bluuebunny/crossref_metadata_2025 huggingface dataset:
Uterine Smooth Muscle Tumors: An Overview
Authors: Pinto Andre
Published: April 2024

Uterine smooth muscle tumors are a heterogeneous group of mesenchymal neoplasms with multiple histologic variants and distinct biological behaviors. Pathologic classification (benign, uncertain malignant potential, malignant) relies on the evaluation of mitotic index, necrosis, and degree of cytologic atypia, with different thresholds based on each subtype. Immunohistochemistry and other ancillary studies may be necessary to establish the diagnosis in a subset of cases, given the morphologic overlap with other mesenchymal neoplasms, including low-grade and high-grade endometrial stromal tumors, inflammatory myofibroblastic tumors, and PEComa. Recent advances in molecular diagnostics have refined the classification of smooth muscle tumors, but most cases are diagnosed purely on histologic grounds.
Hemodynamic Reactivity to Mental Stress and Cognitive Function in Coronary Artery Disease
Authors: Moazzami Kasra , Kulshreshtha Ambar , Gold Matthew , Rahbar Alireza , Goldstein Felicia , Shah Amit J. , Bremner J. Douglas , Vaccarino Viola , Quyyumi Arshed A.
Published: April 2024

Objective

People with coronary artery disease (CAD) are at higher risk of cognitive impairment than those without CAD. Psychological stress is a risk factor for both conditions, and assessing the hemodynamic reactivity to mental stress could explain the link between stress and cognitive function.

Methods

A total of 779 individuals with stable CAD from two prospective cohort studies were included. All individuals underwent acute mental stress testing, as well as conventional stress testing. Cognitive function was assessed both at baseline and at a 2-year follow-up. The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. RPP reactivity was defined as the maximum RPP during standardized mental stress test minus the RPP at rest.

Results

After multivariable adjustment, every standard deviation decrease in RPP reactivity with mental stress was associated with slower completion of Trail-A and Trail-B in both cohorts (13% and 11% in cohort 1, and 15% and 16% in cohort 2, respectively; p for all <.01). After a 2-year follow-up period, every standard deviation decrease in RPP reactivity with mental stress was associated with a 8% and 9% slower completion of Trail-A and Trail-B, respectively (p for all <.01). There was no significant association between RPP reactivity with conventional stress testing and any of the cognitive tests.

Conclusion

In the CAD population, a blunted hemodynamic response to mental stress is associated with slower visuomotor processing and worse executive function at baseline and with greater decline in these abilities over time.
Social Engagement in HIV Cure (Research) in the Netherlands: Understanding the Perceived Necessity and Concerns of People With HIV
Authors: Noorman Maaike A. J. , de Wit John B.F. , Marcos Tamika A. , Stutterheim Sarah E. , Jonas Kai J. , Den Daas Chantal
Published: April 2024

Objective:

As the developments toward HIV cure are gaining prominence, engagement of people with HIV (PWH) becomes crucial. The aim of this study was to gain deeper insight into how PWH engage with HIV cure (research) by exploring their perspectives regarding awareness, importance, and meaning of HIV cure (research).

Methods:

Semistructured interviews were conducted with 30 purposively sampled PWH in the Netherlands. Interviews were transcribed verbatim, and thematic data analysis was undertaken.

Results:

The overall necessity for an HIV cure was high, but personal perceived necessity varied based on participants' lived experiences with HIV. Most participants saw less personal necessity due to their high quality of life, while those more affected by their HIV status expressed a stronger need for a cure. Participants held high expectations for an HIV cure, considering viral eradication as the only cure. Lack of awareness of potential HIV cure strategies and techniques shaped concerns. Antiretroviral treatment-free viral suppression was met with concerns and not considered a cure, but rather an improved form of treatment. Engagement with HIV cure manifested in various forms and levels, with only a few participants actively engaged or willing to participate in HIV cure clinical research. Most participants were interested but inactive and unsure about participating in HIV cure clinical research.

Conclusions:

PWH's social engagement in HIV cure (research) is shaped by their perceived necessity and concerns. Understanding these perceptions can increase social engagement.
HIV Pre-exposure Prophylaxis Use Among Men Experiencing Incarceration in the United States: A Prospective Cohort Study
Authors: Murphy Matthew , Rogers Brooke , Galipeau Drew , Toma Emily , Almonte Alexi , Napoleon Siena , Schmid Christopher H. , Ahluwalia Jasjit S. , Chan Philip
Published: April 2024

Background:

Pre-exposure prophylaxis (PrEP) is an effective approach to preventing HIV acquisition and recommended for populations over-represented in carceral systems, given the overlap with populations disproportionately impacted by HIV. However, few studies have focused on PrEP initiation outcomes in a carceral setting to maximize public health impact.

