bluuebunny/crossref_metadata_2025 huggingface dataset:
Rupture of a dermoid cyst in the subarachnoid space a case report
Authors: Jamal Oufaa , Makhchoune Marouane , Laidi Abdelkoudous , Misbahi Tarek , Haouas Mohamed Yassine , Chellaoui Abdelmajid , Bertal Abderrazak , Hilmani Said , Ibahiouine Khadija , Naja Abdesamad , Lakhder Abdelhakim
Published: March 2024

Introduction and importance

Intracranial dermoid cysts (IDC) are defined as rare, slow-growing cystic congenital neoplasms. Rupture of an intracranial dermoid cyst occurs rarely and most often spontaneously and results in potentially serious symptoms.

Case presentation

A39-year-old female, with mechanical prosthetic heart valve presented with history of headache for 10 months and generalized tonicoclonic seizures. On the admission, the patient had a normal neurological and cranial nerve exam. We performed a CT of the brain, The MRI could not be performed because of the presence of the prosthetic valve, revealed rupture of the dermoid cyst in the bilateral subarachnoid spaces. The patient underwent a large temporal craniotomy and the tumor was well exposed and completely removed without incident, the histopathological exam concludes to dermoid cyst, the patient recovered well from surgery.

Clinical discussion:

Rupture is a very rare phenomenon. there are about 60 cases reported in the literature. the contents of the cyst disseminate into the subarachnoid and ventricular spaces in the event of rupture. A variety of clinical symptoms is usually caused. The mechanism of spontaneous rupture of the dermoid cyst is unclear. Among the proposed mechanisms is a rapid expansion of the cyst. Complete surgical resection of dermoid cysts is the only effective treatment for the prevention of recurrences and/or complications.

Conclusion:

Rupture of an intracranial dermoid cyst is associated with significant morbidity and mortality, although it remains a rare phenomenon. Surgical excision should be considered as soon as the diagnosis is made in order to prevent more severe intracranial complication.
Factors Associated With Delay in Lung Cancer Diagnosis and Surgery in a Lung Cancer Screening Program
Authors: El Alam Raquelle , Hammer Mark M. , Byrne Suzanne C.
Published: March 2024

Purpose:

Delays to biopsy and surgery after lung nodule detection can impact survival from lung cancer. The aim of this study was to identify factors associated with delay in a lung cancer screening (LCS) program.

Materials and Methods:

We evaluated patients in an LCS program from May 2015 through October 2021 with a malignant lung nodule classified as lung CT screening reporting and data system (Lung-RADS) 4B/4X. A cutoff of more than 30 days between screening computed tomography (CT) and first tissue sampling and a cutoff of more than 60 days between screening CT and surgery were considered delayed. We evaluated the relationship between delays to first tissue sampling and surgery and patient sex, age, race, smoking status, median income by zip code, language, Lung-RADS category, and site of surgery (academic vs community hospital).

Results:

A total of 185 lung cancers met the inclusion criteria, of which 150 underwent surgical resection. The median time from LCS CT to first tissue sampling was 42 days, and the median time from CT to surgery was 52 days. 127 (69%) patients experienced a first tissue sampling delay and 60 (40%) had a surgical delay. In multivariable analysis, active smoking status was associated with delay to first tissue sampling (odds ratio: 3.0, CI: 1.4-6.6, P = 0.005). Only performing enhanced diagnostic CT of the chest before surgery was associated with delayed lung cancer surgery (odds ratio: 30, CI: 3.6-252, P = 0.02). There was no statistically significant difference in delays with patients’ sex, age, race, language, or Lung-RADS category.

Conclusion:

Delays to first tissue sampling and surgery in a LCS program were associated with current smoking and performing diagnostic CT before surgery.
Single-center Outcomes After Liver Transplantation With SARS-CoV-2–Positive Donors: An Argument for Increased Utilization
Authors: Connor Ashton A. , Adelman Max W. , Mobley Constance M. , Moaddab Mozhgon , Erhardt Alexandra J. , Hsu David E. , Brombosz Elizabeth W. , Sanghvi Mansi , Cheah Yee Lee , Simon Caroline J. , Hobeika Mark J. , Saharia Ashish S. , Victor David W. , Kodali Sudha , Basra Tamneet , Graviss Edward A. , Nguyen Duc T. , Elsaiey Ahmed , Moore Linda W. , Nigo Masayuki , Drews Ashley L. , Grimes Kevin A. , Arias Cesar A. , Li Xian C. , Gaber A. Osama , Ghobrial R. Mark
Published: March 2024

Background.

The COVID-19 pandemic has led to an increase in SARS-CoV-2–test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19–positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19–positive donors at a single center are presented here.

Methods.

A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19–positive (n = 29 total; 25 index, 4 redo) and COVID-19–negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared.

Results.

COVID-19–positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19–negative donors. Recipients of COVID-19–positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19–positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants.

Conclusions.

