bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal depression screening of frontline critical care nurses during the COVID-19 pandemic
Authors: Draganic Keri , Denke Linda , Atem Folefac D. , Kershaw Corey , Williams Kandace , England Victoria
Published: March 2023

Purpose:

To evaluate the severity and longitudinal trends of depression in critical care nurses caring for patients with COVID-19 in the US during a global pandemic.

Methods:

The study employed longitudinal mixed methods. Using the Patient Health Questionnaire (PHQ-9), nurses were sent electronic surveys at baseline, 1 month, and between 3 and 6 months to measure the severity and trends of depression during the prevaccination stage of the COVID-19 pandemic. One-on-one interviews were conducted with critical care nurses to evaluate their depressive symptoms.

Results:

Forty-eight nurses completed the questionnaire at baseline, 40 completed 1-month surveys, and 20 completed the 3 to 6 month surveys. The mean PHQ-9 score was 5.85, 6.20, and 8.30 at baseline, at 1 month, and at 3 to 6 months, respectively. PHQ-9 scores increased significantly over time (estimate = 1.120, P = .037). The probability of participants being moderately to severely depressed was 0.980 (P = .049) at baseline, 0.990 (P = .013) at 1 month, and 1.0 (P = .002) at 3 to 6 months. Fourteen nurses were included in a single, one-on-one interview. Eight major themes were found in qualitative analyses. For example, nurses expressed fear of spreading COVID-19 to their loved one and community. Common themes identified within the interviews included uncertainty, limited human interaction, fluctuations in mood, life is in my hands, a threat to others, positive and negative coping, nurses as scapegoats, and emerging vulnerability to COVID-19 exposure. All 14 nurses who were interviewed denied accessing any mental health services.

Conclusions:

More research is needed to evaluate critical care nurses who care for patients with COVID-19 and their levels of depression to improve practice at the bedside further and develop policies to promote their well-being.
COVID-19 Impact on Teaching Substance Use Disorders
Authors: Fay-Hillier Theresa , Regan Roseann V. , Murphy-Parker Dana
Published: March 2023

Vulnerable populations such as those with substance use disorders (SUDs) are at a higher risk for early morbidities and mortalities yet are less likely to receive primary care and other necessary psychosocial services essential for comprehensive care of these clients. This need has been magnified by the COVID-19 pandemic. Evidence supports an increase in alcohol sales in 2020, and overdoses from illicit drugs have been reported to have more than doubled by May 2020 from the 2018 and 2019 baseline rates, and one reason for these increases is because of COVID-19. The healthcare system is overwhelmed with the cost of treating and addressing the impact of SUDs. Individuals with SUDs often meet providers who are not sufficiently prepared to address their complex issues that include co-occurring mental and physical health disorders. In addition to changes in practice, nursing education must change their curricular approach to meet the challenges in health services across the life span, and nursing education should include lessons being learned during the COVID-19 pandemic. Nurses must be prepared to recognize and screen individuals for SUDs at the undergraduate level as well as assess and treat individuals with SUDs at the advanced practice level in all areas of healthcare services. SUDs should not continue to be siloed and separated into the psychiatric–mental health nursing course within the nursing curriculum but should be addressed in multiple specialties across the curricula and include health responses in regard to the impact that the COVID-19 pandemic is having on SUDs.
The Effect of Video-Assisted Training and Visual Feedback With UV Germ Technology on Nursing Students' Hand Hygiene Beliefs, Practices, and Compliance
Authors: Karahan Okuroğlu Gülten , Kaynar Şimşek Aynur , Pazar Nazlı , Ecevit Alpar Şule
Published: March 2023

Background:

Hand hygiene (HH) is the most effective way to prevent health care–associated infections; however, HH compliance rates continue to be suboptimal.

Purpose:

To determine the effectiveness of video-assisted training and visual feedback with ultraviolet (UV) germ technology on nursing students' HH beliefs, practices, and compliance.

Methods:

This study used a double-blind, posttest randomized controlled design. The experimental group received training, visual feedback with UV germ technology, and instructional videos.

Results:

A total of 46 students were included in the study (experimental 21 and control 25). The mean score of the HH skills checklist of the experimental group was significantly higher than that of the control group (P = .0001). The HH compliance rate was also higher in the experimental group (52.62%) compared with the control group (39.1%).

Conclusions:

The training, visual feedback with UV germ technology, and instructional videos increased HH compliance rates in nursing students.
The thoracodorsal artery perforator (TDAP) flap for the treatment of hidradenitis suppurativa of the axilla: A prospective comparative study
Authors: La Padula Simone , Pensato Rosita , Pizza Chiara , D’Andrea Francesco , Roccaro Giovanni , Meningaud Jean Paul , Hersant Barbara
Published: March 2023

Introduction:

Hidradenitis suppurativa (HS) is a common chronical condition. It is often resistant to conservative treatment and requires a wide and aggressive surgical approach to avoid recurrence. A prospective study was compared comparing the outcomes of thoracodorsal artery perforator (TDAP) flap-based reconstruction and secondary intention closure (SIC) following wide local excision (WLE) of axillary HS.