Setting:

This study was conducted in a unified jail/prison system within the state of Rhode Island located in the United States.

Methods:

A prospective observational cohort of men initiating PrEP within a jail setting was enrolled in this trial. Men were referred by providers, staff, or after self-presenting for HIV preventive care, these individuals were offered enrollment in the study that involved evaluation for clinical PrEP eligibility, PrEP initiation while incarcerated, continuation upon community re-entry, and linkage to a community PrEP provider after release.

Results:

A total of 100 men in the jail facility (eg, “intake”) were enrolled in the cohort. Of the 100 men enrolled, 83% were determined to be PrEP eligible through standard clinical evaluation, 37% were prescribed PrEP, and 26% initiated PrEP while incarcerated. In total, 5% of enrolled individuals were linked successfully to PrEP care in the community.

Conclusion:

Our findings suggest preliminary feasibility and acceptability of initiating PrEP within a jail setting. There were significant challenges across the PrEP care continuum that can be used to inform future studies and practice.
International Collaborative Study Comparing Outcomes of Fenestrated Endovascular Aortic Repair in OCtogenarian vs Non-Octogenarian Patients
Authors: Prendes Carlota F. , Spath Paolo , Khashram Manar , Dias Nuno , Furlan Federico , Gouveia e Melo Ryan , Gallitto Enrico , Sonesson Björn , Mendes Pedro Luis , Gormley Sinead , Gargiulo Mauro , Wanhainen Anders , Tsilimparis Nikolaos , Mani Kevin
Published: April 2024

Objective:

With an increasing life expectancy, more octogenarian patients are referred with complex aortic aneurysms (cAAA). The aim of this study was to evaluate short and mid-term outcomes following fenestrated aortic repair (FEVAR) in octogenarians.

Summary Background Data:

Few studies looking at octogenarian-specific outcomes with diverging results.

Methods:

Retrospective, multicentre cohort study including consecutive patients undergoing elective FEVAR for cAAAs or type IV thoracoabdominal aortic aneurysms between 2007-2022 in eight high-volume centres. Octogenarians vs. non-octogenarians were compared. The primary outcome was 30-day mortality. Secondary outcomes included 1, 2 and 5-year survival and reintervention rates.

Results:

A total of 729 patients (median age of 74.8 years [IQR 69.2 - 79.14]) were included, 169 (23%) of which were octogenarians, with 316 (43.3%) patients undergoing juxta/pararenal aneurysm repair. Although octogenarians presented less complex but larger (61 mm vs. 58 mm) aneurysms, the number of fenestrations was similar across groups. No differences in in-hospital mortality (4.1 vs. 3.0%), MAE (16.6% vs 12.2%) or reintervention rates (11.2 vs. 10%) were found. Multivariable logistic regression of in-hospital mortality identified BMI (OR 0.66, 95% CI 0.51-0.95, P=0.003), chronic heart failure (OR 7.70, 95% CI 1.36–36.15, P=0.003) and GFR<45 ml/min/1.73 m2 (OR 5.25, 95% CI 1.20–22.86, P=0.027) as independent predictors. Median follow-up was 41 months. The 1, 2 and 5-year survival rates were 91.3%, 81.8% and 49.5% in octogenarians vs 90.6%, 86.5% and 68.8% in non-octogenarian patients (Log-rank: =0.001). Freedom from aortic-related death and freedom from reintervention at five-years were similar across groups (log-rank=0.94 and .76, respectively). Age>80 was not an independent predictor of 30-day or long-term mortality on multivariable and Cox regression analysis.

Conclusions:

Elective FEVAR in octogenarians appears to be safe, with similar outcomes as in younger patients. Future studies looking at improved patient selection methods to ensure long-term survival benefits in both octogenarians and younger patients are warranted.
Factors That Influence the Pain Response of Patients Admitted to an Emergency Department for Acute Musculoskeletal Trauma
Authors: Leigheb Massimiliano , Montaño-Ocaña Juan , Sabbatini Maurizio
Published: April 2024

Objective:

To monitor factors influencing pain intensity variations in patients admitted to an emergency department (ED).