The utilization of liver grafts from COVID-19–positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19–positive donors may be used safely to expand the deceased donor pool.
Selective Elimination and Rationalization of Cell-based Assays in Deceased Donor Kidney Transplant Crossmatching
Authors: Khalili Myriam , Famure Olusegun , Minkovich Michelle , Tinckam Kathryn J. , Kim Sang Joseph
Published: March 2024

Background.

While there is increasing reliance on a negative virtual crossmatch to proceed with deceased donor kidney transplantation, a flow cytometry crossmatch (FCXM) is still usually performed after the transplant has already occurred. Our center has eliminated pretransplant physical crossmatches for most patients, and since 2018, we have eliminated the systematic performance of posttransplant FCXMs.

Methods.

We studied all deceased donor kidney transplants in our program between June 1, 2018, and March 31, 2021, to evaluate the impact of eliminating retrospective FCXMs on resource utilization and graft outcomes (ie, the occurrence of antibody-mediated rejection [AMR] in the first 3-mo posttransplant).

Results.

A total of 358 kidney transplants occurred during the study period, and approximately 70% of these transplants proceeded without the performance of any FCXM. Incidence rates of AMR were low (9.63 per 1000 person-months), which compared favorably with the incidence rate of AMR during the 3-y period preceding the policy (4.82 per 1000 person-months, P = 0.21).

Conclusions.

Our results suggest that moving away from retrospective FCXM and relying exclusively on the virtual crossmatch is safe and efficient for kidney allocation.
The Relationship Between Rehabilitation and Frailty in Advanced Heart or Lung Disease
Authors: Dinesh Vaishnavi , Pierce Rachel , Hespe Lauren , Thakkar Sonali , Wong Marko , El Sabbagh Luke , Honeysett Liarna , Brown Peter , Delbaere Kim , Havryk Adrian , Malouf Monique , Macdonald Peter S.
Published: March 2024

Background.

Frailty increases morbidity and mortality in patients with advanced heart and lung disease. Emerging evidence shows that postoperative cardiac or pulmonary rehabilitation can improve the frailty status of these patients. The aim of this hypothesis-generating study was to test the relationship between prehabilitation and frailty in patients with advanced heart or lung disease referred for heart and lung transplantation.

Methods.

The study was a retrospective audit of consecutive patients with advanced heart or lung disease referred for transplant assessment between January 2021 and December 2022. Frailty scores were recorded using Fried’s frailty phenotype (range, 0–5), and rehabilitation status of patients at the time of frailty assessment was recorded.

Results.

Of 286 patients, 124 patients had advanced heart disease (mean age 53 ± 12 y; 82% men) and 162 patients had advanced lung disease (mean age 55 ± 12 y; 43% men). Sixty-nine (24%) patients were robust (score 0), 156 (55%) were prefrail (score, 1–2), and 61 (21%) were frail (score, 3–5). Eighty-two (29%) patients participated in hospital-based rehabilitation, 72 (25%) in home-based rehabilitation, and 132 (46%) in no rehabilitation. Frailty scores were significantly lower in patients participating in hospital-based or home-based rehabilitation compared with patients not participating in rehabilitation (0.8 ± 1.0 versus 0.8 ± 0.9 versus 2.3±1.2, P < 0.0001).

Conclusions.

This study shows that patients participating in cardiac or pulmonary rehabilitation are less frail compared with patients not participating in rehabilitation. These findings suggest that prehabilitation could be beneficial for patients awaiting heart or lung transplantation.
Ocular Manifestations of Multiple Sclerosis: A Population-Based Study
Authors: Kraker Jessica A. , Xu Sarah Chaoying , Flanagan Eoin P. , Foster Robert , Wang Feng , Chen John J.
Published: March 2024

Background:

To evaluate the population-based frequency and severity of multiple sclerosis (MS)-related ocular diseases.

Methods:

Retrospective, population-based study examining patients with MS between January 1, 1998 and December 31, 2011. Patients were identified using the Rochester Epidemiology Project, which is a record-linkage system of medical records for all patient–physician encounters among Olmsted County, Minnesota residents. Diagnosis of MS was confirmed based on neuroimaging, cerebrospinal fluid studies, and serum studies for each patient according to the 2017 McDonald criteria. Patient data were obtained using the medical records and followed through April 1, 2018.

Results:

Of the 116 patients with MS, 66% were female and the median age of onset was 36 years (interquartile range 27.5–43.5 years). About half (61/116, 53%) had MS-related neuro-ophthalmic manifestations during their disease course, and about one-fourth (33/116, 28%) had visual symptoms as their presenting symptom of MS, most commonly as optic neuritis (26/116, 22%). Optic neuritis was the leading MS-related ocular condition (37%), followed by internuclear ophthalmoplegia (16%) and nystagmus (13%). Optic neuritis was mostly unilateral (40/43, 93%), with 16% (6/43) having a visual acuity of 20/200 or worse at nadir but ultimately 95% (35/37) improving to a visual acuity of 20/40 or better.