Material and Methods:

A prospective study was conducted on sixty-eight patients suffering from stage III axillary HS. Thirty-three patients underwent a WLE procedure and were left to heal by secondary intention (SIC group), whereas 35 patients underwent immediate reconstruction with a homolateral TDAP flap (TDAP group). The inpatient stay, the healing time, the post-operative complications rate and pain were analysed in both groups, comparing preoperative shoulder function (using Constant-Murley shoulder outcome score), and quality of life (using a dermatology life quality index) with post-operative shoulder function and quality of life.

Results:

TDAP patients had significantly faster recovery, fewer complications, and fewer overall number of procedures than those who underwent SIC. All patients reported an improved quality of life after their operation and the TDAP group showed significantly more improvement than the SIC group (P<0.001). TDAP patients reported a significant reduction in pain/discomfort and a better shoulder function compared to SIC patients (P<0.001).

Conclusions:

WLE and TDAP flap-based reconstruction for axillary stage III HS provide optimal post-procedural functional results with a low complication rate. The complete remission of the disease was observed after the procedure. Despite the relatively slow learning curve of this procedure, we strongly recommend this technique as a very good option for the management of stage III axillary HS.
Sagittal Craniosynostosis: Comparing Surgical Techniques using 3D Photogrammetry
Authors: Abdel-Alim Tareq , Kurniawan Melissa , Mathijssen Irene , Dremmen Marjolein , Dirven Clemens , Niessen Wiro , Roshchupkin Gennady , van Veelen Marie-Lise
Published: March 2023

OBJECTIVE:

The aim of this study is to compare three surgical interventions to correct sagittal synostosis: frontobiparietal remodeling (FBR), extended strip craniotomy (ESC), and spring assisted correction (SAC), based on 3D photogrammetry and operation characteristics.

METHODS:

All patients diagnosed with non-syndromic sagittal synostosis, born between 1991 and 2019, who underwent FBR, ESC or SAC, and had at least one postoperative 3D photogrammetry image taken during one of six follow-up moments until the age of six, were considered for this study. Operation characteristics, postoperative complications, re-interventions, and presence of intracranial hypertension were collected. To assess cranial growth, orthogonal cranial slices and 3D photocephalometric measurements were extracted automatically and evaluated from 3D photogrammetry images.

RESULTS:

A total of 322 postoperative 3D images from 218 patients were included. After correcting for age and gender, no significant differences were observed in 3D photocephalometric measurements. Mean cranial shapes suggest that postoperative growth and shape gradually normalize with higher OFC and ICV values compared to normal, regardless of type of surgery. Flattening of the vertex seems to persist after surgical correction. Our cranial 3D mesh processing tool has been made publicly available as a part of this study.

CONCLUSION:

Our findings suggest that until the age of six, there are no significant differences between the FBR, ESC, and SAC in their ability to correct sagittal synostosis with regard to 3D photocephalometric measurements. Therefore, efforts should be made to ensure early diagnosis so that minimally invasive surgery is still a viable treatment option.
Surgery-first orthognathic approach for correction of dentofacial deformity in unilateral cleft lip and palate
Authors: Liao Yu-Fang , Chen Yun-Fang , Chang Chun-Shin , Lu Ting-Chen , Chen Ying-An , Yao Chuan-Fong , Chen Philip Kuo-Ting , Chen Yu-Ray
Published: March 2023

Background:

Although several studies have reported the advantages of the surgery-first approach for orthognathic correction of class III deformity, there is no report of the success of this approach for patients with cleft lip and palate. Therefore, the purpose of this study was to evaluate the stability and outcome of bimaxillary surgery for cleft-related dentofacial deformity using a surgery-first approach.

Methods:

Forty-one patients with unilateral cleft lip and palate who consecutively underwent Le Fort I and bilateral sagittal split osteotomies for skeletal class III deformity were included. Cone-beam computed tomography scans before surgery, 1-week post-surgery and after orthodontic treatment were used to measure the surgical and post-surgical changes in jaw position by landmarks, and outcomes of jaw protrusion and relation, incisor angle and occlusion, and menton deviation after treatment. Self-report questionnaires regarding satisfaction with overall appearance of the face and seven facial regions were administered after treatment.

Results:

A clinically insignificant relapse was found in the maxilla (< 1 mm) and mandible (< 2 mm). There was a significant improvement in the jaw protrusion and relation, incisor angle and occlusion, and menton deviation. Responses from the self-report questionnaires completed after treatment indicated patient satisfaction was high.