Method:

A prospective observational study included 904 patients. Pain intensity was assessed at ED admission and discharge using a novel Visual Analog Scale interpretation. Patient data included trauma type, pain location, the injury environment, age, race, and the time elapse between assessments.

Results:

Distinct personal, temporal and contextual factors revealed characteristic pain improvement, and worsening patterns post-ED management.

Conclusions:

The ED's pivotal role in pain relief, influenced by various factors, underscores the importance of optimizing patient care.
Analysis of Motor Learning Principles Applied in Tasks or Motor Skills Trained by Stroke Patients
Authors: Sánchez-Silverio Víctor , Abuín-Porras Vanesa , Pedersini Paolo , Villafañe Jorge Hugo , Leigheb Massimiliano , Rodríguez-Costa Isabel
Published: April 2024

Objective:

To analyze the principles applied to promote and evaluate motor learning in tasks or motor skills trained by stroke patients.

Methods:

Articles were included if they used motor learning principles in tasks or motor skills trained by stroke patients.

Results:

Twelve studies were included in this review. Quality was good for the included studies. Articles used motor learning principle based on practice (N = 12), repetitive training (N = 9), and feedback (N = 5).

Conclusions:

There are different motor learning principles to promote and evaluate motor learning in stroke patients. These findings could guide clinicians during training of tasks or motor skills.
Optimizing Telehealth Strategies for Rehabilitation
Authors: Bustamante-Vázquez Jorge Luis , Rodrigo-Morales Gaudencio Jonathan , De-Dios-Pérez Jhonatan Iván , Artiles-Sánchez Justo , Barragán-Caraballar Carlos , Alonso-Perez José Luís , Villafañe Jorge Hugo
Published: April 2024

Background:

To investigate the experiences and perspectives of rural physical therapists in relation to various telehealth strategies in physical therapy.

Methods:

A qualitative field study was conducted in (n = 4344) remote regions of (n = 6) Mexico. Using telehealth technology, 16 physical therapists from 6 clinics expanded their reach and provided physical therapy care to patients located in nonmetropolitan sites. The outcomes measured were the sociodemographic characteristics, telemedicine modalities employed, and the types of treatments administered. These assessments were conducted pre-, post-intervention, and during the follow-up period.

Results:

This study included 4344 participants, averaging 44.5 ± 20.7 years old. Most visits (80.1%) were initial, while 19.9% were follow-ups, with an average of 12.4 ± 4.7 sessions. “Puebla sur” had the highest case frequency (29.3%), followed by “Tlalnepantla” (27.5%), “CAPU” (17.4%), “Tlalpan” (15.5%), and “Guadalajara” and “Guatemala” clinics with lower frequencies (8.8% and 1.5%, respectively).

Conclusions:

This study highlights the potential of telemedicine to surmount barriers such as limited access to health care facilities, physical impediments faced by patients in rural areas, and financial burdens on families. The findings contribute to the optimization of telehealth strategies, specifically tailored to the unique challenges of rehabilitation care in underserved rural communities.
Annular Ligament Instability
Authors: Abellán-Miralles César , Berlanga-de-Mingo Daniel , Samaniego-Alonso Raquel , Villafañe Jorge Hugo , Bascones-Rodríguez Karla
Published: April 2024

Purpose:

Lateral elbow pain is frequently attributed to epicondylalgia; yet, less common pathologies with limited literature representation exist. This study aims to delineate the diagnostic significance of alterations in the biomechanics and morphology of the annular ligament as a distinctive factor in lateral elbow pain.

Methods:

A retrospective observational analysis was conducted on patients surgically treated for lateral elbow pain with arthroscopic assistance from January 2015 to December 2018. Initial preoperative diagnoses primarily indicated epicondylalgia.

Results:

The study encompassed 82 patients (48 men, 34 women; mean age: 44.6 ± 5.3 years), with 91.46% involved in demanding manual work. Notably, 17 patients underwent surgery due to recurrent symptoms. Arthroscopic assessments revealed diverse morphological and biomechanical variations in annular ligaments, designating 36 patients with an identified incompetent annular ligament.

