bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional performance of a vibrotactile sensory substitution device in people with profound vision loss
Authors: Jin Rui , Petoe Matthew A. , McCarthy Chris D. , Stefopoulos Samuel , Battiwalla Xerxes , McGinley Jennifer , Ayton Lauren N.
Published: July 2024

SIGNIFICANCE

This study has shown a vibrotactile sensory substitution device (SSD) prototype, VibroSight, has the potential to improve functional outcomes (i.e., obstacle avoidance, face detection) for people with profound vision loss, even with brief familiarization (<20 minutes).

PURPOSE

Mobility aids such as long canes are still the mainstay of support for most people with vision loss, but they do have limitations. Emerging technologies such as SSDs are gaining widespread interest in the low vision community. The aim of this project was to assess the efficacy of a prototype vibrotactile SSD for people with profound vision loss in the face detection and obstacle avoidance tasks.

METHODS

The VibroSight device was tested in a movement laboratory setting. The first task involved obstacle avoidance, in which participants were asked to walk through an obstacle course. The second was a face detection task, in which participants were asked to step toward the first face they detected. Exit interviews were also conducted to gather user experience data. Both people with low vision (n = 7) and orientation and mobility instructors (n = 4) completed the tasks.

RESULTS

In obstacle avoidance task, participants were able to use the device to detect (p<0.001) and avoid (p<0.001) the obstacles within a significantly larger range, but were slower (p<0.001), when compared with without the device. In face detection task, participants demonstrated a great level of accuracy, precision, and sensitivity when using the device. Interviews revealed a positive user experience, although participants identified that they would require a lighter and compact design for real-world use.

CONCLUSIONS

Overall, the results verified the functionality of vibrotactile SSD prototype. Further research is warranted to evaluate the user performance after an extended training program and to add new features, such as object recognition software algorithms, into the device.
Pilot study of a pedestrian collision detection test for a multisite trial of field expansion devices for hemianopia
Authors: Bowers Alex R. , Manda Sailaja , Shekar Sandhya , Hwang Alex D. , Jung Jae-Hyun , Peli Eli
Published: July 2024

SIGNIFICANCE

Performance-based outcome measures are crucial for clinical trials of field expansion devices. We implemented a test simulating a real-world mobility situation, focusing on detection of a colliding pedestrian among multiple noncolliding pedestrians, suitable for measuring the effects of homonymous hemianopia and assistive devices in clinical trials.

PURPOSE

In preparation for deploying the test in a multisite clinical trial, we conducted a pilot study to gather preliminary data on blind-side collision detection performance with multiperiscopic peripheral prisms compared with Fresnel peripheral prisms. We tested the hypothesis that detection rates for colliding pedestrians approaching on a 40° bearing angle (close to the highest collision risk when walking) would be higher with 100Δ oblique multiperiscopic (≈42° expansion) than 65Δ oblique Fresnel peripheral prisms (≈32° expansion).

METHODS

Six participants with homonymous hemianopia completed the test with and without each type of prism glasses, after using them in daily mobility for a minimum of 4 weeks. The test, presented as a video on a large screen, simulated walking through a busy shopping mall. Colliding pedestrians approached from the left or the right on a bearing angle of 20 or 40°.

RESULTS

Overall, blind-side detection was only 23% without prisms but improved to 73% with prisms. For multiperiscopic prisms, blind-side detection was significantly higher with than without prisms at 40° (88 vs. 0%) and 20° (75 vs. 0%). For Fresnel peripheral prisms, blind-side detection rates were not significantly higher with than without prisms at 40° (38 vs. 0%) but were significantly higher with prisms at 20° (94 vs. 56%). At 40°, detection rates were significantly higher with multiperiscopic than Fresnel prisms (88 vs. 38%).

CONCLUSIONS

The collision detection test is suitable for evaluating the effects of hemianopia and prism glasses on collision detection, confirming its readiness to serve as the primary outcome measure in the upcoming clinical trial.
Evaluation of frailty, cognitive function, and age as prognostic factors for survival in patients with IDH1wild-type high-grade glioma
Authors: Škufca Smrdel Andreja Cirila , Podlesek Anja , Markovič Jana , Jereb Jana , Vidmar Marija Skoblar , Smrdel Uroš
Published: July 2024

INTRODUCTION:

High-grade gliomas without isocitrate dehydrogenase (IDH) mutations are associated with poor survival and have been poorly studied. Our aim was to investigate the prognostic factors for survival in this group, focusing on frailty, age, and cognition.

METHODS:

This study included Slovenian patients with high-grade IDH1 wild-type gliomas. Frailty and cognitive functioning were measured postoperatively using the Clinical Frailty Scale and neuropsychological test battery. Descriptive statistics were used to analyze the demographic and clinical data. Univariate and multivariate Cox proportional hazard regression models were used to examine the clinical predictors and prognostic value of the cognitive test scores. Kaplan-Meier curves were generated, and the log-rank test was used.

RESULTS:

Data from 75 patients were analyzed. The median time to progression was 11.0 months, and the median survival was 12.8 months. Multivariate analysis revealed that frailty, sex, O6-methylguanine-DNA methyltransferase methylation, and verbal fluency, but not the global cognitive functioning, were significant prognostic factors for survival. Age was a statistically significant prognostic factor in the univariate regression model; when other factors were controlled for in the multivariate model, age lost its prognostic value.