Conclusions:

These findings demonstrate surgical-orthodontic treatment with a surgery-first approach can successfully improve cleft-related dentofacial deformity in patients with unilateral cleft lip and palate.
SPECT/CT in Pleuroperitoneal Fistula Associated With Peritoneal Dialysis
Authors: Rojas-Rojas María M. , Camilo Perdomo , Gonzalo Ucrós , Bernal Patricia
Published: March 2023

Pleuroperitoneal fistula is a rare entity found in approximately 1.6% of patients with peritoneal dialysis. The pathophysiology is unknown, and it is usually associated with increased abdominal pressure. Upon pleural fluid analysis, a transudate with elevated glucose concentration is found, and the patients present with acute dyspnea, cough, and decrease in the ultrafiltration rate. We present the case of an 81-year-old woman with history of peritoneal dialysis presenting with recurrent pleural effusion. A peritoneal scintigraphy with 99mTc was performed confirming the diagnosis of pleuroperitoneal fistula.
Host-to-graft Propagation of α-synuclein in a Mouse Model of Parkinson’s Disease: Intranigral Versus Intrastriatal Transplantation
Authors: Patrigeon Maëlig , Brot Sébastien , Bonnet Marie-Laure , Belnoue Laure , Gaillard Afsaneh
Published: March 2023

Background.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies. Ectopic transplantation of human fetal ventral mesencephalic DA neurons into the striatum of PD patients have provided proof-of-principle for the cell replacement strategy in this disorder. However, 10 to 22 y after transplantation, 1% to 27% of grafted neurons contained α-syn aggregates similar to those observed in the host brain. We hypothesized that intrastriatal grafts are more vulnerable to α-syn propagation because the striatum is not the ontogenic site of nigral DA neurons and represents an unfavorable environment for transplanted neurons. Here, we compared the long-term host-to-graft propagation of α-syn in 2 transplantation sites: the SNpc and the striatum.

Methods.

Two mouse models of PD were developed by injecting adeno-associated-virus2/9-human α-syn A53T into either the SNpc or the striatum of C57BL/6 mice. Mouse fetal ventral mesencephalic DA progenitors were grafted into the SNpc or into the striatum of SNpc or striatum of α-syn injected mice, respectively.

Results.

First, we have shown a degeneration of the nigrostriatal pathway associated with motor deficits after nigral but not striatal adeno-associated-virus-hαsyn A53T injection. Second, human α-syn preferentially accumulates in striatal grafts compared to nigral grafts. However, no differences were observed for phosphorylated α-syn, a marker of pathological α-syn aggregates.

Conclusions.

Taken together, our results suggest that the ectopic site of the transplantation impacts the host-to-graft transmission of α-syn.
Virtual and Reality: An Analysis of the UCLA Virtual Crossmatch Exchanges
Authors: Locke Arlene F. , Hickey Michelle , Valenzuela Nicole M. , Butler Carrie , Sosa Rebecca , Zheng Ying , Gjertson David , Reed Elaine F. , Zhang Qiuheng
Published: March 2023

The “virtual” crossmatch (VXM) has become a critical tool to predict the compatibility between an organ donor and a potential recipient. Yet, nonstandardized laboratory practice can lead to variability in VXM interpretation. Therefore, UCLA’s VXM Exchange survey was designed to understand factors that influence the variability of VXM prediction in the presence of HLA donor-specific antibody (DSA). Thirty-six donor blood samples and 72 HLA reference sera were sent to 35 participating laboratories to perform HLA antibody testing, flow crossmatch (FXM), and VXM from 2014 to 2019, consisting of 144 T/B-cell FXM pairs and 112 T/B-cell VXM pairs. In the FXM survey, 86% T-cell FXM and 84% B-cell FXM achieved >80% concordance among laboratories. In the VXM survey, 81% T-cell VXM and 80% VXM achieved >80% concordance. The concordance between FXM and VXM was 79% for T cell and 87% for B cell. The consensus between VXM and FXM was high with strong DSA. However, significant variability was observed in sera with (1) very high titer antibodies that exit prozone effect; (2) weak-to-moderate DSA, particularly in the presence of multiple weak DSAs; and (3) DSA against lowly expressed antigens. With the increasing use the VXM, standardization and continuous learning via exchange surveys will provide better understanding and quality controls for VXM to improve accuracy across all centers.
Evaluation of the Diagnostic Performance of urine dipstick test for Detection of urinary tract infections in patients treated in Kenyan hospitals.
Authors: Maina John , Mwaniki John , Mwiti Franklin , Kiiru Susan , Katana Japhet , Wanja Fredrick , Mukaya Joel , Khasabuli Osborn , Asiimwe Benon , Gillespie Stephen , Stelling John , Mshana Stephen , Holden Matthew , Sabiiti Wilber , Kiiru John
Published: March 2023