Conclusions:

Our arthroscopic study on lateral epicondylalgia cases involved a comprehensive analysis of annular ligament anatomy and radiocapitellar joint biomechanics. The formulated anatomic classification, incorporating crucial variables such as radial head coverage and ligament tension, unveiled implications for joint instability. Recognition of simultaneous pathologies, notably annular ligament lesions, signifies a potential, yet unexplored, avenue for differential diagnosis in cases of lateral elbow pain.
Transposable elements in a cold-tolerant fly species,Drosophila montana: a link to adaptation to the harsh cold environments
Authors: Tahami Mohadeseh S. , Vargas-Chavez Carlos , Poikela Noora , Coronado-Zamora Marta , González Josefa , Kankare Maaria
Published: April 2024

Background

Substantial discoveries during the past century have revealed that transposable elements (TEs) can play a crucial role in genome evolution by affecting gene expression and inducing genetic rearrangements, among other molecular and structural effects. Yet, our knowledge on the role of TEs in adaptation to extreme climates is still at its infancy. The availability of long-read sequencing has opened up the possibility to identify and study potential functional effects of TEs with higher precision. In this work, we usedDrosophila montanaas a model for cold-adapted organisms to study the association between TEs and adaptation to harsh climates.

Results

Using the PacBio long-read sequencing technique, wede novoidentified and manually curated TE sequences in fiveDrosophila montanagenomes from eco-geographical distinct populations. We identified 489 new TE consensus sequences which represented 92% of the total TE consensus inD. montana. Overall, 11-13% of theD. montanagenome is occupied by TEs, which as expected are non-randomly distributed across the genome. We identified five potentially active TE families, most of them from the retrotransposon class of TEs. Additionally, we found TEs present in the five analyzed genomes that were located nearby previously identified cold tolerant genes. Some of these TEs contain promoter elements and transcription binding sites. Finally, we detected TEs nearby fixed and polymorphic inversion breakpoints.

Conclusions

Our research revealed a significant number of newly identified TE consensus sequences in the genome ofD. montana, suggesting that non-model species should be studied to get a comprehensive view of the TE repertoire in Drosophila species and beyond. Genome annotations with the newD. montanalibrary allowed us to identify TEs located nearby cold tolerant genes, and present at high population frequencies, that contain regulatory regions and are thus good candidates to play a role inD. montanacold stress response. Finally, our annotations also allow us to identify for the first time TEs present in the breakpoints of threeD. montanainversions.
Gfi1 controls the formation of exhausted effector-like CD8 T cells during chronic infection and cancer
Authors: Ojo Oluwagbemiga A , Shen Hongxing , Ingram Jennifer T , Bonner James A , Welner Robert S , Lacaud Georges , Zajac Allan J , Shi Lewis Z
Published: April 2024

During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108−CX3CR1+effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108+CX3CR1+state. These Ly108+CX3CR1+cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells.
ProLLM: Protein Chain-of-Thoughts Enhanced LLM for Protein-Protein Interaction Prediction
Authors: Jin Mingyu , Xue Haochen , Wang Zhenting , Kang Boming , Ye Ruosong , Zhou Kaixiong , Du Mengnan , Zhang Yongfeng
Published: April 2024

The prediction of protein-protein interactions (PPIs) is crucial for understanding biological functions and diseases. Previous machine learning approaches to PPI prediction mainly focus on direct physical interactions, ignoring the broader context of nonphysical connections through intermediate proteins, thus limiting their effectiveness. The emergence of Large Language Models (LLMs) provides a new opportunity for addressing this complex biological challenge. By transforming structured data into natural language prompts, we can map the relationships between proteins into texts. This approach allows LLMs to identify indirect connections between proteins, tracing the path from upstream to downstream. Therefore, we propose a novel frameworkProLLMthat employs an LLM tailored for PPI for the first time. Specifically, we proposeProtein Chain of Thought (ProCoT), which replicates the biological mechanism of signaling pathways as natural language prompts. ProCoT considers a signaling pathway as a protein reasoning process, which starts from upstream proteins and passes through several intermediate proteins to transmit biological signals to downstream proteins. Thus, we can use ProCoT to predict the interaction between upstream proteins and downstream proteins. The training of ProLLM employs the ProCoT format, which enhances the model’s understanding of complex biological problems. In addition to ProCoT, this paper also contributes to the exploration of embedding replacement of protein sites in natural language prompts, and instruction fine-tuning in protein knowledge datasets. We demonstrate the efficacy of ProLLM through rigorous validation against benchmark datasets, showing significant improvement over existing methods in terms of prediction accuracy and generalizability. Our results highlight the potential of LLMs to transform the field of PPI, serving as a robust potential tool for various categories of biological and medical research. The code is available at:https://github.com/MingyuJ666/ProLLM.
Sucrase isomaltase dysfunction influences dietary sucrose intake and preference
Authors: Aldiss Peter , Torices Leire , Ramne Stina , Jørgensen Marit Eika ,   Sucrase-Isomaltase Working Group, D’Amato Mauro , Andersen Mette K
Published: April 2024

Objective

To characterise the role of Sucrase-isomaltase (SI) in regulating dietary behaviours, such as sweet preference and food liking in Si knockout (Sis-KO) mice and in population-based cohorts from Greenland and the UK.