CONCLUSION:

Frailty is an important prognostic factor for survival of patients with high-grade IDH1 wild-type gliomas. Cognitive functioning in the domain of verbal fluency remained an independent prognostic factor for survival after controlling for other factors.
Inflammatory Giant Cell Carcinoma of the Lung
Authors: Suster David I. , Mackinnon A. Craig , Ronen Natali , Mejbel Haider A. , Harada Shuko , Michal Michael , Suster Saul
Published: July 2024

A distinctive histological variant of poorly differentiated, sarcomatoid, non-small cell lung carcinoma characterized by a discohesive population of giant tumor cells associated with prominent interstitial inflammatory cell infiltrates is described. The tumors occurred in 7 women and 7 men, 42 to 72 years of age (mean: 56 y). They predominantly affected the upper lobes and measured 1.3 to 9 cm in greatest diameter (mean: 4.6 cm). The tumor cells were characterized by large pleomorphic nuclei with prominent nucleoli, ample cytoplasm, and frequent abnormal mitoses, and were surrounded by a dense inflammatory cell infiltrate, often associated with emperipolesis. Immunohistochemical stains were positive in the tumor cells for cytokeratin AE1/AE3 and CK8/18 and negative for TTF1, napsin A, p40, and CK5/6. Next-generation sequencing was performed in all cases using the Oncomine Precision Assay; the most common abnormalities found included TP53 mutations (9 cases) and AKT1 amplification (8 cases), followed by KRAS mutations (4 cases) and MAP2K1/2 mutations (4 cases). Clinical follow-up was available in 13 patients. Three patients presented with metastases as the initial manifestation of disease; 8 patients died of their tumors from 6 months to 8 years (mean: 2.7 y); 3 patients were alive and well from 4 to 6 years; and 2 patients had metastases when last seen but were lost to follow-up thereafter. The importance of recognizing this distinctive and aggressive variant of non-small cell lung carcinoma lies in avoiding confusion with a sarcoma or other types of malignancy.
Clear Cell Carcinomas of Müllerian Type and Rete Testis Origin Presenting as Scrotal Masses
Authors: Kilic Irem , Acosta Andrés M. , Ulbright Thomas M.
Published: July 2024

Ovarian-type epithelial tumors involving the testis and paratestis are rare, with clear cell carcinomas (CCC) one of the least frequent. We report our experience with 4 müllerian-type (MT) CCCs presenting as testicular/scrotal masses and arising in the paratestis (n=2) and seminal vesicle (n=2; well supported in 1 case and likely in the other). In addition, we document 3 cases of papillary CCC exclusively within the rete testis (RTCCC) and seminiferous tubules and differing from the MT tumors. The patients with MTCCC were 24 to 85 years old (median, 42 y), and 2 had metastases at presentation. The 2 originating in the paratestis were associated with other MT tumors, an endometrioid borderline tumor and a papillary serous borderline tumor. The other 2 MTCCCs likely involved the testis via extension from seminal vesicle primaries through the vasa deferentia. All MTCCCs showed typical features, including tubules, simple papillae with hyalinized cores, and solid nests of polygonal clear cells with occasional hobnail features. Both paratesticular primaries showed sarcomatoid foci with tumor-associated neutrophilic infiltrates. The 3 RTCCCs presented in 54-, 57-, and 60-year-old men as testicular masses; they showed intrarete arborizing papillary growth with nonhyalinized fibrous cores and piled-up, solid foci, lacked hobnail cells, and expressed carbonic anhydrase IX (2/2) and CD10 (2/2) but not CA125, unlike the MTCCCs. On follow-up, 2 patients with MTCCC died of metastatic tumor (4 and 13.5 mo), a third developed ileal and retroperitoneal metastases at 13 months; and the fourth died at 13.5 months of unspecified cause. Follow-up of 2 patients with RTCCCs showed 1 disease free at 8 months and another alive with unknown disease status at 13 years. We conclude that CCCs involving the testis may either be of MT with often aggressive courses or show some features of renal tumors, with confinement to the rete testis and indolent behavior.
Importance of Lumbar Instability in the Study of Associations Between Muscle Morphology, Pain, and Disability in Chronic Low Back Pain
Authors: Seyedhoseinpoor Tahere , Dadgoo Mehdi , Taghipour Mohammad , Takamjani Ismail Ebrahimi , Sanjari Mohammad Ali , Kazemnejad Anoshirvan
Published: July 2024

Objective

The purpose of this study was to (1) evaluate the relationship between lumbar extensor muscle morphology, with pain and disability in patients with chronic low back pain and (2) compare these relationships in subgroup of chronic low back pain with and without lumbar structural segmental instability.

Design and Methods

This cross-sectional study included 183 patients with chronic low back pain. Standing lateral lumbar flexion/extension radiographs were used to assess lumbar structural segmental instability. Lumbar multifidus, erector spinae, and psoas major morphology were determined from axial magnetic resonance imaging. Associations between lumbar muscle morphologies and patient pain and disability were evaluated in two groups with and without lumbar instability.

Results

Patients’ disability was negatively associated with psoas major total cross-sectional area (beta = −22.82, 95% CI = −37.05 to −8.59) and functional cross-sectional area (beta = −23.45, 95% CI = −37.81 to −9.09). Multifidus morphology was negatively associated with disability in the lumbar instability group. Pain intensity was only associated to psoas major total cross-sectional area (beta = −3.33, 95% CI = −6.43 to −2.24) and functional cross-sectional area (beta = −3.22, 95% CI = −6.40 to −0.05) only in the lumbar instability group.