Conclusions:

This study provides the population-based frequency of MS-related ocular disease, which demonstrates a high frequency of ocular manifestations in MS both at disease onset and during the disease course, emphasizing the utility of neuro-ophthalmologists, or collaboration between neurologists and ophthalmologists, in the care of patients with MS.
Should I See You Again Soon? Multispecialty Assessment of Impact and Burden of Preoperative History and Physical Update Visits
Authors: Soegaard Ballester Jacqueline M , Ginzberg Sara P , Finn Caitlin B , Passman Jesse , Miranda Stephen P , Blue Rachel , Stein Jacob , Mahmoud Najjia N , Kelz Rachel R , Wachtel Heather
Published: March 2024

BACKGROUND:

Federal regulations require a history and physical (H&P) update performed 30 days or less before a planned procedure. We evaluated the use and burdens of H&P update visits by determining impact on operative management, suitability for telehealth, and visit time and travel burden.

STUDY DESIGN:

We identified H&P update visits performed in our health system during 2019 for 8 surgical specialties. As available, up to 50 visits per specialty were randomly selected. Primary outcomes were interval changes in history, examination, or operative plan between the initial and updated H&P notes, and visit suitability for telehealth, as determined by 2 independent physician reviewers. Clinic time was captured, and round-trip driving time and distance between patients’ home and clinic ZIP codes were estimated.

RESULTS:

We identified 8,683 visits and 362 were randomly selected for review. Documented changes were most commonly identified in histories (60.8%), but rarely in physical examinations (11.9%) and operative plans (11.6%). Of 362 visits, 359 (99.2%) visits were considered suitable for telehealth. Median clinic time was 52 minutes (interquartile range 33.8 to 78), driving time was 55.6 minutes (interquartile range 35.5 to 85.5), and driving distance was 20.2 miles (interquartile range 8.5 to 38.4). At the health system level, patients spent an estimated aggregate 7,000 hours (including 4,046 hours of waiting room and travel time) and drove 142,273 miles to attend in-person H&P update visits in 2019.

CONCLUSIONS:

Given their minimal impact on operative management, regulatory requirements for in-person H&P updates should be reconsidered. Flexibility in update timing and modality might help defray the substantial burdens these visits impose on patients.
Cross-Sectional and Longitudinal Associations between Forearm Bone Mineral Density and Anthropometry in Adult Japanese Men and Women
Authors: Ishizawa Masahiro , Fujihara Kazuya , Yachida Junko , Ikeda Izumi , Sato Takaaki , Yamada Takaho , Kobayashi Ayako , Tanaka Shiro , Nakagawa Yoshimi , Matsuzaka Takashi , Shimano Hitoshi , Tashiro Minoru , Kodama Satoru , Kato Kiminori , Sone Hirohito
Published: March 2024

Background: No consensus exists regarding which anthropometric measurements are related to bone mineral density (BMD), and this relationship may vary according to sex and age. A large Japanese cohort was analyzed to provide an understanding of the relationship between BMD and anthropometry while adjusting for known confounding factors. Methods: Our cohort included 10,827 participants who underwent multiple medical checkups including distal forearm BMD scans. Participants were stratified into four groups according to age (≥50 years or <50 years) and sex. The BMD values were adjusted for confounding factors, after which single and partial correlation analyses were performed. The prevalence of osteopenia was plotted for each weight index (weight or body mass index [BMI]) class. Results: Cross-sectional studies revealed that weight was more favorably correlated than BMI in the older group (R=0.278 and 0.212 in men and R=0.304 and 0.220 in women, respectively), whereas weight and BMI were weakly correlated in the younger age groups. The prevalence of osteopenia exhibited a negative linear relationship with weight among older women ≥50 years of age, and an accelerated increase was observed with decreasing weight in older men weighing <50 kg and younger women weighing <60 kg. When weight was replaced with BMI, the prevalence was low in most subgroups classified by weight. Conclusions: Weight, rather than BMI, was the most important indicator of osteopenia but it might not be predictive of future bone loss.
Mortality Rate and Outcomes of Omicron Variant Positive Patients with Osteoporotic Fractures: A Retrospective Study
Authors: Chung Hoe Jeong , Lee Bum Seok , Sohn Hoon-Sang
Published: March 2024

Background: During the lockdown period associated with the coronavirus disease 2019 (COVID-19) pandemic, increased mortality rates among patients with COVID-19 have been reported. This study aimed to analyze the mortality rate of osteoporotic hip fractures in patients who were COVID-19-positive after the lockdown during the Omicron period.Methods: A retrospective study was performed with 194 patients who were aged 70 years or more and diagnosed with osteoporotic hip fracture. The patients were divided into two groups according to their COVID-19 diagnoses. Surgery was performed within 10 days of diagnosis. Age, sex, past medical history, time until surgery, postoperative complications, and the primary outcome of mortality rate at 30 and 90 days were analyzed.Results: Among the 194 patients, 13 and 181 were in the COVID-19-positive and negative group, respectively. The total, 30-day, and 90-day mortality rates in the control and COVID-positive group were 11% and 0% (P=0.368), 1.7% and 0% (P=1.000), and 5.0% and 0% (P=1.000), respectively. No significant differences were observed in age, sex, history, time to surgery, postoperative complications, or postoperative mortality. In 1:1 propensity score matching, the time to surgery was 5.34 days in patients who were COVID-19-positive, and 3.00 days in patients who were COVID-19 negative, with no statistical significance (P=0.09). Age, sex, medical history, postoperative complications, and postoperative mortality were not significantly different between the groups.Conclusions: Regardless of the COVID-19 diagnosis, surgical treatment without delay is believed to result in positive outcomes in older patients with osteoporotic hip fractures, as no significant differences in mortality rate and respiratory complications were observed between patients who were COVID-19-positive and those who were COVID-19 negative.
Comparison of Clinical and Radiological Outcomes after Vertebroplasty and Balloon Kyphoplasty in the Treatment of Osteoporotic Vertebral Compression Fractures
Authors: Yoon Sung-Hyun , Park Hee-Gon , Lee Dae-Hee , Lee Dong-Uk
Published: March 2024