Abstract
Introduction
Culture is the gold-standard diagnosis for Urinary Tract Infections (UTIs). However, most hospitals in poor-resource countries lack adequately equipped laboratories and relevant expertise to perform culture and, therefore, rely heavily on dipstick tests for UTI diagnosis.
Research gap
In many Kenyan hospitals, routine evaluations are rarely done to assess the accuracy of popular screening tests such as the dipstick test. As such, there is a substantial risk of misdiagnosis emanating from inaccuracy in proxy screening tests. This may result in misuse, under-use, or over-use of antimicrobials.
Aim
The present study aimed to assess the accuracy of the urine dipstick test as a proxy for the diagnosis of urinary tract infections in selected Kenyan hospitals.
Methods
A hospital-based cross-sectional method was used in the present study. Utility of dipstick  in the diagnosis of UTI was assessed using Mid stream urine against culture as gold standard
Results
The dipstick test predicted 1,416 positive UTIs, but only 1,027 were confirmed positive by culture, translating to a true prevalence of 54.1%. The sensitivity of the dipstick test was better when leukocytes and nitrite tests were combined (63.1%) than when the two tests were separate (62.6% and 50.7%, respectively). Similarly, the two tests combined had a better positive predictive value (87.0%) than either test alone. The nitrite test had the best specificity (89.8%) and negative predictive value (97.4%) than leukocytes esterase (L.E) or both tests combined. In addition, sensitivity in samples from the inpatients (69.2%) was higher than outpatients (62.7%). Furthermore, the dipstick test had a better sensitivity and positive predictive value among female (66.0% and 88.6%) patients than male patients (44.3% and 73.9%). Among the various patients' age groups, the dipstick test's sensitivity and positive predictive value were exceptionally high in patients ≥75 years  (87.5% and 93.3%).
Conclusion
The prevalence discrepancies from the urine dipstick test and culture, the gold standard, indicate dipstick test inadequacy for accurate UTI diagnosis. The finding also demonstrates the need for urine culture for accurate UTI diagnosis. However considering it’s not always possible to perform a culture, especially in low resource settings, future studies can combine specific UTI symptoms and dipstick results to assess possible increase in the test’s sensitivity. There is also need to develop readily available and affordable algorithms that can detected UTI where culture is not available.
Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells
Authors: Sanmarco Liliana M. , Rone Joseph M. , Polonio Carolina M. , Giovannoni Federico , Lahore Gonzalo Fernandez , Ferrara Kylynne , Gutierrez-Vazquez Cristina , Li Ning , Sokolovska Anna , Plasencia Agustin , Akl Camilo Faust , Nanda Payal , Heck Evelin S. , Li Zhaorong , Lee Hong-Gyun , Chao Chun-Cheih , Rejano-Gordillo Claudia M. , Fonseca-Castro Pedro H. , Illouz Tomer , Linnerbauer Mathias , Kenison Jessica E. , Barilla Rocky M. , Farrenkopf Daniel , Piester Gavin , Dailey Lucas , Kuchroo Vijay K. , Hava David , Wheeler Michael A. , Clish Clary , Nowarski Roni , Balsa Eduardo , Lora Jose M. , Quintana Francisco J.
Published: March 2023

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.
S3-CIMA: Supervised spatial single-cell image analysis for the identification of disease-associated cell type compositions in tissue
Authors: Babaei Sepideh , Christ Jonathan , Makky Ahmad , Zidane Mohammed , Wistuba-Hamprecht Kilian , Schürch Christian M. , Claassen Manfred
Published: March 2023

The spatial organization of various cell types within the tissue microenvironment is a key element for the formation of physiological and pathological processes, including cancer and autoimmune diseases. Here, we present S3-CIMA, a weakly supervised convolutional neural network model that enables the detection of disease-specific microenvironment compositions from high-dimensional proteomic imaging data. We demonstrate the utility of this approach by determining cancer outcome- and cellular signaling-specific spatial cell state compositions in highly multiplexed fluorescence microscopy data of the tumor microenvironment in colorectal cancer. Moreover, we use S3-CIMA to identify disease onset-specific changes of the pancreatic tissue microenvironment in type 1 diabetes using imaging mass cytometry data. We evaluated S3-CIMA as a powerful tool to discover novel disease-associated spatial cellular interactions from currently available and future spatial biology datasets.
A machine-readable specification for genomics assays
Authors: Booeshaghi A. Sina , Chen Xi , Pachter Lior
Published: March 2023

Understanding the structure of sequenced fragments from genomics libraries is essential for accurate read preprocessing. Currently, different assays and sequencing technologies require custom scripts and programs that do not leverage the common structure of sequence elements present in genomics libraries. We presentseqspec, a machine-readable specification for libraries produced by genomics assays that facilitates standardization of preprocessing and enables tracking and comparison of genomics assays. The specification and associatedseqspeccommand line tool is available athttps://github.com/IGVF/seqspec.
A Spatiotemporal Map of Co-Receptor Signaling Networks Underlying B Cell Activation
Authors: Susa Katherine J. , Bradshaw Gary A. , Eisert Robyn J. , Schilling Charlotte M. , Kalocsay Marian , Blacklow Stephen C. , Kruse Andrew C.
Published: March 2023

