxidative burst increased over the time course of trauma, which may signify a change in subset polarization after injury not captured by the typical macrophage phenotypes.
High proportion of Ugandans with pre-pandemic SARS-CoV-2 cross-reactive CD4+ and CD8+ T-cell responses
Authors: Namuniina Annemarie , Muyanja Enoch S , Biribawa Victoria M , Okech Brenda A , Ssemaganda Aloysious , Price Matt A , Hills Nancy , Nanteza Ann , Bagaya Bernard Ssentalo , Weiskopf Daniela , Riou Catherine , Reynolds Steven J , Galwango Ronald M , Redd Andrew D
Published: January 2023

The estimated mortality rate of the SARS-CoV-2 pandemic varied greatly around the world with multiple countries in East, Central, and West Africa having significantly lower rates of COVID-19 related fatalities than many resource-rich nations with significantly earlier wide-spread access to life-saving vaccines. One possible reason for this lower mortality could be the presence of pre-existing cross-reactive immunological responses in these areas of the world. To explore this hypothesis, stored peripheral blood mononuclear cells (PBMC) from Ugandans collected from 2015-2017 prior to the COVID-19 pandemic (n=29) and from hospitalized Ugandan COVID-19 patients (n=3) were examined using flow-cytometry for the presence of pre-existing SARS-CoV-2 cross-reactive CD4+ and CD8+ T-cell populations using four T-cell epitope mega pools. Of pre-pandemic participants, 89.7% (26/29) had either CD4+ or CD8+, or both, SARS-CoV-2 specific T-cell responses. Specifically, CD4+ T-cell reactivity (72.4%) and CD8+ T-cell reactivity (65.5%) were relatively similar, and 13 participants (44.8%) had both types of cross-reactive types of T-cells present. There were no significant differences in response by sex in the population. The rates of cross-reactive T-cell populations in these Ugandans is higher than previous estimates from resource-rich countries like the United States (20-50% reactivity). It is unclear what role, if any, this cross-reactivity played in decreasing COVID-19 related mortality in Uganda and other African countries, but does suggest that a better understanding of global pre-existing immunological cross-reactivity could be an informative data of epidemiological intelligence moving forward.
Increased TCR signaling in regulatory T cells is disengaged from TCR affinity
Authors: Jing Yi , Kong Yuelin , Allard Denise , Liu Baoyu , Kolawole Elizabeth , Sprouse Maran , Evavold Brian , Bettini Matthew , Bettini Maria
Published: January 2023

Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, TCR affinity and specificities that support Treg function, and how these compare to autoimmune T cells remain unresolved. In this study, we used antigen agnostic and epitope-focused analyses to compare TCR repertoires of regulatory and effector T cells that spontaneously infiltrate pancreatic islets of non-obese diabetic mice. We show that effector and regulatory T cell-derived TCRs possess similar wide-ranging reactivity for self-antigen. Treg-derived TCRs varied in their capacity to confer optimal protective function, and Treg suppressive capacity was in part determined by effector TCR affinity. Interestingly, when expressing the same TCR, Tregs showed higher Nur77-GFP expression than Teffs, suggesting Treg-intrinsic ability to compete for antigen. Our findings provide a new insight into TCR-dependent and independent mechanisms that regulate Treg function and indicate a TCR-intrinsic insufficiency in tissue-specific Tregs that may contribute to the pathogenesis of type 1 diabetes.
Regulation ofPYR/PYL/RCARABA receptors mRNA stability: involvement of miR5628 in decay ofPYL6mRNA
Authors: Vieira João G. P. , Duarte Gustavo T. , Barrera-Rojas Carlos H. , Matiolli Cleverson C. , Viana Américo J. C. , Canesin Lucas E. D. , Vicentini Renato , Nogueira Fabio T. S. , Vincentz Michel
Published: January 2023