Conclusions

Psoas major atrophy was associated with greater disability and pain in chronic low back pain, but multifidus atrophy was associated with greater disability in chronic low back pain patients with lumbar structural segmental instability.
Recalcitrant Ulnar-Sided Hand Pain in a Collegiate Golfer
Authors: Cushman Daniel M. , Leach John , Foley Justin , Willick Stuart E.
Published: July 2024

This case report details a diagnosis of myositis ossificans in a collegiate golfer with right ulnar-sided hand pain after striking the ground on a swing. Despite conservative treatment and a thorough workup, the patient’s ulnar-sided hand pain did not improve. An ultrasound eventually revealed myositis ossificans within the abductor digiti minimi muscle. The patient received an ultrasound-guided fenestration and injection of lidocaine and dexamethasone into the affected muscle, leading to complete symptom resolution. Myositis ossificans is often secondary to trauma, causing bone formation in soft tissue, leading to pain, limited range of motion, and disability. This case highlights the importance of considering myositis ossificans in cases of persistent muscular pain and the diagnostic challenges related to ulnar-sided hand anatomy.
Pediatric Cranial Ultrasound Revisited
Authors: Richer Edward J. , Riedesel Erica L.
Published: July 2024

Cranial ultrasound (CUS) is an indispensable tool in the evaluation of intracranial pathology in premature and term neonates and older infants. Familiarity with standard cranial ultrasound techniques and parameters, normal anatomy, and commonly encountered abnormalities is crucial for providing appropriate care for these patients. This review provides a comprehensive overview of cranial ultrasound in clinical practice.
Risk Factor Targeted Perioperative Care Reduces Anastomotic Leakage after Colorectal Surgery
Authors: de Wit Anne , Bootsma Boukje T. , Huisman Daitlin E. , van Wely Bob , van Hoogstraten Julie , Sonneveld Dirk J.A. , Moes Daan , Wegdam Johannes A. , Feo Carlo V. , Verdaasdonk Emiel G.G. , Brokelman Walter J.A. , ten Cate David W.G. , Lubbers Tim , Lagae Emmanuel , Roks David J.G.H. , Kazemier Geert , Stens Jurre , Slooter Gerrit D. , Daams Freek ,   on behalf of the Taskforce Anastomotic Leakage
Published: July 2024

Objective:

The DoubleCheck study aimed to introduce pre- and perioperative interventions minimizing exposure to modifiable risk factors and determine its effect on CAL.

Summary Background Data:

Colorectal anastomotic leakage (CAL) is a severe complication. In order to predict and prevent its occurrence, the LekCheck study identified intraoperative modifiable risk factors for CAL: anemia, hyperglycemia, hypothermia, incorrect timing of antibiotic prophylaxis, administration of vasopressors and epidural analgesia.

Methods:

This international open-labelled interventional study was performed between September 2021 and December 2023. An enhanced care bundle consisting of anemia correction, glucose measurement, attaining normothermia, antibiotics administration within 60 to 15 minutes preoperatively, refraining from vasopressors and epidural analgesia was introduced. Primary outcome was the occurrence of intraoperative risk factors just prior to the anastomosis creation. Secondary outcomes were CAL and mortality. Univariate and multivariate regression analysis were performed to establish the relationship between the enhanced care bundle, exposure to the six factors and CAL.

Results:

The historical LekCheck group consisted of 1572 patients versus 902 in the DoubleCheck. The LekCheck group had a mean of 1.84 risk factors versus 1.63 in DoubleCheck (P<0.001). In the DoubleCheck significantly less patients had ≥3 risk factors (P<0.001). CAL was significantly lower in the DoubleCheck group (8.6% vs. 6.2%, P=0.039). The reduction of CAL was associated with the enhanced care bundle in multivariate regression analysis (OR 1.521, 95% CI 1.01-2.29, P=0.045). The mortality rate did not differ significantly (1.3%, vs. 0.8%, P=0.237).

Conclusions:

The DoubleCheck study showed that optimization of modifiable risk factors reduced CAL in colorectal surgery.
Superiority of Robotic Over Laparoscopic Spleen-Preserving Distal Pancreatectomy With Warshaw Procedure for Reducing the Incidence of Postoperative Splenic Infarction
Authors: Murata Yasuhiro , Noguchi Daisuke , Ito Takahiro , Hayasaki Aoi , Iizawa Yusuke , Fujii Takehiro , Tanemura Akihiro , Kuriyama Naohisa , Kishiwada Masashi , Mizuno Shugo
Published: July 2024

Background:

Minimally invasive spleen-preserving distal pancreatectomy with Warshaw procedure (MI-WP), has gained widespread recognition for the treatment of benign and low-grade malignant tumors of the pancreatic body and tail. However, the comparative advantages of the robotic Warshaw procedure (R-WP) over the laparoscopic Warshaw procedure (L-WP) remain uncertain. This study aimed to compare the surgical outcomes between R-WP and L-WP.

Materials and Methods:

Among the 146 cases of MI-DP conducted between October 2020 and December 2023 (L-DP:115, R-DP:31), 33 cases of MI-WP were subjected to analysis, comprising the R-WP group (n=10) and the L-WP group (n=23).