The B cell receptor (BCR) signals together with a multi-component co-receptor complex to initiate B cell activation in response to antigen binding. This process underlies nearly every aspect of proper B cell function. Here, we take advantage of peroxidase-catalyzed proximity labeling combined with quantitative mass spectrometry to track B cell co-receptor signaling dynamics from 10 seconds to 2 hours after BCR stimulation. This approach enables tracking of 2,814 proximity-labeled proteins and 1,394 quantified phosphosites and provides an unbiased and quantitative molecular map of proteins recruited to the vicinity of CD19, the key signaling subunit of the co-receptor complex. We detail the recruitment kinetics of essential signaling effectors to CD19 following activation, and then identify new mediators of B cell activation. In particular, we show that the glutamate transporter SLC1A1 is responsible for mediating rapid metabolic reprogramming immediately downstream of BCR stimulation and for maintaining redox homeostasis during B cell activation. This study provides a comprehensive map of the BCR signaling pathway and a rich resource for uncovering the complex signaling networks that regulate B cell activation.
Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations
Authors: Zhao Shujuan , Mekbib Kedous Y. , van der Ent Martijn A. , Allington Garrett , Prendergast Andrew , Chau Jocelyn E. , Smith Hannah , Shohfi John , Ocken Jack , Duran Daniel , Furey Charuta G. , Le Hao Thi , Duy Phan Q. , Reeves Benjamin C. , Zhang Junhui , Nelson-Williams Carol , Chen Di , Li Boyang , Nottoli Timothy , Bai Suxia , Rolle Myron , Zeng Xue , Dong Weilai , Fu Po-Ying , Wang Yung-Chun , Mane Shrikant , Piwowarczyk Paulina , Fehnel Katie Pricola , See Alfred Pokmeng , Iskandar Bermans J. , Aagaard-Kienitz Beverly , Kundishora Adam J. , DeSpenza Tyrone , Greenberg Ana B.W. , Kidanemariam Seblewengel M. , Hale Andrew T. , Johnston James M. , Jackson Eric M. , Storm Phillip B. , Lang Shih-Shan , Butler William E. , Carter Bob S. , Chapman Paul , Stapleton Christopher J. , Patel Aman B. , Rodesch Georges , Smajda Stanislas , Berenstein Alejandro , Barak Tanyeri , Erson-Omay E. Zeynep , Zhao Hongyu , Moreno-De-Luca Andres , Proctor Mark R. , Smith Edward R. , Orbach Darren B. , Alper Seth L. , Nicoli Stefania , Boggon Titus J. , Lifton Richard P. , Gunel Murat , King Philip D. , Jin Sheng Chih , Kahle Kristopher T.
Published: March 2023

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-functionde novovariants (p=4.79×10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22×10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants inACVRL1,NOTCH1,ITGB1, andPTPN11.ACVRL1variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specificEPHB4kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.
Breast Cancers That Disseminate to Bone Marrow Acquire Aggressive Phenotypes through CX43-related Tumor-Stroma Tunnels
Authors: Sinha Saptarshi , Callow Brennan W. , Farfel Alex P. , Roy Suchismita , Chen Siyi , Rajendran Shrila , Buschhaus Johanna M. , Espinoza Celia R. , Luker Kathryn E. , Ghosh Pradipta , Luker Gary D.
Published: March 2023

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between ‘borrowed’ and ‘intrinsic’ components. Bioinformatics prioritized one of the ‘borrowed’ components,CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced ∼20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
Pharmacologically targeting KRASG12Din PDAC models: tumor cell intrinsic and extrinsic impact
Authors: Kumarasamy Vishnu , Frangou Costakis , Wang Jianxin , Wan Yin , Dynka Andrew , Rosenheck Hanna , Dey Prasenjit , Abel Ethan V. , Knudsen Erik S. , Witkiewicz Agnieszka K.
Published: March 2023