Hormone signaling fine-tuning involves feedback regulatory loops. Abscisic acid (ABA) plays key functions in development and tolerance to abiotic stress. ABA is sensed by the PYR/PYL/RCAR receptors and it also represses their gene expression. Conversely, ABA inducesPP2Cphosphatases expression, which are negative regulators of the ABA signaling pathway. This feedback regulatory scheme is likely important for the modulation of ABA signal transduction. Here, we provide a new insight into the mechanisms underlying the ABA-induced negative control ofPYR/PYL/RCARexpression inArabidopsis thaliana. The strong and sustained repression ofPYR/PYL/RCARsrevealed by ABA time course treatment defines the regulation of receptors genes as an important step in resetting the ABA signaling pathway. Transcription inhibition by cordycepin showed that destabilization ofPYL1/4/5/6mRNA is involved in ABA-induced repression of these genes. Furthermore, genetic evidence indicated that decapping may play a role inPYL4/5/6mRNAs decay. In addition, we provide evidence that theArabidopsis-specificmicroRNA5628 (miR5628), which is transiently induced by the ABA core signaling pathway, guides the cleavage ofPYL6transcript in response to ABA. After cleavage, the resulting RISC 5’- and 3’-cleaved fragments ofPYL6mRNA may be degraded by exoribonuclease XRN4. MiR5628 is an evolutionary novelty that may contribute, with decapping and XRN4 activities, to enhancePYL6mRNA degradation. Thus, control of stability ofPYR/PYL/RCARtranscripts is an important step in maintaining homeostasis of ABA signaling.

One Sentence Summary

Attenuation of ABA signaling involves destabilization ofPYL1/4/5/6transcripts. ABA core signaling induces miR5628 expression to enhancePYL6mRNA degradation in conjunction with decapping and XRN4 activities.
Fetal exposure to endocrine disrupting-bisphenol A (BPA) alters testicular fatty acid metabolism in the adult offspring: relevance to sperm maturation and quality
Authors: Varma Saikanth , Molangiri Archana , Kona Suryam Reddy , Ibrahim Ahamed , Duttaroy Asim K , Basak Sanjay
Published: January 2023

Daily exposure to bisphenols can affect reproductive functions due to their pseudo-estrogenic and/or anti-androgenic effects. Testicular lipids contain high levels of polyunsaturated fatty acids necessary for sperm maturity, motility, and spermatogenesis. Whether prenatal exposure to bisphenols alters testicular fatty acid metabolism in adult offspring is unknown. Pregnant Wistar rats were gavaged from gestational day 4 to 21 with BPA and BPS (0.0, 0.4, 4.0, 40.0 μg/kg bw/d). Despite increased body and testis weight, the total testicular cholesterol, triglyceride, and plasma fatty acids were unaffected in offspring. Lipogenesis was upregulated by increased SCD-1, SCD-2, and expression of lipid storage (ADRP) and trafficking protein (FABP4). The arachidonic acid, 20:4 n-6 (ARA) and docosapentaenoic acid, 22:5 n-6 (DPA) levels were decreased in the BPA-exposed testis, while BPS exposure had no effects. The expression of PPARα, PPARγ proteins and CATSPER2 mRNA were decreased, which are important for energy dissipation and motility of the sperm in the testis. The endogenous conversion of linoleic acid,18:2n-6 (LA), to ARA was impaired by a reduced ARA/LA ratio and decreased FADS1 expression in BPA-exposed testis. Collectively, fetal BPA exposure affected endogenous long-chain fatty acid metabolism and steroidogenesis in the adult testis, which might dysregulate sperm maturation and quality.

Highlights

In utero BPA exposure not BPS affected testicular long-chain n-6 PUFA metabolism in offspring

Fetal exposure to BPA alters delta-9-desaturase indices in the adult testis

BPA exposure reduced fatty acid desaturase1 expression in offspring testis

Fetal BPA exposure dysregulated lipogenesis in offspring testis
Application of Elastic Net Regression for Modeling COVID-19 Sociodemographic Risk Factors
Authors: Moxley Tristan A. , Johnson-Leung Jennifer , Seamon Erich , Williams Christopher , Ridenhour Benjamin J.
Published: January 2023

Objectives

COVID-19 has been at the forefront of global concern since its emergence in December of 2019. Determining the social factors that drive case incidence is paramount to mitigating disease spread. We gathered data from the Social Vulnerability Index (SVI) along with Democratic voting percentage to attempt to understand which county-level sociodemographic metrics had a significant correlation with case rate for COVID-19.