Results:

R-WP successfully completed all procedures under a purely laparoscopic approach, whereas L-WP necessitated conversion to open surgery in 2 cases (8.7%). Despite the significantly prolonged operative time in R-WP compared with L-WP (R-WP vs. L-WP: 421vs. 300 min), there was no significant difference in estimated blood loss between the 2 groups (R-WP vs. L-WP: 19 vs. 20 mL). Although the rate of major complications did not significantly differ between the 2 groups, 2 cases (8.7%) of L-WP required reoperation, including splenectomy in 1 instance. Furthermore, the incidence of postoperative splenic infarction was significantly higher in L-WP than in R-WP (R- vs. L-WP:0 vs. 43.5%, P=0.015). The length of hospital stay after surgery did not exhibit a significant difference between the 2 groups (R-WP vs. L-WP: 11 vs. 12 d).

Discussion:

R-WP demonstrated superiority to L-WP for reducing the incidence of postoperative splenic infarction, potentially contributing to enhancing the spleen preservation rate.
A Randomized Controlled Trial of Consent for Patients Undergoing Transobturator Slings
Authors: Demtchouk Veronica , Winkelman William D. , Cornely Ronald M. , Modest Anna , Hacker Michele R. , Elkadry Eman A.
Published: July 2024

Importance

Improving patients' recall and understanding of their planned surgery is essential for fully informed consent.

Objective

The objective of this study was to assess if the addition of an information handout to the standard preoperative consent process for the transobturator midurethral sling procedure improved patient understanding, recall, and satisfaction.

Study Design

This is a randomized controlled trial of adult women undergoing a transobturator midurethral sling procedure for the treatment of stress urinary incontinence. After standard counseling, participants were randomly assigned to either the control or the intervention group, with the latter receiving an extra informational handout detailing surgical information. Before surgery, all participants filled out a questionnaire assessing key points discussed during the surgical consent, which was used to calculate a knowledge score, the primary endpoint. Secondary outcomes included perception of the consent process and patient satisfaction.

Results

Of 98 randomized participants (50 control, 48 intervention), knowledge scores were 43% for controls and 57% for the intervention group (P = 0.015). Despite low scores, high self-rated understanding and satisfaction were noted across both groups (78% control, 71% intervention, P = 0.4). Notably, younger individuals, those with some college education, and patients undergoing additional prolapse surgery benefited most from the handout.

Conclusions

The informational handout improved knowledge scores, though overall knowledge scores were low in both groups. High satisfaction and perceived understanding of the planned procedure persisted, but the addition of a handout was not associated with a significant difference in knowledge scores.
Orchid mycorrhizal communities associated withOrchis italicaare shaped by ecological factors and geographical gradients
Authors: Balducci Marco G. , Calevo Jacopo , Duffy Karl J.
Published: July 2024

Aim

The influence of mutualists on plant distributions is only beginning to be understood. Orchids depend on orchid mycorrhizal (OrM) fungi to germinate, yet the distribution of OrM and how they vary according to both abiotic and biotic factors is unclear. We investigated the abundance and diversity of OrM communities associated with the Mediterranean orchidOrchis italicaand quantified how they vary according to both geographical and ecological factors.

Location

Mediterranean Basin.

Taxon

Orchis italicaPoir. (Orchidaceae)

Methods

We used metabarcoding of the ITS2 region to identify OrM fungi associated with adult individuals in 23 populations ofO. italicaacross latitudinal and longitudinal gradients in the Mediterranean region. We used both multivariate analyses and Joint Species Distribution Models (JSDMs) based on geographical, climate, and soil variables to test how both common OrM fungi and their communities vary according to geographical and ecological factors.

Results

Eighty OrM OTUs were found associating withO. italica. However, five Tulasnellaceae OTUs and one Ceratobasidiaceae OTU were found in every population. Abundance of these taxa, as measured by number of reads, increased from west to east and decreased from south to north, indicating OrM abundance may be determined by geographical gradients. OrM community composition varied according to precipitation, annual mean temperature, and soil phosphorous content. JSDMs revealed there were both positive and negative co-occurrences among these ubiquitous OrM.

Main Conclusions

Despite associating with many OrM across its range, only six OrM were widespread, indicating thatO. italicamay be an apparent generalist in its association with OrM. Abundance of these OrM is determined by geographical gradients and ecological factors. This highlights the importance of quantifying the distribution of belowground mutualists in understanding the limits to plant distributions.
Global-scale quantification of responses to anthropogenic stressors in six riverine organism groups
Authors: Kaijser Willem , Schürings Christian , Schneider Andrea , Prati Sebastian , Musiol Michelle , Wenskus Franziska , Brauer Verena S. , Feldhaus Lena , Wagner Cornelia S. , Bayer Rike , Madge Pimentel Iris , Birk Sebastian , Mario Brauns , Dunne Louisa , Enss Julian , Farias Luan , Feld Christian K. , Gillmann Svenja M. , Hupalo Kamil , Osakpolor Stephen E. , Olberg Sarah , Schlautmann Christian , Schwelm Jessica , Wells Nicole E. , Sures Bernd , Schäfer Ralf B. , Hering Daniel
Published: July 2024