Background: Vertebroplasty (VP) and balloon kyphoplasty (KP) are effective means with which to improve pain and function in osteoporotic vertebral compression fractures. However, the risk of complications after these procedures is poorly understood, with concerns regarding adjacent vertebral fractures. This study retrospectively investigated the clinical and radiological outcomes of these procedures.Methods: A total of 115 patients who experienced their first vertebral fracture were treated with VP (N=63) or KP (N=52) at the Dankook University Hospital between January 2013 and December 2022. The clinical outcomes were evaluated using the visual analog scale (VAS) preoperative and at 1-year follow-up. Radiological comparisons were performed for kyphosis correction, vertebral height restoration, and postoperative cement leakage. Results: KP was more effective than VP, especially for vertebral body height restoration and kyphotic angle reduction (P<0.05). However, the incidence of cement leakage, new adjacent vertebral fractures, and improvement in pain assessed by VAS did not differ statistically between the 2 groups (P>0.05).Conclusions: Considering that KP was performed on fractures with severe deformity, no differences were observed in the clinical outcomes and incidence of adjacent vertebral fractures compared Considering that KP was performed for fractures with severe deformity, there was no difference in clinical outcomes and incidence of adjacent vertebral fractures compared to VP. Improvements in radiological measurements were demonstrated. Therefore, KP may be a good treatment option for pain relief and long-term prognosis in patients with high-compressive-rate vertebral fractures.
Generalizable Neural Models of Emotional Engagement and Disengagement
Authors: Nanni Zepeda Melanni , Evans Travis , Jagger-Rickels Audreyana , Raz Gal , Hendler Talma , Fan Yan , Grimm Simone , Walter Martin , Esterman Michael , Zuberer Agnieszka
Published: March 2024

Emotional reactivity and regulation are essential for mental well-being, as they are critical for managing emotional responses, fostering resilience, and maintaining overall emotional balance. Despite their importance, little is known about the underlying neural mechanisms that support these processes, which is needed to develop more effective interventions for emotional dysregulation and related mental health disorders. Previous research has predominantly relied on discrete trials and experimental task manipulations to isolate emotional processes. However, the use of emotional movies offers an ecologically valid method, allowing for the investigation of emotional processing in a context that simulates dynamic real-world experiences. Using functional magnetic resonance imaging (fMRI), during the viewing of neutral and sad movies, along with subsequent real-time emotional annotations of participants' experiences, we differentiated distinct phases of emotional engagement and disengagement. Functional connectivity across large-scale networks dynamically covaried with the viewer's engagement and disengagement patterns. A common pattern emerged across films: emotional engagement was primarily associated with connections within the Visual and between the Visual and Dorsal Attention Network. Only for highly emotional movies, emotional engagement was associated with connections between the Visual and Default Mode Network. In contrast, emotional disengagement was associated with connections mostly within the Visual and connections between the Sensorimotor Network and Salience Network. We then applied predictive modeling to test whether these neural connectivity markers of engagement and disengagement generalized to other independent movie-watching datasets. Our findings revealed that disengagement patterns generalized specifically across intense clips, while engagement patterns generalized across all movie clips, including neutral contexts. Together this work helps to better understand cognitive and neural mechanisms underpinning engagement in and disengagement from emotionally evocative narratives, offering potential pathways for identifying generalizable neural patterns that can inform future affective research and clinical applications.
Cohort-specific Boolean models highlight different regulatory modules during Parkinson’s disease progression
Authors: Hemedan Ahmed Abdelmonem , Satagopam Venkata , Schneider Reinhard , Ostaszewski Marek
Published: March 2024