Methods

We used elastic net regression due to issues with variable collinearity and model overfitting. Our modelling framework included using the ten Health and Human Services regions as submodels for the two time periods 22 March 2020 to 15 June 2021 (prior to the Delta time period) and 15 June 2021 to 1 November 2021 (the Delta time period).

Results

Statistically, elastic net improved prediction when compared to multiple regression, as almost every HHS model consistently had a lower root mean square error (RMSE) and satisfactoryR2coefficients. These analyses show that the percentage of minorities, disabled individuals, individuals living in group quarters, and individuals who voted Democratic correlated significantly with COVID-19 attack rate as determined by Variable Importance Plots (VIPs).

Conclusions

The percentage of minorities per county correlated positively with cases in the earlier time period and negatively in the later time period, which complements previous research. In contrast, higher percentages of disabled individuals per county correlated negatively in the earlier time period. Counties with an above average percentage of group quarters experienced a high attack rate early which then diminished in significance after the primary vaccine rollout. Higher Democratic voting consistently correlated negatively with cases, coinciding with previous findings regarding a partisan divide in COVID-19 cases at the county level. Our findings can assist policymakers in distributing resources to more vulnerable counties in future pandemics based on SVI.
Quality of life in adolescents with chronic non-traumatic knee pain: An analysis of 323 adolescents with Patellofemoral Pain and Osgood-Schlatter Disease
Authors: Djurtoft Chris , Yona Tomer , Roos Ewa Maria , Thorborg Kristian , Hölmich Per , Rasmussen Sten , Olesen Jens Lykkegaard , Rathleff. Michael Skovdal
Published: January 2023

Introduction

We aimed to describe Quality of life (QoL) among adolescents with Patellofemoral Pain (PFP) and Osgood-Schlatter Disease (OSD) according to the QoL subscale of The Knee injury and Osteoarthritis Outcome Score (KOOS) and the EuroQol 5-dimensions (EQ-5D) and to investigate the characteristics associated with QoL.

Methods

This individual participant analysis included data from three clinical trials on adolescents diagnosed with PFP or OSD. We relabeled individual data and constructed a single dataset.

Results

We included 323 adolescents with PFP or OSD. Total score of KOOS-QoL was 51±18 and total index score for the EQ5D was 0.67±0.21. KOOS-QoL subscale showed that 59% reported being aware of their knee problems daily or constantly, 37% reported severe to extreme lack of confidence in their knees, 27% reported severe to extreme difficulty with their knees, and 20% reported severely or totally modifying their lifestyle to avoid potentially damaging activities to their knee. EQ-5D showed that 77% experienced problems with everyday activities, 47% reported mobility problems, 17% felt worried, sad, or unhappy, and 7% reported problems looking after themselves. Older participants (age 17-19) reported worse QoL than younger participants. None of the other characteristics were associated with QoL.

Conclusions

A high proportion of adolescents with chronic non-traumatic knee pain experience low QoL. More than half were aware of their knee problems at least daily, one in three reported a severe lack of confidence in their knee, and one in six felt worried, sad, or unhappy. QoL was lowest among older adolescents.

Highlights

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One in every three adolescents with PFP or OSD reported a severe lack of confidence in their knee.

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Many adolescents reported being sad or worried, and modified their usual activities due to their knee pain.

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Clinicians may extend the scope and include pain management strategies to address psychological perspectives when managing adolescents diagnosed with PFP or OSD.