Rivers globally are impacted by numerous anthropogenic stressors, including water pollution, habitat degradation, and climate change, which collectively stress biodiversity and ecosystem functioning. This study systematically reviews and analyses published and unpublished data to understand how five aquatic organism groups (bacteria, algae, macrophytes, invertebrates, fish) respond to seven common stressors (salinization, oxygen depletion, fine sediment enrichment, temperature increase, flow modifications and nitrogen or phosphorus enrichment). Using an analytical framework that includes Generalized Linear Models (GLMs) and Robust Bayesian Meta Analysis (RoBMA), we extracted data from 143 relevant datasets out of 29,749 screened articles. Our results reveal a negative relationship between invertebrates and salinity, fine sediment enrichment, and temperature increase, while fish respond positively to increased oxygen levels and temperature. Bacteria and algae show variable responses, with algae positively associated with nitrogen. The findings highlight strong variability in stressor-response relations across organism groups and stressor types, and emphasize the need for more targeted studies on underrepresented groups like macrophytes and microorganisms. This analysis enhances the predictive understanding of stressor impacts on riverine biodiversity, informing future river ecosystem management and restoration efforts.
Nasal tissue-resident memory CD4+T cells persist after influenza A virus infection and provide heterosubtypic protection
Authors: Mathew Nimitha R. , Gailleton Romain , Scharf Lydia , Schön Karin , Strömberg Anneli , Lycke Nils , Bemark Mats , Tang Ka-Wei , Angeletti Davide
Published: July 2024

CD4 tissue-resident memory T (CD4 TRM) cells are crucial adaptive immune components involved in preventing influenza A virus (IAV) infection. Despite their importance, their physiological role in the upper respiratory tract, the first site of contact with IAV, remains unclear. Here, we find that, after IAV infection, antigen-specific CD4 TRM persist in the nasal tissue (NT) compartment and play a prime role in local viral clearance. Single cell RNA sequencing analysis reveals that NT CD4 TRM are heterogeneous and transcriptionally distinct as compared to their lung counterparts. Mechanistically, we demonstrate that the CXCR6- CXCL16 axis is involved in CD4 TRM residency in the NT. Furthermore, we show that the NT of mice and humans contains a high frequency of IL-17-producing CD4 TRM that aid in local viral clearance and in reducing tissue damage. Collectively, our results support a robust physiological role for nasal tissue CD4 TRM in preventing IAV infection.
Basement membrane patterning by spatial deployment of a secretion-regulating protease
Authors: Ku Hui-Yu , Bilder David
Published: July 2024

While paradigms for patterning of cell fates in development are well-established, paradigms for patterning morphogenesis, particularly when organ shape is influenced by the extracellular matrix (ECM), are less so. Morphogenesis of the Drosophila egg chamber (follicle) depends on anterior-posterior distribution of basement membrane (BM) components such as Collagen IV (Col4), whose symmetric gradient creates tissue mechanical properties that specify the degree of elongation. Here we show that the gradient is not regulated by Col4 transcription but instead relies on post-transcriptional mechanisms. The metalloprotease ADAMTS-A, expressed in a gradient inverse to that of Col4, limits Col4 deposition in the follicle center and manipulation of its levels can cause either organ hyper- or hypo-elongation. We present evidence that ADAMTS-A acts within the secretory pathway, rather than extracellularly, to limit Col4 incorporation into the BM. High levels of ADAMTS-A in follicle termini are normally dispensable but suppress Col4 incorporation when transcription is elevated. Our data show how an organ can employ patterned expression of ECM proteases with intracellular as well as extracellular activity to specify BM properties that control shape.
Integrated functional genomic analysis identifies the regulatory variants underlying a major QTL for disease resistance in European sea bass
Authors: Mukiibi Robert , Ferraresso Serena , Franch Rafaella , Peruzza Luca , Rovere Giulia Dalla , Babbucci Massimiliano , Bertotto Daniela , Toffan Anna , Pascoli Francesco , Faggion Sara , Peñaloza Carolina , Tsigenopoulos Costas S. , Houston Ross D. , Bargelloni Luca , Robledo Diego
Published: July 2024

Background

Viral nervous necrosis (VNN) is a viral disease threatening the sustainability of global aquaculture, and affecting over 50 of farmed and ecologically important species. A major QTL for resistance to VNN has been previously described in European sea bass, but the underlying causal gene(s) and mutation(s) are unknown. To identify the mechanisms and genetic factors underpinning resistance to VNN, we integrated farmed and wild genetic data with multiple functional genomics assays in a farmed European sea bass population.

Results

A high heritability (h2 ∼ 0.40) was estimated for VNN resistance. A major QTL for this trait was confirmed on chromosome 3, and whole-genome resequencing narrowed its location to a small region containing 4 copies of interferon alpha inducible protein 27-like 2A (IFI27L2A) genes, and one copy of the interferon alpha inducible protein 27-like 2 (IFI27L2) gene. RNA sequencing revealed a clear association between the QTL genotype and the expression of two of theIFI27L2Agenes, and theIFI27L2gene. Integration with chromatin accessibility and histone modification data pinpointed two SNPs in active regulatory regions of two of these genes (IFI27L2AandIFI27L2), and transcription factor binding site gains for the resistant alleles were predicted. These alleles, particularly the SNP variant CHR3:10077301, exhibited higher frequency in Eastern Mediterranean sea bass populations, which show considerably higher levels of resistance to VNN.