1

Parkinson’s Disease (PD) is a multifaceted neurodegenerative disorder characterised by complex molecular dysregulations and diverse comorbidities. It is critical to decode the molecular pathophysiology of PD, which involves complex molecular interactions and their changes over time. Systems medicine approaches can help with this by a) encoding knowledge about the mechanisms into computational models b) simulating these models using patient-specific omics data. This study employs the PD map, a detailed repository of PD-related molecular interactions, as a comprehensive knowledge resource. We aim to dissect and understand the intricate molecular pathways implicated in PD by using logical modelling. This approach is essential for capturing the dynamic interplay of molecular components that contribute to the disease. We incorporate cohort-level and real-world patient data to ensure our models accurately reflect PD’s subtype-specific pathway deregulations. This integration is crucial for addressing the heterogeneity observed in PD manifestations and responses to treatment. To combine logical modelling with empirical data, we rely on Probabilistic Boolean Networks (PBNs).These networks provide a robust framework, capturing the stochastic nature of molecular interactions and offering insights into the variable progression of the disease. By combining logical modelling with empirical data through PBNs, we achieve a more refined and realistic representation of PD’s molecular landscape. The findings provide insights into the molecular mechanisms of PD. We identify key regulatory biomolecules and pathways that differ significantly across PD subtypes. These discoveries have substantial implications for the development of precise medical treatments. The study provides hypothesis for targeted therapeutic interventions by linking molecular dysregulation patterns to clinical phenotypes and advancing our understanding of PD progression and patient stratification.
Coordination of cytochromebc1complex assembly at MICOS
Authors: Zerbes Ralf M. , Colina-Tenorio Lilia , Bohnert Maria , Peikert Christian D. , von der Malsburg Karina , Mehnert Carola S. , Perschil Inge , Klar Rhena , van der Klei Ida , Oeljeklaus Silke , Warscheid Bettina , Rampelt Heike , van der Laan Martin
Published: March 2024

The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as determinant in the biogenesis of the cytochromebc1complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruitment of complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, directly contributes to the spatial and temporal coordination of respiratory chain biogenesis.
Discovery of a pentose as a cytosine nucleobase modification inShewanellaphage Thanatos-1 genomic DNA mediating enhanced resistance towards host restriction systems
Authors: Brandt David , Dörrich Anja K. , Persicke Marcus , Leonhard Tabea , Haak Markus , Nölting Sophia , Ruwe Matthias , Schmid Nicole , Thormann Kai M. , Kalinowski Jörn
Published: March 2024

Co-evolution of bacterial defense systems and phage counter defense mechanisms has resulted in an intricate biological interplay between bacteriophages and their prey. To evade nuclease-based mechanisms targeting the DNA, various bacteriophages modify their nucleobases, which impedes or even inhibits recognition by endonucleases. We found thatShewanellaphage Thanatos-1 DNA is insensitive to multiple restriction enzymes and, partially, also to Cas I-Fv and Cas9 cleavage. Furthermore, the phage genome shows strongly impaired basecalling with nanopore sequencing. We characterised the phage adenine methyltransferase TH1_126 in methylase-freeE. coliER3413 and derived and confirmed its recognition motif 5’-ATC-3’. Moreover, the data pointed to an additional, much more substantial nucleobase modification. Using LC-MS, we identified a deoxypentose of unknown configuration attached to cytosine as a yet undiscovered phage DNA modification, which is present in Thanatos-1 genomic DNA, likely mediates the observed resistance to restriction endonucleases, as well as a strong reduction in Cas nuclease activity. To elucidate the underlying enzyme functions, we determined structural homologs of Thanatos-1 proteins among known glycosyltransferase folds and experimentally proved a UDP-xylose pyrophosphorylase function of phage protein TH1_063 byin vitroenzyme assays.
Exploration of a European-centered strawberry diversity panel provides markers and candidate genes for the control of fruit quality traits
Authors: Prohaska Alexandre , Rey-Serra Pol , Petit Johann , Petit Aurélie , Perrotte Justine , Rothan Christophe , Denoyes Béatrice
Published: March 2024

Fruit quality traits are major breeding targets in cultivated strawberry (Fragaria × ananassa). Taking into account the requirements of both growers and consumers when selecting high quality cultivars is a real challenge. Here, we used an original diversity panel enriched with unique European accessions and the 50K FanaSNP array to highlight the evolution of strawberry diversity over the past 160 years, investigate the molecular basis of 12 major fruit quality traits by GWAS, and provide genetic markers for breeding. Results show that considerable improvements of key breeding targets including fruit weight, firmness, composition and appearance occurred simultaneously in European and American populations. Despite the high genetic diversity of our panel, we observed a drop in nucleotide diversity in certain chromosome regions, revealing the impact of selection. GWAS identified 71 associations with 11 quality traits and, while validating known associations (firmness, sugar), highlighted the predominance of new QTL, demonstrating the value of using untapped genetic resources. Three of the six selective sweeps detected are related to glossiness or skin resistance, two little-studied traits important for fruit attractiveness and, potentially, postharvest shelf-life. Moreover, major QTL for firmness, glossiness, skin resistance and susceptibility to bruising are found within a low diversity region of chromosome 3D. Stringent search for candidate genes underlying QTL uncovered strong candidates for fruit color, firmness, sugar and acid composition, glossiness and skin resistance. Overall, our study provides a potential avenue for extending shelf-life without compromising flavor and color as well as the genetic markers needed to achieve this goal.
Local adaptation of a fungal pathogen to temperature along a latitudinal gradient
Authors: Fox Quinn N. , Goodson Carrie , Penczykowski Rachel M.
Published: March 2024