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Modifiable targets such as adolescents understanding of pain may be a beneficial management strategy to consider in rehabilitation for PFP or OSD.
The scheduling of adolescence with Netrin-1 and UNC5C
Authors: Hoops Daniel , Kyne Robert F. , Salameh Samer , MacGowan Del , Avramescu Radu G. , Ewing Elise , He Alina T. , Orsini Taylor , Durand Anais , Popescu Christina , Zhao Janet M. , Schatz Kelcie C. , Li LiPing , Carroll Quinn E. , Liu Guofa , Paul Matthew J. , Flores Cecilia
Published: January 2023

Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons towards the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1 expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters;Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.
GUIFold - A graphical user interface for local AlphaFold2
Authors: Kempf Georg , Cavadini Simone
Published: January 2023

GUIFold is a graphical user interface for the open-source structure prediction pipeline AlphaFold2. A particular emphasis lies on tracking prediction jobs in a database as well as user-friendly submission to queueing systems. GUIFold is built on top of a modified AlphaFold2 pipeline that primarily allows more control of the feature generation step. Additionally, the application provides an evaluation pipeline to rank predictions and visualize confidence metrics. GUIFold can be installed along with AlphaFold2 in a virtual environment and, after initial setup, allows running jobs without particular technical expertise.
Quantitative proteomics combined with network pharmacology analysis unveils the biological basis of Schisandrin B in treating diabetic nephropathy
Authors: Song Jianying , Zhang Bo , Lyu Xudong , Zhang Huiping , Cheng Wenbo , Liu Peiyuan , Kang Jun
Published: January 2023

Background

Diabetic nephropathy (DN) is a major complication of diabetes. Schisandrin B (Sch) is a natural pharmaceutical monomer that was shown to prevent kidney damage caused by diabetes and restore its function. However, there is still a lack of comprehensive and systematic understanding of the mechanism of Sch treatment in DN.

Objective

We aim to provide a systematic overview of the mechanisms of Sch in multiple pathways to treat DN in rats.

Methods

Streptozocin was used to build a DN rat model, which was further treated with Sch. The possible mechanism of Sch protective effects against DN was predicted using network pharmacology and was verified by quantitative proteomics analysis.

Results

High dose Sch treatment significantly downregulated fasting blood glucose, creatinine, blood urea nitrogen, and urinary protein levels and reduced collagen deposition in the glomeruli and tubule-interstitium of DN rats. The activities of superoxide dismutase (SOD) and plasma glutathione peroxidase (GSH-Px) in the kidney of DN rats significantly increased with Sch treatment. In addition, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in DN rats treated with Sch. 11 proteins that target both Sch and DN were enriched in pathways such as MAPK signaling, PI3K-Akt signaling, renal cell carcinoma, gap junction, endocrine resistance, and TNF signaling. Furthermore, quantitative proteomics showed that Xaf1 was downregulated in the model vs. control group and upregulated in the Sch-treated vs. model group. Five proteins, Crb3, Tspan4, Wdr45, Zfp512, and Tmigd1, were found to be upregulated in the model vs. control group and downregulated in the Sch vs. model group. Three intersected proteins between the network pharmacology prediction and proteomics results, Crb3, Xaf1, and Tspan4, were identified.

Conclusion

Sch functions by relieving oxidative stress and the inflammatory response by regulating Crb3, Xaf1, and Tspan4 protein expression levels to treat DN disease.
Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression
Authors: Savchuk Solomiia , Gentry Kaylee , Wang Wengang , Carleton Elana , Yalçın Belgin , Liu Yin , Pavarino Elisa C. , LaBelle Jenna , Toland Angus M. , Woo Pamelyn J. , Qu Fangfei , Filbin Mariella G. , Krasnow Mark A. , Sabatini Bernardo L. , Sage Julien , Monje Michelle , Venkatesh Humsa S.
Published: January 2023

Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.
A haptic illusion created by gravity
Authors: Opsomer Laurent , Delhaye Benoit , Théate Vincent , Thonnard Jean-Louis , Lefèvre Philippe
Published: January 2023