Conclusions

The SNP variant CHR3:10077301, through modulation ofIFI27L2andIFI27L2Agenes, is likely the causative mutation underlying resistance to VNN in European sea bass. This is one of the first causative mutations discovered for disease resistance traits, and paves the way for marker-assisted selection as well as biotechnological approaches to enhance resistance to VNN in European sea bass and other susceptible species.
Mouse parasubthalamicCrhneurons drive alcohol drinking escalation and behavioral disinhibition
Authors: Kreifeldt Max , Okhuarobo Agbonlahor , Dunning Jeffery L , Lopez Catherine , Macedo Giovana , Sidhu Harpreet , Contet Candice
Published: July 2024

Corticotropin-releasing factor (CRF, encoded byCrh) signaling is thought to play a critical role in the development of excessive alcohol drinking and the emotional and physical pain associated with alcohol withdrawal. Here, we investigated the parasubthalamic nucleus (PSTN) as a potential source of CRF relevant to the control of alcohol consumption, affect, and nociception in mice. We identified PSTNCrhneurons as a neuronal subpopulation that exerts a potent and unique influence on behavior by promoting not only alcohol but also saccharin drinking, while PSTN neurons are otherwise known to suppress consummatory behaviors. Furthermore, PSTNCrhneurons are causally implicated in the escalation of alcohol and saccharin intake produced by chronic intermittent ethanol (CIE) vapor inhalation, a mouse model of alcohol use disorder. In contrast to our predictions, the ability of PSTNCrhneurons to increase alcohol drinking is not mediated by CRF1signaling. Moreover, the pattern of behavioral disinhibition and reduced nociception driven by their activation does not support a role of negative reinforcement as a motivational basis for the concomitant increase in alcohol drinking. Finally, silencingCrhexpression in the PSTN slowed down the escalation of alcohol intake in mice exposed to CIE and accelerated their recovery from withdrawal-induced mechanical hyperalgesia. Altogether, our results suggest that PSTNCrhneurons may represent an important node in the brain circuitry linking alcohol use disorder with sweet liking and novelty seeking.
Genome assembly of a diversity panel ofChenopodium quinoa
Authors: Rey Elodie , Abrouk Michael , Dufau Isabelle , Rodde Nathalie , Saber Noha , Cizkova Jana , Fiene Gabriele , Stanschewski Clara , Jarvis David E , Jellen Eric N , Maughan Peter J , von Baer Ingrid , Troukhan Maxim , Kravchuk Maksym , Hribova Eva , Cauet Stephane , Krattinger Simon G. , Tester Mark
Published: July 2024

Quinoa (Chenopodium quinoa) is an important crop for the future challenges of food and nutrient security. Deep characterization of quinoa diversity is needed to support the agronomic improvement and adaptation of quinoa as its worldwide cultivation expands. In this study, we report the construction of chromosome-scale genome assemblies of eight quinoa accessions covering the range of phenotypic and genetic diversity of both lowland and highland quinoas. The assemblies were produced from a combination of PacBio HiFi reads and Bionano Saphyr optical maps, with total assembly sizes averaging 1.28 Gb with a mean N50 of 71.1 Mb. Between 43,733 and 48,564 gene models were predicted for the eight new quinoa genomes, and on average, 66% of each quinoa genome was classified as repetitive sequences. Alignment between the eight genome assemblies allowed the identification of structural rearrangements including inversions, translocations, and duplications. These eight novel quinoa genome assemblies provide a resource for association genetics, comparative genomics, and pan-genome analyses for the discovery of genetic components and variations underlying agriculturally important traits.
Extracellular vesicle-derived miRNA-mediated cell-cell communication inference for single-cell transcriptomic data with miRTalk
Authors: Shao Xin , Li Chengyu , Qian Jingyang , Yang Haihong , Yang Xinyu , Liao Jie , Xu Xiao , Fan Xiaohui
Published: July 2024

MicroRNAs are released from cells in extracellular vesicles (EVs), representing an essential mode of cell-cell communication (CCC) via an inhibitory effect on gene expression. The advent of single-cell RNA-sequencing (scRNA-seq) technologies has ushered in an era of elucidating EV-derived miRNA-mediated CCC. However, the lack of computational methods to infer such CCC poses an outstanding challenge. Herein, we present miRTalk (https://github.com/multitalk/miRTalk), a pioneering framework for inferring EV-derived miRNA-mediated CCC with a probabilistic model and a curated database, miRTalkDB, which includes EV-derived miRNA-target associations. The benchmarking against simulated and real-world datasets demonstrated the remarkable accuracy and robustness of miRTalk. Subsequently, we employed miRTalk to uncover the in-depth CCC mechanisms underlying three disease scenarios. In summary, miRTalk represents the first approach for inferring EV-derived miRNA-mediated CCC with scRNA-seq data, providing invaluable insights into the CCC dynamics underpinning biological processes.
Single-Platelet Mapping of Jugular, Puncture-Wound Thrombi Reveals the Spatial Evolution of Platelet Activation
Authors: Rhee Sung , Pokrovskaya Irina D. , Ball Kelly , Webb Michael W. , Kamykowski Jeffrey A. , Zhao Oliver , Driehaus Elizabeth R. , Aronova Maria A. , Whiteheart Sidney W. , Leapman Richard D. , Storrie Brian
Published: July 2024

Background

The contributions of platelet activation to thrombus formation during hemostatic bleeding cessation likely involve multiple activation states. However, the spatial and temporal distribution of platelets in these states has not been defined in a clot.

Objectives

To use single-platelet mapping of activation states within jugular vein puncture thrombi to determine how the spatial distribution of platelet state evolves during hemostasis.