Whether climate warming will increase or decrease prevalence of an infectious disease partly depends on the potential for pathogens to adapt to higher temperatures. This potential can be assessed by investigating regional variation in pathogen thermal performance and testing for local adaptation to current temperature regimes and host populations. We collected seeds of a host plant (Plantago rugelii, a perennial herb) and isolated strains of its specialist fungal pathogen (Golovinomyces sordidus, a powdery mildew) from five locations along a latitudinal transect from southern Mississippi to northern Wisconsin, USA. In a laboratory experiment, we placed sympatric and allopatric host–pathogen pairings into seven temperature treatments from 7 to 33 °C. We fitted thermal performance curves to pathogen growth data for each strain. Pathogen strains were locally adapted to temperature, with estimated thermal optima ranging from 20.6 °C (southernmost strain) to 16.7 °C (second-northernmost strain) and generally decreasing 0.26 °C for each degree increase in latitude of origin. However, there was no evidence of pathogen local adaptation to sympatric hosts. Given that powdery mildew spores can disperse long distances via wind, our results suggest that northward spread of warm-adapted strains could facilitate pathogen adaptation to warming climates in this and similar systems.
Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation
Authors: Feng Xiaogang , Andersson Tilde , Gschwend Julia , Flüchter Pascal , Berest Ivan , Muff Julian L. , Carchidi Daniele , Lechner Antonie , de Tenorio Jeshua C. , Brander Nina , Boehm Ulrich , Klose Christoph S. N. , Artis David , Leinders-Zufall Trese , Zufall Frank , Schneider Christoph
Published: March 2024

The tuft cell–ILC2 circuit orchestrates rapid type 2 responses upon detecting microbe-derived succinate and luminal helminths. Our findings delineate key mechanistic steps, involving IP3R2 engagement and Ca2+flux, governing IL-25 production by tuft cells triggered by succinate detection. While IL-17RB plays a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutiveIl25expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basalIl25expression. Suboptimal ILC2 stimulation by IL-25 resulting from tuft cellIl17rb-deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.
Identification of regional astrocyte heterogeneity associated with cuprizone-induced de- and remyelination using spatial transcriptomics
Authors: Miedema Anneke , Wijering Marion H.C. , Alsema Astrid M. , Gerrits Emma , Meijer Michel , Koster Mirjam , Wesseling Evelyn M. , Baron Wia , Eggen Bart J.L. , Kooistra Susanne M.
Published: March 2024

The cuprizone model is a well-characterized model to study processes of demyelination and remyelination, which are known features of multiple sclerosis. Cuprizone induces oligodendrocyte loss and severe demyelination in the brain, including the corpus callosum, hippocampus, and cortex. Loss of oligodendrocytes and myelin is accompanied by microgliosis and astrogliosis, wherein microglia and astrocytes partially lose their homeostatic functions and acquire a reactive/activated state. Cuprizone-induced demyelination peaks later in grey matter (GM) than in white matter (WM), and remyelination is more efficient in WM areas. Here, we aim to better understand regional diversity in microglia, astrocytes, and oligodendrocytes and their respective role in remyelination efficiency, by characterizing their response to cuprizone across brain regions. We applied spatial transcriptomics (ST) for unbiased gene activity profiling of multiple brain regions in a single tissue section, to identify region-associated changes in gene activity following cuprizone treatment. Gene activity changes were detected in highly abundant cell types, like neurons, oligodendrocytes, and astrocytes, but challenging to detect in low-abundant cell types such as microglia and oligodendrocyte precursor cells. ST revealed a significant increase in the expression of astrocyte markersClu,Slc1a3,andGfapduring the demyelination phase in the WM fiber tract. In the cortex, the changes in GFAP expression were less prominent, both at the transcriptional and protein level. By mapping genes obtained from scRNAseq of FACS-sorted ACSA2-positive astrocytes onto the ST data, we observed astrocyte heterogeneity beyond the simple classification of WM– and GM-astrocytes in both control and cuprizone-treated mice. In the future, the characterization of these regional astrocyte populations could aid the development of novel strategies to halt the progression of demyelination and support remyelination.

Highlights

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Astrocyte markersClu,Slc1a3,andGfapare increased in WM fiber tracts during demyelination

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Expression dynamics of astrogliosis markersGfapandVimduring de-and remyelination depend on the brain region

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Combining scRNAseq with ST data revealed astrocyte heterogeneity beyond WM– and GM-differences

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scRNAseq-identified gene sets were differently affected by cuprizone treatment across brain regions
Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated transcriptome in human cells
Authors: Boehm Volker , Wallmeroth Damaris , Wulf Paul O. , Alves Luiz Gustavo Teixeira , Popp Oliver , Riedel Maximilian , Wyler Emanuel , Franitza Marek , Gerbracht Jennifer V. , Becker Kerstin , Polkovnychenko Karina , Del Giudice Simone , Benlasfer Nouhad , Mertins Philipp , Landthaler Markus , Gehring Niels H.
Published: March 2024