Haptic force estimation is a critical aspect of human dexterity. To manipulate objects or interact with a haptic interface successfully, the normal and tangential components of the contact forces produced by our fingertips must be carefully coordinated. The tight coupling between tangential and normal contact forces observed during voluntary movements indicates that the nervous system can estimate these forces with high accuracy. Here, we examined the influence of gravity on manual force production in an isometric task. We trained participants to produce isometric tangential forces with the thumb and index finger on a dynamometer held in precision grip. They were tasked with reproducing these forces in a normal gravitational environment (1g) and during parabolic maneuvers creating phases of micro- (0g) and hypergravity (1.6g). The isometric task results showed that arm weight biases estimation of the forces exerted by the fingertips. Reproduced tangential forces were consistently larger downward than upward in 1g. This asymmetry was reduced under microgravity and increased under hypergravity. Critically, the normal forces did not reflect this asymmetry, demonstrating that tangential forces were misestimated and pointing to a haptic illusion created by gravity. This gravitational effect on haptic force estimation may have implications for the design of prostheses incorporating force feedback, haptic devices for teleoperations, or haptic supports aimed at improving sensorimotor performance in space.
Dissecting unsupervised learning through hidden Markov modelling in electrophysiological data
Authors: Masaracchia Laura , Fredes Felipe , Woolrich Mark W. , Vidaurre Diego
Published: January 2023

Unsupervised, data-driven methods are commonly used in neuroscience to automatically decompose data into interpretable patterns. These patterns differ from one another depending on the assumptions of the models. How these assumptions affect specific data decompositions in practice, however, is often unclear, which hinders model applicability and interpretability. For instance, the hidden Markov model (HMM) automatically detects characteristic, recurring activity patterns (so-calledstates) from time series data. States are defined by a certain probability distribution, whose state-specific parameters are estimated from the data. But what specific features, from all of those that the data contain, do the states capture? That depends on the choice of probability distribution and on other model hyperparameters. Using both synthetic and real data, we aim at better characterizing the behavior of two HMM types that can be applied to electrophysiological data. Specifically, we study which differences in data features (such as frequency, amplitude or signal-to-noise ratio) are more salient to the models and therefore more likely to drive the state decomposition. Overall, we aim at providing guidance for an appropriate use of this type of analysis on one or two-channel neural electrophysiological data, and an informed interpretation of its results given the characteristics of the data and the purpose of the analysis.

NEW & NOTEWORTHY

Compared to classical supervised methods, unsupervised methods of analysis have the advantage to be freer of subjective biases. However, it is not always clear what aspects of the data these methods are most sensitive to, which complicates interpretation. Focusing on the Hidden Markov Model, commonly used to describe electrophysiological data, we explore in detail the nature of its estimates through simulations and real data examples, providing important insights about what to expect from these models.
Acoustically Targeted Noninvasive Gene Therapy in Large Brain Regions
Authors: Nouraein Shirin , Lee Sangsin , Saenz Vidal A. , Del Mundo Huckie C. , Yiu Joycelyn , Szablowski Jerzy O.
Published: January 2023

Focused Ultrasound Blood-Brain Barrier Opening (FUS-BBBO) can deliver adeno-associated viral vectors (AAVs) to treat genetic disorders of the brain. However, such disorders often affect large brain regions. Moreover, the applicability of FUS-BBBO in the treatment of brain-wide genetic disorders has not yet been evaluated. Herein, we evaluated the transduction efficiency and safety of opening up to 105 sites simultaneously. Increasing the number of targeted sites increased gene delivery efficiency at each site. We achieved transduction of up to 60% of brain cells with comparable efficiency in the majority of the brain regions. Furthermore, gene delivery with FUS-BBBO was safe even when all 105 sites were targeted simultaneously without negative effects on animal weight, neuronal loss, or astrocyte activation. To evaluate the application of multi-site FUS-BBBO for gene therapy, we used it for gene editing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, and found effective gene editing, but also a loss of neurons at the targeted sites. Overall, this study provides a brain-wide map of transduction efficiency and the first example of gene editing after site-specific noninvasive gene delivery to a large brain region.
Honey bee drones are synchronously hyperactive inside the nest
Authors: Neubauer Louisa C. , Davidson Jacob D. , Wild Benjamin , Dormagen David M. , Landgraf Tim , Couzin Iain D. , Smith Michael L.
Published: January 2023