Design

We profiled the appetitive and post-ingestive response to dietary carbohydrates in SI knockout (Sis-KO) mice. Alongside this, we conducted detailed dietary analysis of 45 foods in two Greenlandic population-based cohorts (IHIT, n=2778 and 68 foods, and B2018, n=2203 and 45 foods) with the presence of a common (allele frequency = 14.3%) SI Loss of function (LoF) variant, c.273-274delAG. Finally, we explored the association between SI hypomorphic variants, liking of 140 foods, and sucrose content using data from 134,766 UKBB participants with exome sequencing and questionnaire data available.

Results

Sucrose naïve Sis-KO mice had a significantly reduced intake of dietary sucrose, and preference for 10% liquid sucrose, in two-bottle preference studies. Mechanistically, oral administration of the short-chain fatty acid acetate reduced sucrose-preference in wild-type mice. In Greenlandic LoF homozygous carriers we show that the previously reported reduction in sugar intake may primarily be explained by a lower intake of cake and pastries, and of candy and chocolate and that added sugar is the main factor explaining these associations. In the UKBB, a negative association with “cake icing”, the food with the highest sucrose content per 100g, was detected in SI hypomorphic carriers, as well as in sensitivity analyses conducted only including carriers of known CSID LoF variants. Further, a negative linear relationship was also observed between the effect estimates of hypomorphic SI variants on food liking and the estimated sucrose content per 100g of 88 sucrose-containing foods, indicating that food dislike in SI carriers correlates with the amount of sucrose in food.

Conclusion

Collectively, we demonstrated that genetic variation in the SI gene is associated with significant changes in sucrose preference, characterised by a rapid avoidance of dietary sucrose in Sis-KO mice, as well as lower consumption and increased disliking of sucrose rich foods in Greenlanders and Europeans, respectively. This work demonstrates that genetic variation in the SI gene may impact physiology beyond the gastrointestinal tract and suggest the possibility to target SI to reduce the preference, and intake, of dietary sucrose with implications for digestive and metabolic health.
Neural correlates of pure presence
Authors: Boly Melanie , Smith Richard , Borrego Giulietta Vigueras , Pozuelos Joan Paul , Alauddin Tariq , Malinowski Peter , Tononi Giulio
Published: April 2024

Pure presence (PP) is described in several meditative traditions as an experience of a vast, vivid luminosity devoid of perceptual objects, thoughts, and self. Integrated information theory (IIT) predicts that such vivid experiences may occur when the substrate of consciousness in the cerebral cortex is virtually silent. To assess this prediction, we recorded 256-electrode high-density electroencephalography (hdEEG) in long-term meditators of Vajrayana and Zen traditions who were able to reach PP towards the end of a retreat. Because neural activity is typically associated with increased EEG gamma power, we predicted that PP should be characterized by widespread gamma decreases. For meditators of both traditions, PP was associated with decreased broadband hdEEG power compared to within-meditation mind-wandering, most consistent in the gamma range (30–45 Hz). Source reconstruction indicated that gamma decrease was widespread but especially pronounced in posteromedial cortex. PP broadband power also decreased compared to all other control conditions, such as watching or imagining a movie, active thinking, and open-monitoring. PP delta power (1–4Hz) was also markedly decreased compared to dreamless sleep. PP with minimal perceptual contents or accompanied by a feeling of bliss showed hdEEG signatures close to PP. In contrast, gamma activity increased during phases characterized by rich perceptual contents, such as visualization or mantra recitation. Overall, these results are consistent with PP being a state of vivid consciousness during which the cerebral cortex is highly awake (decreased delta activity) but neural activity is broadly reduced (decreased gamma activity), in line with IIT’s predictions.