The helicase UPF1 acts as the central essential factor in human nonsense-mediated mRNA decay (NMD) and is involved in various other mRNA degradation processes. Given its multifunctionality, distinguishing between mRNAs regulated directly and indirectly by UPF1 remains a critical challenge. We engineered two different conditional degron tags into endogenous UPF1 in human cell lines to probe the consequences of UPF1 rapid depletion. UPF1 degradation inhibits NMD within hours and strongly stabilizes endogenous NMD substrates, which can be classified into different groups based on their expression kinetics. Extended UPF1 depletion results in massive transcript and isoform alterations, partially driven by secondary effects. We define a high-confidence UPF1-regulated core set of transcripts, which consists mostly of NMD substrates. NMD-regulated genes are involved in brain development and the integrated stress response, among other biological processes. In summary, UPF1 degron systems rapidly inhibit NMD, providing valuable insights into its roles across various experimental systems.
Extended Poisson Gaussian-Process Latent Variable Model for Unsupervised Neural Decoding
Authors: Luo Della Daiyi , Giri Bapun , Diba Kamran , Kemere Caleb
Published: March 2024

Dimension reduction on neural activity paves a way for unsupervised neural decoding by dissociating the measurement of internal neural state repetition from the measurement of external variable tuning. With assumptions only on the smoothness of latent dynamics and of internal tuning curves, the Poisson Gaussian-process latent variable model (P-GPLVM) (Wu et al., 2017) is a powerful tool to discover the low-dimensional latent structure for high-dimensional spike trains. However, when given novel neural data, the original model lacks a method to infer their latent trajectories in the learned latent space, limiting its ability for estimating the internal state repetition. Here, we extend the P-GPLVM to enable the latent variable inference of new data constrained by previously learned smoothness and mapping information. We also describe a principled approach for the constrained latent variable inference for temporally-compressed patterns of activity, such as those found in population burst events (PBEs) during hippocampal sharp-wave ripples, as well as metrics for assessing whether the inferred new latent variables are congruent with a previously learned manifold in the latent space. Applying these approaches to hippocampal ensemble recordings during active maze exploration, we replicate the result that P-GPLVM learns a latent space encoding the animal’s position. We further demonstrate that this latent space can differentiate one maze context from another. By inferring the latent variables of new neural data during running, certain internal neural states are observed to repeat, which is in accordance with the similarity of experiences encoded by its nearby neural trajectories in the training data manifold. Finally, repetition of internal neural states can be estimated for neural activity during PBEs as well, allowing the identification for replay events of versatile behaviors and more general experiences. Thus, our extension of the P-GPLVM framework for unsupervised analysis of neural activity can be used to answer critical questions related to scientific discovery.
Multielectrode array characterization of human induced pluripotent stem cell derived neurons in co-culture with primary human astrocytes
Authors: Lemieux Maddie R. , Freigassner Bernhard , Thathey Zahra , Opp Mark R. , Hoeffer Charles A , Link Christopher D.
Published: March 2024

Human induced pluripotent stem cells (hiPSCs) derived into neurons offer a powerfulin vitromodel to study cellular processes. One method to characterize functional network properties of these cells is using multielectrode arrays (MEAs). MEAs can measure the electrophysiological activity of cellular cultures for extended periods of time without disruption. Here we used WTC11 hiPSCs with a doxycycline-inducible neurogenin 2 (NGN2) transgene differentiated into neurons co-cultured with primary human astrocytes. We achieved a synchrony index ∼0.9 in as little as six-weeks with a mean firing rate of ∼13 Hz. Previous reports show that derived 3D brain organoids can take several months to achieve similar strong network burst synchrony. We also used this co-culture to model aspects of sporadic Alzheimer’s disease by mimicking blood-brain barrier breakdown using a human serum. Our fully human co-culture achieved strong network burst synchrony in a fraction of the time of previous reports, making it an excellent first pass, high-throughput method for studying network properties and neurodegenerative diseases.
Decoding auditory working memory content from EEG aftereffects of auditory-cortical TMS
Authors: Uluç Işıl , Daneshzand Mohammad , Jas Mainak , Kotlarz Parker , Lankinen Kaisu , Fiedler Jennifer L. , Mamashli Fahimeh , Pajankar Netri , Turpin Tori , Navarro de Lara Lucia , Sundaram Padmavathi , Raij Tommi , Nummenmaa Aapo , Ahveninen Jyrki
Published: March 2024