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here we assessed the cellular response to pharmacological KRAS inhibition, which target the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of KRASG12Dallele, with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR screens identify new drivers for enhanced therapeutic response that regulate focal adhesion and signaling cascades, which were confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures andin vivoPDAC patient-derived xenografts. In syngeneic models, KRASG12Dinhibition elicits potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133 activates interferon-γ signaling and induces antigen presentation that modulate the tumor microenvironment. Further investigation on the immunological response using single cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8+T-cells. Thus, both tumor cell intrinsic and extrinsic events contribute to response and credential KRASG12Dinhibition as promising strategy for a large percentage of PDAC tumors.
Uncovering the Environmental Conditions Required forPhyllachora maydisInfection and Tar Spot Development on Corn in the United States for Use as Predictive Models for Future Epidemics
Authors: Webster Richard W. , Nicolli Camila , Allen Tom W. , Bish Mandy D. , Bissonette Kaitlyn , Check Jill C. , Chilvers Martin I. , Duffeck Maíra R. , Kleczewski Nathan , Luis Jane Marian , Mueller Brian D. , Paul Pierce A. , Price Paul P. , Robertson Alison E. , Ross Tiffanna J. , Schmidt Clarice , Schmidt Roger , Schmidt Teryl , Shim Sujoung , Telenko Darcy E. P. , Wise Kiersten , Smith Damon L.
Published: March 2023

Phyllachora maydisis a fungal pathogen causing tar spot of corn (Zea maysL.), a new and emerging, yield-limiting disease in the United States. Since being first reported in Illinois and Indiana in 2015,P. maydiscan now be found across much of the corn growing of the United States. Knowledge of the epidemiology ofP. maydisis limited but could be useful in developing tar spot prediction tools. The research presented here aims to elucidate the environmental conditions necessary for the development of tar spot in the field and the creation of predictive models to anticipate future tar spot epidemics. Extended periods (30-day windowpanes) of moderate ambient temperature were most significant for explaining the development of tar spot. Shorter periods (14- to 21-day windowpanes) of moisture (relative humidity, dew point, number of hours with predicted leaf wetness) were negatively correlated with tar spot development. These weather variables were used to develop multiple logistic regression models, an ensembled model, and two machine learning models for the prediction of tar spot development. This work has improved the understanding ofP. maydisepidemiology and provided the foundation for the development of a predictive tool for anticipating future tar spot epidemics.
Compartment-Specific Activation of the Proton-Sensor GPR65 is Uncoupled from Receptor Trafficking
Authors: Morales Rodríguez Loyda M. , Crilly Stephanie E. , Rowe Jacob B. , Isom Daniel G. , Puthenveedu Manojkumar A.
Published: March 2023

The canonical view of G protein-coupled receptor (GPCR) function is that receptor trafficking is tightly coupled to signaling. GPCRs remain on the plasma membrane (PM) at the cell surface until they are activated, after which they are desensitized and internalized into endosomal compartments. This canonical view presents an interesting context for proton-sensing GPCRs because they are more likely to be activated in acidic endosomal compartments than at the PM. Here we show that the trafficking of the prototypical proton-sensor GPR65 is fully uncoupled from signaling, unlike that of other known mammalian GPCRs. GPR65 internalized and localized to early and late endosomes, from where they signal at steady state, irrespective of extracellular pH. Acidic extracellular environments stimulated receptor signaling at the PM in a dose-dependent manner, although endosomal GPR65 was still required for a full signaling response. Receptor mutants that were incapable of activating cAMP trafficked normally, internalized, and localized to endosomal compartments. Our results show that GPR65 is constitutively active in endosomes, and suggest a model where changes in extracellular pH reprograms the spatial pattern of receptor signaling and biases the location of signaling to the cell surface.
Clonal associations of lymphocyte subsets and functional states revealed by single cell antigen receptor profiling of T and B cells in rheumatoid arthritis synovium
Authors: Dunlap Garrett , Wagner Aaron , Meednu Nida , Zhang Fan , Jonsson A. Helena , Wei Kevin , Sakaue Saori , Nathan Aparna ,   Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Bykerk Vivian P. , Donlin Laura T. , Goodman Susan M. , Firestein Gary S. , Boyle David L. , Holers V. Michael , Moreland Larry W. , Tabechian Darren , Pitzalis Costantino , Filer Andrew , Raychaudhuri Soumya , Brenner Michael B. , McDavid Andrew , Rao Deepak A. , Anolik Jennifer H.
Published: March 2023

Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched inGZMK+ cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC),NR4A1+activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.
Reconstruction of segmental duplication rates and associated genomic features by network analysis
Authors: Abdullaev Eldar T , Haridoss Dinesh A , Arndt Peter F
Published: March 2023

Abstract

Segmental duplications (SDs) are long genomic duplications fixed in a genome. SDs play an important evolutionary role: entire genes together with regulatory sequences can be duplicated. Ancestral segmental duplications gave rise to genes involved in human brain development, as well as provided sites for further genomic rearrangements. Some duplicated loci were extensively studied, however, universal principles or biological factors of SDs propagation are not fully described yet. Segmental duplications can be arranged into a network where edges correspond to real duplication events, while nodes to affected genomic sites. This gave us an opportunity to estimate how many duplications happened in each locus. We studied genomic features associated with increased duplication rates with especial interest in high-copy repeats distribution relative to duplicated regions breakpoints. Our comprehensive study of genomic features associated with duplications and those associated with increased duplication rates allowed us to identify several biological factors affecting a segmental duplication process. We found genomic features associated with increased duplication rates, three signatures of duplication process and associations of SDs with different classes of high-copy repeats.
Contribution of default mode network to game and delayed-response task performance: power and connectivity analyses of theta oscillation in the monkey
Authors: Kodama Tohru , Kojima Takashi , Honda Yoshiko , Hosokawa Takayuki , Karashima Akihiro , Watanabe Masataka
Published: March 2023

Neuroimaging studies have demonstrated the presence of a default mode network (DMN) which shows greater activity during rest, and an executive network (EN) which is activated during cognitive tasks. DMN and EN are thought to have competing functions.