Methods

Montaged, wide-area electron micrographs (EM) were taken at various time points, post-puncture, and annotated for platelet activation state. These classifications were mapped onto the images to identify regions of platelet activation and calculate neighbor associations. The importance of α-granule secretion was tested using VAMP8-/-mice.

Results

mapping of platelet activation states at 1 min post-puncture showed extensive spatial intermixing of most platelet activation classes. No high-activation-state, platelet-rich core was observed in 5-min post-puncture thrombi, rather such platelets tended to be localized on the interior surfaces of thrombus vaults open to the circulation. Only at a later stage, 20 min post-puncture, was distinct clustering of high activation, degranulated, cytosol-rich platelets observed. These clusters localized to the central portion of the intravascular platelet-rich crown, and they were now inaccessible to the circulation. Counterintuitively, deletion of the primary platelet v-SNARE, VAMP8, increased the frequency and spatial clustering of highly activated, degranulated platelets in association with intra-thrombus vault surfaces at 5 min post puncture.

Conclusions

We conclude recent multi-activation state models can provide a realistic thrombus formation framework if linked together to encompass the dynamics of puncture wound formation.
SMCHD1 maintains heterochromatin and genome compartments in human myoblasts
Authors: Huang Zhijun , Cui Wei , Ratnayake Ishara , Tawil Rabi , Pfeifer Gerd P.
Published: July 2024

Mammalian genomes are subdivided into euchromatic A compartments that contain mostly active chromatin, and inactive, heterochromatic B compartments. However, it is unknown how A and B genome compartments are established and maintained. Here we studied SMCHD1, an SMC-like protein in human male myoblasts. SMCHD1 colocalizes with Lamin B1 and the heterochromatin mark H3K9me3. Loss of SMCHD1 leads to extensive heterochromatin depletion at the nuclear lamina and acquisition of active chromatin states along all chromosomes. In absence of SMCHD1, long range intra-chromosomal and inter-chromosomal contacts between B compartments are lost while many new TADs and loops are formed. Inactivation of SMCHD1 promotes numerous B to A compartment transitions accompanied by activation of silenced genes. SMCHD1 functions as an anchor for heterochromatin domains ensuring that these domains are inaccessible to epigenome modification enzymes that typically operate in active chromatin. Therefore, A compartments are formed by default when not prevented by SMCHD1.
A differentiable Gillespie algorithm for simulating chemical kinetics, parameter estimation, and designing synthetic biological circuits
Authors: Rijal Krishna , Mehta Pankaj
Published: July 2024

The Gillespie algorithm is commonly used to simulate and analyze complex chemical reaction networks. Here, we leverage recent breakthroughs in deep learning to develop a fully differentiable variant of the Gillespie algorithm. The differentiable Gillespie algorithm (DGA) approximates discontinuous operations in the exact Gillespie algorithm using smooth functions, allowing for the calculation of gradients using backpropagation. The DGA can be used to quickly and accurately learn kinetic parameters using gradient descent and design biochemical networks with desired properties. As an illustration, we apply the DGA to study stochastic models of gene promoters. We show that the DGA can be used to: (i) successfully learn kinetic parameters from experimental measurements of mRNA expression levels from two distinctE. colipromoters and (ii) design nonequilibrium promoter architectures with desired input-output relationships. These examples illustrate the utility of the DGA for analyzing stochastic chemical kinetics, including a wide variety of problems of interest to synthetic and systems biology.
Molecular dynamics investigation of the influenza hemagglutinin conformational changes in acidic pH
Authors: Badiee Shadi A , Kumar Vivek Govind , Moradi Mahmoud
Published: July 2024

The surface protein hemagglutinin (HA) of the influenza virus plays a pivotal role in facilitating viral infection by binding to sialic acid receptors on host cells. Its conformational state is pH-sensitive, impacting its receptor-binding ability and evasion of the host immune response. In this study, we conducted extensive equilibrium microsecond-level all-atom molecular dynamics (MD) simulations of the HA protein to explore the influence of low pH on its conformational dynamics. Specifically, we investigated the impact of protonation on conserved histidine residues (His1062) located in the hinge region of HA2. Our analysis encompassed comparisons between non-protonated (NP), partially protonated (1P, 2P), and fully-protonated (3P) conditions. Our findings reveal substantial pH-dependent conformational alterations in the HA protein, affecting its receptor-binding capability and immune evasion potential. Notably, the non-protonated form exhibits greater stability compared to protonated states. Conformational shifts in the central helices of HA2 involve outward movement, counterclockwise rotation of protonated helices, and fusion peptide release in protonated systems. Disruption of hydrogen bonds between the fusion peptide and central helices of HA2 drives this release. Moreover, HA1 separation is more likely in the fully-protonated system (3P) compared to non-protonated systems (NP), underscoring the influence of protonation. These insights shed light on influenza virus infection mechanisms and may inform the development of novel antiviral drugs targeting HA protein and pH-responsive drug delivery systems for influenza.
Predicting Enzyme Functions Using Contrastive Learning with Hierarchical Enzyme Structure Information
Authors: Duan Hongyu , Li Ziyan , Wu Yixuan , Chen Wen , Xia Li C
Published: July 2024