Working memory (WM), short term maintenance of information for goal directed behavior, is essential to human cognition. Identifying the neural mechanisms supporting WM is a focal point of neuroscientific research. One prominent theory hypothesizes that WM content is carried in “activity-silent” brain states involving short-term synaptic changes. Information carried in such brain states could be decodable from content-specific changes in responses to unrelated “impulse stimuli”. Here, we used single-pulse transcranial magnetic stimulation (spTMS) as the impulse stimulus and then decoded content maintained in WM from EEG using multivariate pattern analysis (MVPA) with robust non-parametric permutation testing. The decoding accuracy of WM content significantly enhanced after spTMS was delivered to the posterior superior temporal cortex during WM maintenance. Our results show that WM maintenance involves brain states, which are activity silent relative to other intrinsic processes visible in the EEG signal.
DR5 disulfide bonding as a sensor and effector of protein folding stress
Authors: Law Mary E. , Dulloo Zaafir M. , Eggleston Samantha R. , Takacs Gregory P. , Alexandrow Grace M. , Wang Mengxiong , Su Hanyu , Forsyth Bianca , Chiang Chi-Wu , Sharma Abhisheak , Kanumuri Siva Rama Raju , Guryanova Olga A. , Harrison Jeffrey K. , Tirosh Boaz , Castellano Ronald K. , Law Brian K.
Published: March 2024

New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity, but TRAIL analogs or agonistic antibodies targeting these receptors have not received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may bypass some of the pharmacological limitations of these protein drugs. Previously described Disulfide bond Disrupting Agents (DDAs) activate DR5 by altering its disulfide bonding through inhibition of the Protein Disulfide Isomerases (PDIs) ERp44, AGR2, and PDIA1. Work presented here extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of Caspase 8-Caspase 3 mediated pro-apoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy. Disulfide-defective DR5 mutants do not activate the ER stress response or stimulate autophagy, indicating that these DDA-mediated responses are separable from DR5 activation and pro-apoptotic signaling. Importantly, other ER stressors, including Thapsigargin and Tunicamycin also alter DR5 disulfide bonding in various cancer cell lines and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the Integrated Stress Response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands.
DenoiseST: A dual-channel unsupervised deep learning-based denoising method to identify spatial domains and functionally variable genes in spatial transcriptomics
Authors: Cui Yaxuan , Wang Ruheng , Zeng Xin , Cui Yang , Zhu Zheyong , Nakai Kenta , Ye Xiucai , Sakurai Tetsuya , Wei Leyi
Published: March 2024

Spatial transcriptomics provides a unique opportunity for understanding cellular organization and function in a spatial context. However, spatial transcriptome exists the problem of dropout noise, exposing a major challenge for accurate downstream data analysis. Here, we proposed DenoiseST, a dual-channel unsupervised adaptive deep learning-based denoising method for data imputing, clustering, and identifying functionally variable genes in spatial transcriptomics. To leverage spatial information and gene expression profiles, we proposed a dual-channel joint learning strategy with graph convolutional networks to sufficiently explore both linear and nonlinear representation embeddings in an unsupervised manner, enhancing the discriminative information learning ability from the global perspectives of data distributions. In particular, DenoiseST enables the adaptively fitting of different gene distributions to the clustered domains and employs tissue-level spatial information to accurately identify functionally variable genes with different spatial resolutions, revealing their enrichment in corresponding gene pathways. Extensive validations on a total of 18 real spatial transcriptome datasets show that DenoiseST obtains excellent performance and results on brain tissue datasets indicate it outperforms the state-of-the-art methods when handling artificial dropout noise with a remarkable margin of ∼15%, demonstrating its effectiveness and robustness. Case study results demonstrate that when applied to identify biological structural regions on human breast cancer spatial transcriptomic datasets, DenoiseST successfully detected biologically significant immune-related structural regions, which are subsequently validated through Gene Ontology (GO), cell-cell communication, and survival analysis. In conclusion, we expect that DenoiseST is a novel and efficient method for spatial transcriptome analysis, offering unique insights into spatial organization and function.
FGF21 acts in the brain to drive macronutrient-specific changes in behavioral motivation and brain reward signaling
Authors: Khan Md Shahjalal H. , Kim Sora Q. , Ross Robert C. , Corpodean Florina , Spann Redin A. , Albarado Diana A. , Fernandez-Kim Sun O. , Clarke Blaise , Berthoud Hans-Rudolf , Münzberg Heike , McDougal David H. , He Yanlin , Yu Sangho , Albaugh Vance L. , Soto Paul , Morrison Christopher D.
Published: March 2024

Dietary protein restriction induces adaptive changes in food preference, increasing protein consumption over carbohydrates or fat. We investigated whether motivation and reward signaling underpin these preferences. In an operant task, protein-restricted male mice responded more for liquid protein rewards, but not carbohydrate, fat, or sweet rewards compared to non-restricted mice. The protein restriction-induced increase in operant responding for protein was absent inFgf21-KO mice and mice with neuron-specific deletion of the FGF21 co-receptor beta-Klotho (KlbCam2ka) mice. Fiber photometry recording of VTA dopamine neurons revealed that oral delivery of maltodextrin triggered a larger activation as compared to casein in control-fed mice, whereas casein triggered a larger activation in protein-restricted mice. This restriction-induced shift in nutrient-specific VTA dopamine signaling was lost inFgf21-KO mice. These data strongly suggest that the increased FGF21 during protein restriction acts in the brain to induce a protein-specific appetite by specifically enhancing the reward value of protein-containing foods and the motivation to consume them.