Significance Statement

Pure presence (PP) is described in several meditative traditions as an experience of a vast, vivid luminosity devoid of perceptual objects, thoughts, and self. Integrated information theory (IIT) predicts that such vivid experiences may occur when the substrate of consciousness in the cerebral cortex is virtually silent. We recorded 256-electrode high-density electroencephalography (hdEEG) in Vajrayana and Zen long-term meditators who could reach PP towards the end of a retreat. Compared to all control conditions, PP was characterized by decreased broadband hdEEG power, most consistent in the gamma range. These results are consistent with PP being a state of vivid consciousness during which the cerebral cortex is highly awake but neural activity is broadly reduced, in line with IIT’s predictions.
Does post-ejaculatory sperm experience prior to fertilization alter offspring performance beyond paternity in an external fertilizing fish?
Authors: Wagle Ranjan , Purchase Craig F.
Published: April 2024

Recent research has suggested that the environment encountered by sperm post-ejaculation may impact offspring development beyond the transfer of the paternal genome. The mechanisms that underlie such effects remain unclear, but two non-mutually exclusive processes have been proposed. 1) Haploid selection, whereby stressful conditions act as stronger post-ejaculation pre-fertilization selective pressures on semen than under benign situations, resulting in the fertilization of, on average higher quality sperm and the production of offspring that exhibit superior performance across all environmental conditions that they might encounter. 2) Epigenetic inheritance, where environmental conditions induce changes in sperm that are passed down to offspring, resulting in altered gene expression in offspring. This would be adaptive if sperm experiences anticipate what is to come and improve offspring performance to match those conditions. Capelin (Mallotus villosus) sperm and embryos are sensitive to salinity and may represent a good system to investigate these phenomena. We used a split-ejaculate and split-brood experimental block design to expose capelin sperm to known benign (25 psu) and stressful (35 psu) salinity prior to egg contact, and split each batch of fertilized eggs for incubation at matched and mismatched salinity to those of sperm exposure. Our findings revealed no differences in hatch characteristics between offspring produced by sperm exposed to benign and stressful salinity conditions. A follow-up experiment found the same result with an increased selection gradient at 5 psu and 35 psu. Our study does not support the hypothesis that sperm experiences exert an influence on the development of offspring characteristics, independent of paternity. Instead, our results suggest that the sole influential factor in sperm determining offspring characteristics is the transfer of the paternal genome.
Ade novovariant inPAK2detected in an individual with Knobloch type 2 syndrome
Authors: Werren Elizabeth A. , Kalsner Louisa , Ewald Jessica , Peracchio Michael , King Cameron , Vats Purva , Audano Peter A. , Robinson Peter N. , Adams Mark D. , Kelly Melissa A. , Matson Adam P.
Published: April 2024

P21-activated kinase 2 (PAK2) is a serine/threonine kinase essential for a variety of cellular processes including signal transduction, cellular survival, proliferation, and migration. A recent report proposed monoallelicPAK2variants cause Knobloch syndrome type 2 (KNO2)—a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novelde novoheterozygous missense variant inPAK2, NM_002577.4:c.1273G>A, p.(D425N), by whole genome sequencing in an individual with features consistent with KNO2. Notable clinical phenotypes include global developmental delay, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, FTT, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(D425N) variant lies within the protein kinase domain and is predicted to be functionally damaging byin silicoanalysis. Previous clinical genetic testing did not report this variant due to unknown relevance ofPAK2variants at the time of testing, highlighting the importance of reanalysis. Our findings also substantiate the candidacy ofPAK2variants in KNO2 and expand the KNO2 clinical spectrum.
Cell-TIMP: Cellular Trajectory Inference based on Morphological Parameter
Authors: Raj Piyush , Gupta Himanshu , Anantha Pooja , Barman Ishan
Published: April 2024

Cellular morphology, shaped by various genetic and environmental influences, is pivotal to studying experimental cell biology, necessitating precise measurement and analysis techniques. Traditional approaches, which rely on geometric metrics derived from stained images, encounter obstacles stemming from both the imaging and analytical domains. Staining processes can disrupt the cell’s natural state and diminish accuracy due to photobleaching, while conventional analysis techniques, which categorize cells based on shape to discern pathophysiological conditions, often fail to capture the continuous and asynchronous nature of biological processes such as cell differentiation, immune responses, and cancer progression. In this work, we propose the use of quantitative phase imaging for morphological assessment due to its label-free nature. For analysis, we repurposed the genomic analysis toolbox to perform trajectory inference analysis purely based on morphology information. We applied the developed framework to study the progression of leukemia and breast cancer metastasis. Our approach revealed a clear pattern of morphological evolution tied to the diseases’ advancement, highlighting the efficacy of our method in identifying functionally significant shape changes where conventional techniques falter. This advancement offers a fresh perspective on analyzing cellular morphology and holds significant potential for the broader research community, enabling a deeper understanding of complex biological dynamics.
A neural compass in the human brain during naturalistic virtual navigation
Authors: Lu Zhengang , Julian Joshua B. , Aguirre Geoffrey K. , Epstein Russell A.
Published: April 2024