Enzyme functional annotation is a fundamental challenge in biology, and many computational tools have been developed. Accurate function prediction of enzymes relies heavily on sequence and structural information, providing critical insights into enzyme activity and specificity. However, for less studied proteins or proteins with previously uncharacterized functions or multiple activities, most of these tools cannot accurately predict functional annotations, such as enzyme commission (EC) numbers. At the same time, functional hierarchical information between enzyme species categorized based on EC numbers has not been sufficiently investigated. To address these challenges, we propose a machine learning algorithm named EnzHier, which assigns EC numbers to enzymes with better accuracy and reliability compared to state-of-the-art tools. EnzHier cleverly learns the functional hierarchy of enzymes by optimizing triplet loss, enabling it to annotate understudied enzymes confidently and identify confounding enzymes with two or more EC numbers. By incorporating both sequence and structural information, EnzHier enhances its predictive capabilities. We experimentally demonstrate its excellent performance. We anticipate that this tool will be widely used to predict the function of uncharacterized enzymes, thereby advancing many fields such as drug design and discovery and medical diagnostics.
A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing
Authors: Hwang Joyce K. , Marston Daniel J. , Wrapp Daniel , Li Dapeng , Tuyishime Marina , Brackenridge Simon , Rhodes Brianna , Quastel Max , Kapingidza A. Brenda , Gater Jacob , Harner Austin , Wang Yunfei , Rountree Wes , Ferrari Guido , Borrow Persephone , McMichael Andrew J. , Gillespie Geraldine M. , Haynes Barton F. , Azoitei Mihai L.
Published: July 2024

Natural killer (NK) cells kill target cells following triggering via germline-encoded receptors interacting with target cell-expressed ligands (direct killing), or via antibody-dependent cellular cytotoxicity (ADCC) mediated by FcγRIIIa. NK cytotoxicity is modulated by signaling through activating or inhibitory receptors. A major checkpoint is mediated by the NK inhibitory receptor NKG2A/CD94 and its target cell ligand, HLA-E, which is complexed with HLA signal sequence-derived peptides termed VL9 (HLA-E-VL9). We have previously reported the isolation of a murine HLA-E-VL9-specific IgM antibody 3H4 and the generation of a higher affinity IgG version (3H4v3). Here we have used phage display library selection to generate a high affinity version of 3H4v3, called 3H4v31, with an ∼700 fold increase in binding affinity. We show using an HLA-E-VL9+ K562 tumor model that, in vitro, the addition of 3H4v31 to target cells increased direct killing of targets by CD16-negative NK cell line NK-92 and also mediated ADCC by NK-92 cells transfected with CD16. Moreover, ADCC by primary NK cells was also enhanced in vitro by 3H4v31. 3H4v31 was also able to bind and enhance target cell lysis of endogenously expressed HLA-E-VL9 on human cervical cancer and human pancreatic cancer cell lines. In vivo, 3H4v31 slowed the growth rate of HLA-E-VL9+ K562 tumors implanted into NOD/SCID/IL2rγnullmice compared to isotype control when injected with NK-92 cells intratumorally. Together, these data demonstrate that mAb 3H4v31 can enhance NK cell killing of HLA-E-VL9-expressing tumor cells in vitro by both direct killing activity and by ADCC. Moreover, mAb 3H4v31 can enhance NK cell control of tumor growth in vivo. We thus identify HLA-E-VL9 monoclonal antibodies as a promising novel anti-tumor immunotherapy.

One Sentence Summary

A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing by checkpoint inhibition and antibody dependent cellular cytotoxicity.
Elucidating the Type 2 Diabetes Regulatory Network: Identification of EGFR as a Key Hub and Novel Drug Candidates
Authors: Ochoa Ricardo Romero , Rojas Celic Abigail Cohen
Published: July 2024

Introduction

Type 2 diabetes (T2D) is a complex metabolic disorder with incompletely understood molecular mechanisms. This study aimed to elucidate the T2D regulatory network and identify potential drug targets and candidates.

Methods

We performed differential gene expression analysis on multiple T2D datasets, constructed protein-protein interaction networks, and conducted a meta-analysis to identify key hub genes. Functional enrichment analysis was performed on the resulting network. Structure-based virtual screening targeting EGFR, followed by molecular dynamics simulations, was used to identify potential drug candidates.

Results

EGFR emerged as a consistently top-ranked hub gene across studies. The regulatory network comprised hub genes, transcription factors, and miRNAs involved in processes such as apoptosis regulation, cellular response to organic substances, and reactive oxygen species metabolism. Virtual screening identified three compounds with favorable ADMET properties and strong binding affinities to EGFR, outperforming control drugs. These compounds demonstrated stable interactions in molecular dynamics simulations.

Conclusions

Our integrative analysis provides new insights into the T2D regulatory network, highlighting EGFR as a potential therapeutic target. The identified drug candidates offer promising avenues for T2D treatment and related disorders involving EGFR signaling, bridging systems biology and drug discovery approaches in metabolic disease research.
Molecular bases and specificity behind the activation of the immune system OAS/RNAse L pathway by viral RNA
Authors: Jung-Rodriguez Emma , Barbault Florent , Bignon Emmanuelle , Monari Antonio
Published: July 2024

The first line of defense against invading pathogens usually relies on the innate immune systems. In this context the recognition of exogenous RNA structure is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turns triggers the activity of RNase L and, thus, cleaving cellular and viral RNA. In this contribution by using long range molecular dynamics simulation, complemented with enhanced sampling techniques, we elu-cidate the structural features leading to the activation of OAS by interaction with a model double strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to down-regulate OAS activation, in shaping the protein/nucleic acid interface and the conformational land-scape of OAS are also analyzed.