However, recent studies reported that the two networks show coactivation during some cognitive tasks. To clarify how DMN works and how DMN interacts with EN for cognitive control, we recorded EEG activities in the medial prefrontal (anterior DMN: aDMN), posterior cingulate/precuneus (posterior DMN: pDMN), and lateral prefrontal (EN) areas in the monkey. As cognitive tasks, we employed a monkey-monkey competitive video game (GAME) and a delayed-response (DR) task. We focused on theta oscillation because of its importance in cognitive control. We also examined theta band connectivity among the three network areas using the Granger causality analysis.

DMN and EN were found to work cooperatively in both tasks. In all the three network areas, we found GAME-task-related, but no DR-task-related, increase in theta power from the resting level, maybe because of the higher cognitive demand associated with the GAME task performance. The information flow conveyed by the theta oscillation was directed more to aDMN than from aDMN for both tasks. The GAME-task-related increase in theta power in aDMN is supposed to be supported by more information flow conveyed by the theta oscillation from EN and pDMN.
FIREBALL: A tool to fit protein phase diagrams based on mean-field theories for polymer solutions
Authors: Farag Mina , Holehouse Alex S. , Zeng Xiangze , Pappu Rohit V.
Published: March 2023

Biomolecular condensates form via phase transitions of condensate-specific biomacromolecules. Intrinsically disordered regions (IDRs) featuring the appropriate sequence grammar can contribute homotypic and heterotypic interactions to the driving forces for phase separation of multivalent proteins. At this juncture, experiments and computations have matured to the point where the concentrations of coexisting dense and dilute phases can be quantified for individual IDRs in complex milieus bothin vitroandin vivo. For a macromolecule such as a disordered protein in a solvent, the locus of points that connects concentrations of the two coexisting phases defines a phase boundary or binodal. Often, only a few points along the binodal, especially in the dense phase, are accessible for measurement. In such cases and for quantitative and comparative analysis of parameters that describe the driving forces for phase separation, it is useful to fit measured or computed binodals to well-known mean-field free energies for polymer solutions. Unfortunately, the non-linearity of the underlying free energy functions makes it challenging to put mean-field theories into practice. Here, we present FIREBALL, a suite of computational tools designed to enable efficient construction, analysis, and fitting to experimental or computed data of binodals. We show that depending on the theory being used, one can also extract information regarding coil-to-globule transitions of individual macromolecules. Here, we emphasize the ease-of-use and utility of FIREBALL using examples based on data for two different IDRs.

Statement of Significance

Macromolecular phase separation drives the assembly of membraneless bodies known as biomolecular condensates. Measurements and computer simulations can now be brought to bear to quantify how the concentrations of macromolecules in coexisting dilute and dense phases vary with changes to solution conditions. These mappings can be fit to analytical expressions for free energies of solution to extract information regarding parameters that enable comparative assessments of the balance of macromolecule-solvent interactions across different systems. However, the underlying free energies are non-linear and fitting them to actual data is non-trivial. To enable comparative numerical analyses, we introduce FIREBALL, a user-friendly suite of computational tools that allows one to generate, analyze, and fit phase diagrams and coil-to-globule transitions using well-known theories.
The Effect of Intradialytic Exercise on Calcium, Phosphorus and Parathyroid Hormone: A Randomized Controlled Trial
Authors: Tabibi Mohammadali , Wilund Kenneth R , Salimian Nasrin , Nikbakht Saghar , Soleymany Mahsa , Roshanaeian Zahra , Ahmadi Saghar
Published: March 2023

Introduction

Patients with kidney failure experience derangements of circulating markers of mineral metabolism and dysregulation of skeletal and cardiovascular physiology which results in high mortality rate in these patients. This study aimed to evaluate the effect of intradialytic concurrent exercise on regulation of theses abnormalities related parameters in patients receiving hemodialysis (HD).