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Eusocial insects operate as an integrated collective with tasks allocated among individuals. This applies also to reproduction, through coordinated mating flights between male and female reproductives. While in some species male sexuals take only a single mating flight and never return, in the Western honey bee,Apis mellifera, the male sexuals (drones) live in the colony throughout their lives. Prior research has focused almost exclusively on drone behavior outside of the nest (mating flights), while ignoring the majority of their life, which is spent inside the nest. To understand the in-nest behavior of drones across their lives, we used the BeesBook tracking system to track 192 individually-marked drones continuously for over 20 days, to examine how drones moved and spent time in the nest. In agreement with previous work, we find that drones spend most of their time immobile at the nest periphery. However, we also observe that drones have periods of in-nest hyperactivity, during which they become the most active individuals in the entire colony. This in-nest hyperactivity develops in drones after age 7 days, occurs daily in the afternoon, and coincides with drones taking outside trips. We find strong synchronization across the drones in the start/end of activity, such that the drones in the colony exhibit a “shared activation period”. The duration of the shared activation period depends on the weather; when conditions are suitable for mating flights, the activation period is extended. At the individual-level, we see that the activation order changes from day to day, suggesting that both the external influence of weather conditions, as well as exchange of social information, influences individual activation. Using an accumulation-to-threshold model of drone activation, we show that simulations using social information match experimental observations. These results provide new insight into the in-nest behavior of drones, and how their behavior reflects their role as the male gametes of the colony.
Generation of human alveolar epithelial type I cells from pluripotent stem cells
Authors: Burgess Claire L , Huang Jessie , Bawa Pushpinder , Alysandratos Konstantinos-Dionysios , Minakin Kasey , Morley Michael P , Babu Apoorva , Villacorta-Martin Carlos , Hinds Anne , Thapa Bibek R , Wang Feiya , Matschulat Adeline M , Morrisey Edward E , Varelas Xaralabos , Kotton Darrell N
Published: January 2023

In the distal lung, alveolar epithelial type I cells (AT1s) comprise the vast majority of alveolar surface area and are uniquely flattened to allow the diffusion of oxygen into the capillaries. This structure along with a quiescent, terminally differentiated phenotype has made AT1s particularly challenging to isolate or maintain in cell culture. As a result, there is a lack of established models for the study of human AT1 biology, and in contrast to alveolar epithelial type II cells (AT2s), little is known about the mechanisms regulating their differentiation. Here we engineer a human in vitro AT1 model system through the directed differentiation of induced pluripotent stem cells (iPSC). We first define the global transcriptomes of primary adult human AT1s, suggesting gene-set benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, that are enriched in these cells. Next, we generate iPSC-derived AT2s (iAT2s) and find that activating nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier which produces characteristic extracellular matrix molecules and secreted ligands. Our results indicate a role for Hippo-LATS-YAP signaling in the differentiation of human AT1s and demonstrate the generation of viable AT1-like cells from iAT2s, providing an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s that until now have been challenging to viably obtain from patients.
Immunogenicity and safety in pigs of PHH-1V, a SARS-CoV-2 RBD fusion heterodimer vaccine candidate
Authors: Moros Alexandra , Prenafeta Antoni , Barreiro Antonio , Perozo Eva , Fernández Alex , Cañete Manuel , González Luis , Garriga Carme , Pradenas Edwards , Marfil Silvia , Blanco Julià , Rica Paula Cebollada , Sisteré-Oró Marta , Meyerhans Andreas , Cabañas Teresa Prat , March Ricard , Ferrer Laura
Published: January 2023