A central component of wayfinding is the ability to maintain a consistent representation of one’s facing direction when moving about the world. In rodents, head direction cells are believed to support this “neural compass”, but identifying a similar mechanism in humans during dynamic naturalistic navigation has been challenging. To address this issue, we acquired fMRI data while participants freely navigated through a virtual reality city. Encoding model analyses revealed voxel clusters in retrosplenial complex and superior parietal lobule that exhibited reliable tuning as a function of facing direction. Crucially, these directional tunings were consistent across perceptually different versions of the city, spatially separated locations within the city, and motivationally distinct phases of the behavioral task. Analysis of the model weights indicated that these regions may represent facing direction relative to the principal axis of the environment. These findings reveal specific mechanisms in the human brain that allow us to maintain a sense of direction during naturalistic, dynamic navigation.
A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide
Authors: Hu Zhiping , Kurihara Takeshi , Sun Yiyue , Cetin Zeliha , Florentino Rodrigo M. , Faccioli Lanuza A. P. , Liu Zhenghao , Yang Bo , Ostrowska Alina , Soto-Gutierrez Alejandro , Delgado Evan R.
Published: April 2024

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and commonly associated with hepatic fibrosis or cirrhosis. This study aims to establish a rat model mimicking the progression from liver fibrosis to cirrhosis and subsequently to HCC using thioacetamide (TAA). We utilized male Lewis rats, treating them with intra-peritoneal injections of TAA. These rats received bi-weekly injections of either 200 mg/kg TAA or saline (as a control) over a period of 34 weeks. The development of cirrhosis and hepatocarcinogenesis was monitored through histopathological examinations, biochemical markers, and immunohistochemical analyses. Our results demonstrated that chronic TAA administration induced cirrhosis and well-differentiated HCC, characterized by increased fibrosis, altered liver architecture, and enhanced hepatocyte proliferation. Biochemical analyses revealed significant alterations in liver function markers, including elevated alpha-fetoprotein (AFP) levels, without affecting kidney function or causing significant weight loss or mortality in rats. This TAA-induced cirrhosis and HCC rat model successfully replicates the clinical progression of human HCC, including liver function impairment and early-stage liver cancer characteristics. It presents a valuable tool for future research on the mechanisms of antitumor drugs in tumor initiation and development.
Utility Analyses of AVITI Sequencing Chemistry
Authors: Liu Silvia , Obert Caroline , Yu Yan-Ping , Zhao Junhua , Ren Bao-Guo , Liu Jia-Jun , Wiseman Kelly , Krajacich Benjamin J. , Wang Wenjia , Metcalfe Kyle , Smith Mat , Ben-Yehezkel Tuval , Luo Jian-Hua
Published: April 2024

Background

DNA sequencing is a critical tool in modern biology. Over the last two decades, it has been revolutionized by the advent of massively parallel sequencing, leading to significant advances in the genome and transcriptome sequencing of various organisms. Nevertheless, challenges with accuracy, lack of competitive options and prohibitive costs associated with high throughput parallel short-read sequencing persist.

Results

Here, we conduct a comparative analysis using matched DNA and RNA short-reads assays between Element Biosciences’ AVITI and Illumina’s NextSeq 550 chemistries. Similar comparisons were evaluated for synthetic long-read sequencing for RNA and targeted single-cell transcripts between the AVITI and Illumina’s NovaSeq 6000. For both DNA and RNA short-read applications, the study found that the AVITI produced significantly higher per sequence quality scores. For PCR-free DNA libraries, we observed an average 89.7% lower experimentally determined error rate when using the AVITI chemistry, compared to the NextSeq 550. For short-read RNA quantification, AVITI platform had an average of 32.5% lower error rate than that for NextSeq 550. With regards to synthetic long-read mRNA and targeted synthetic long read single cell mRNA sequencing, both platforms’ respective chemistries performed comparably in quantification of genes and isoforms. The AVITI displayed a marginally lower error rate for long reads, with fewer chemistry-specific errors and a higher mutation detection rate.