Methods

In this randomized controlled trial conducted in a HD center in Iran, adult patients receiving chronic HD were randomized to intradialytic exercise (60 minutes) in the second hour of thrice weekly dialysis for 6 months (intervention) or no intradialytic exercise (control). The primary outcomes were serum calcium, serum phosphorous and parathyroid hormone levels. Secondary outcomes were serum alkaline phosphatase and calcium-phosphorous product

Results

The study included 44 participants randomized to intervention (n=22) or control (n=22). During the 6-month intervention period, significant between-group changes were observed in all primary and secondary outcomes between the intervention and control groups. The analysis showed a significant decrease in serum levels of phosphorous and parathyroid hormone (P < 0.05). Statistical analyses reveal a significant increase in serum calcium (P < 0.05) as well as a significant decrease in serum phosphorous, parathyroid hormone, alkaline phosphatase and calcium-phosphorous product (P < 0.05).

Conclusion

Intradialytic exercise performed for at least 60 minutes during thrice weekly dialysis sessions improves bone mineral metabolism in adult patients receiving HD. Further studies should focus on observing the effect of different types of exercise on bone mineral disorders and all-cause mortality in HD patients.

Trial registration

ClinicalTrials.govIdentifier:NCT04916743, Registered on June 8th,2021. Registered trial name: The Effect of Intradialytic Exercise on Calcium, Phosphorous and Parathyroid Hormone: A Randomized Controlled Trial
The Unique Neural Signature of Your Trip: Functional Connectome Fingerprints of Subjective Psilocybin Experience
Authors: Tolle Hanna M. , Farah Juan Carlos , Mallaroni Pablo , Mason Natasha L. , Ramaekers Johannes G. , Amico Enrico
Published: March 2023

The emerging neuroscientific frontier of brain fingerprinting has recently established that human functional connectomes (FCs) exhibitfingerprint-likeidiosyncratic features, which map onto heterogeneously distributed behavioural traits. Here, we harness brain-fingerprinting tools to extract FC features that predict subjective drug experience induced by the psychedelic psilocybin. Specifically, in neuroimaging data of healthy volunteers under the acute influence of psilocybin or a placebo, we show that, post psilocybin administration, FCs become more idiosyncratic due to greater inter-subject dissimilarity. Moreover, whereas in placebo subjects idiosyncratic features are primarily found in the frontoparietal network, in psilocybin subjects they concentrate in the default-mode network (DMN). Crucially, isolating the latter revealed an FC pattern that predicts subjective psilocybin experience and is characterised by reduced within-DMN and DMN-limbic connectivity, as well as increased connectivity between the DMN and attentional systems. Overall, these results contribute to bridging the gap between psilocybin-mediated effects on brain and behaviour, while demonstrating the value of a brain-fingerprinting approach to pharmacological neuroimaging.

Author summary

The trending field of brain fingerprinting focuses on characterising fingerprint-like idiosyncratic features of human functional connectomes (FCs), which have been shown to predict heterogeneously distributed behavioural traits. Here, we apply brain-fingerprinting methods to fMRI data from subjects who were administered the psychedelic psilocybin or a placebo. We find that, compared to the placebo condition, subjects under acute psilocybin effects exhibited more idiosyncratic FCs, with idiosyncratic features being largely concentrated in the default-mode network (DMN). Furthermore, we isolated an idiosyncratic FC pattern that predicted reports of subjective psilocybin experiences. This pattern was characterised by altered DMN connectivity, specifically by reduced within-DMN and DMN-limbic connectivity, and increased connectivity between the DMN and attentional systems. This work paves the way for exciting new research harnessing pharmacological brain fingerprinting.
Characterisation of the bovine C-type lectin receptor Mincle and potential evidence for an endogenous ligand1
Authors: Holder Angela , Kolakowski Jeannine , Rosentreter Chloe , Knuepfer Ellen , Jégouzo Sabine A. F. , Rosenwasser Oliver , Harris Heather , Baumgaertel Lotta , Gibson Amanda , Werling Dirk
Published: March 2023

Innate immune receptors that form complexes with secondary receptors, activating multiple signalling pathways, modulate cellular activation and play essential roles in regulating homeostasis and immunity. We have previously identified a variety of bovine C-type lectin-like receptors that possess similar functionality than their human orthologues. Mincle (CLEC4E), a heavily glycosylated monomer, is involved in the recognition of the mycobacterial component Cord factor (trehalose 6,6′-dimycolate). Here we characterise the bovine homologue of Mincle (boMincle), and demonstrate that the receptor is structurally and functionally similar to the human orthologue (huMincle), although there are some notable differences. In the absence of cross-reacting antibodies, boMincle-specific antibodies were created and used to demonstrate that, like the human receptor, boMincle is predominantly expressed by myeloid cells. BoMincle surface expression increases during the maturation of monocytes to macrophages. However, boMincle mRNA transcripts were also detected in granulocytes, B cells, and T cells. Finally, we show that boMincle binds to isolated bovine CD4+T cells in a specific manner, indicating the potential to recognize endogenous ligands. This suggests that the receptor might also play a role in homeostasis in cattle.