The continuing high global incidence of COVID-19 and the undervaccinated status of billions of persons strongly motivate the development of a new generation of efficacious vaccines. We have developed an adjuvanted vaccine candidate, PHH-1V, based on a protein comprising the receptor binding domain (RBD) of the Beta variant of SARS-CoV-2 fused in tandem with the equivalent domain of the Alpha variant, with its immunogenicity, safety and efficacy previously demonstrated in mouse models. In the present study, we immunized pigs with different doses of PHH-1V in a prime-and-boost scheme showing PHH-1V to exhibit an excellent safety profile in pigs and to produce a solid RBD-specific humoral response with neutralising antibodies to 7 distinct SARS-CoV-2 variants of concern, with the induction of a significant IFNγ+T-cell response. We conclude that PHH-1V is safe and elicits a robust immune response to SARS-CoV-2 in pigs, a large animal preclinical model.
ARPC5 deficiency leads to severe early onset systemic inflammation and early mortality
Authors: Sindram Elena , Caballero-Oteyza Andrés , Kogata Naoko , Huang Shaina , Alizadeh Zahra , Gamez-Diaz Laura , Fazlollhi Mohammad Reza , Peng Xiao , Grimbacher Bodo , Way Michael , Proietti Michele
Published: January 2023

The seven subunit Arp2/3 complex drives the formation of branched actin networks that are essential for many cellular processes including cell migration. In humans, the ARPC5 subunit of the Arp2/3 complex is encoded by two paralogous genes (ARPC5andARPC5L), resulting in proteins with 67% identity. Through whole-exome sequencing, we identified a biallelic ARPC5 frameshift variant in a female child who presented with recurrent infections, multiple congenital anomalies, diarrhea, and thrombocytopenia, and suffered early demise from sepsis. Her consanguineous parents also had a previous child who died with similar clinical features. Using CRISPR/Cas9-mediated approaches, we demonstrate that loss of ARPC5 affects actin cytoskeleton organization and function, as well as chemokine-dependent cell migrationin vitro. HomozygousArpc5-/- mice do not survive past embryonic day 9 due to severe developmental defects, including loss of the second pharyngeal arch which contributes to craniofacial and heart development. Our results indicate that ARPC5 is important for both prenatal development and postnatal immune signaling, in a non-redundant manner with ARPC5L. Moreover, our observations add theARPC5locus to the list of genes that should be considered when patients present with syndromic early-onset immunodeficiency, particularly if recessive inheritance is suspected.
Long-term methylome changes after experimental seed demethylation and their interaction with recurrent water stress inErodium cicutarium(Geraniaceae)
Authors: Balao Francisco , Medrano Mónica , Bazaga Pilar , Paun Ovidiu , Alonso Conchita
Published: January 2023

The frequency and length of drought periods are increasing in subtropical and temperate regions worldwide. Epigenetic responses to water stress could be key for plant resilience to this largely unpredictable challenge. Experimental DNA demethylation together with application of a stress factor stands as a suitable strategy to uncover the contribution of epigenetics to plant responses to stress.

We analysed leaf cytosine methylation changes in adult plants of the Mediterranean weed,Erodium cicutarium, after seed demethylation with 5-Azacytidine and/or recurrent water stress in a greenhouse. We used bisulfite RADseq (BsRADseq) and a newly reported reference genome forE. cicutariumto characterize methylation changes in a 2×2 factorial design, controlling for plant relatedness.

In the long-term, 5-Azacytidine treatment alone caused both hypo and hyper-methylation at individual cytosines, with substantial hypomethylation in CG contexts. In control conditions, drought resulted in a decrease in methylation level in all but CHH contexts. In contrast, the genome of plants that experienced recurrent water stress and had been treated with 5-Azacytidine increased DNA methylation level by ca. 5%.

Seed demethylation and recurrent drought exhibited a highly significant interaction in terms of global and context-specific cytosine methylation supporting an epigenetic contribution in response to stress at molecular level.