Conclusion

These results point to the potential of the AVITI platform as a competitive candidate in high-throughput short read sequencing analyses when juxtaposed with the Illumina NextSeq 550.
Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome
Authors: Nitschke Jahn , Huber Robin , Vossio Stefania , Moreau Dimitri , Marcourt Laurence , Gindro Katia , Queiroz Emerson F. , Soldati Thierry , Hanna Nabil
Published: April 2024

This study evaluated the efficacy of a high-throughputDictyostelium discoideum–Mycobacterium marinumDd-Mm infection system by first benchmarking it against a set of antibiotics and second in screening a library of natural product (NP) derivatives for anti-infective activity against intracellularMycobacterium marinum(Mm). The study observed no activity of pyrazinamide against Mm, consistent with known resistance patterns, and confirmed other antibiotics, such as rifampicin and bedaquiline, with activity below defined antibacterial susceptibility breakpoints. From screening a small library of NP derivatives,trans-δ-viniferins emerged as promising anti-infective scaffolds, particularly two compounds which exhibited an anti-infective activity on Mm during infection but not on Mm in broth,17with an IC50of 18.1 µM, and19with an IC50of 9 µM). Subsequent exploration via halogenation and structure-activity relationship (SAR) studies led to the identification of derivatives with improved selectivity and potency. The observed anti-infective phenotype may involve mechanisms such as blocking mycobacterial virulence factors or boosting host defense. Furthermore, the study highlights the potential of natural product-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.

IMPORTANCE

This study underscores the significance of leveraging natural product-inspired approaches and innovative infection models in search for novel anti-infective compounds. By benchmarking and employing high-throughputDictyostelium discoideum-Mycobacterium marinuminfection system on a small, focused library of natural product derivatives, the study identifiedtrans-δ-viniferins as promising anti-infective scaffolds againstMycobacterium marinum, opening potential therapeutic avenues for combating tuberculosis. The findings highlight the value of exploring nature-inspired chemistry for drug discovery and addressing global health challenges.
Droplet Hi-C for Fast and Scalable Profiling of Chromatin Architecture in Single Cells
Authors: Chang Lei , Xie Yang , Taylor Brett , Wang Zhaoning , Sun Jiachen , Tan Tuyet R. , Bejar Rafael , Chen Clark C. , Furnari Frank B. , Hu Ming , Ren Bing
Published: April 2024

Comprehensive analysis of chromatin architecture is crucial for understanding the gene regulatory programs during development and in disease pathogenesis, yet current methods often inadequately address the unique challenges presented by analysis of heterogeneous tissue samples. Here, we introduce Droplet Hi-C, which employs a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture at single-cell resolution from the mouse cortex and analyzed gene regulatory programs in major cortical cell types. Additionally, we used this technique to detect copy number variation (CNV), structural variations (SVs) and extrachromosomal DNA (ecDNA) in cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We further refined this technique to allow for joint profiling of chromatin architecture and transcriptome in single cells, facilitating a more comprehensive exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C not only addresses critical gaps in chromatin analysis of heterogeneous tissues but also emerges as a versatile tool enhancing our understanding of gene regulation in health and disease.
Relieving the transfusion tissue traffic jam: a network model of radial transport in conifer needles
Authors: Mai Melissa H , Gao Chen , Bork Peter A. R. , Holbrook N. Michele , Schulz Alexander , Bohr Tomas
Published: April 2024

The linear geometry of conifer leaves (e.g., pine needles) imposes architectural constraints on solute transport. The needle's structural solution to prevent axial stagnation, however, introduces an additional challenge to radial transport by restricting loading and unloading of sugar and water, respectively, to a narrow zone at the periphery of the vascular bundle. Moreover, a Casparian strip blocks apoplastic flow through the endodermis between the vasculature and photosynthetic tissue, forcing countercurrents of water and sugar to travel simultaneously through the cell lumen at this interface. In between these two potential bottlenecks is the transfusion tissue, a distinctive anatomical feature of conifer needles. Here we develop a network-based mathematical model to explore how the structure of the intervening transfusion tissue facilitates radial transport of sugar and water. To describe extravascular transport with cellular resolution, we construct networks from images of Pinus pinea needles obtained through X-ray μCT, as well as fluorescence and electron microscopy. Our results show that the physical separation of sugar and water pathways within the transfusion tissue mitigates the consequences of constricting flow at both the vascular access points and the endodermis.
NuCDB: A databank of nucleic acids circular dichroism spectra
Authors: Das Uttam , Magateshvaren Saras Murali Aadhitya , Rathinavelan Thenmalarchelvi
Published: April 2024

Nucleic acids take a variety of secondary structures depending on the sequence and environmental conditions. Circular dichroism (CD) spectroscopy quickly provides the secondary structural information of nucleic acids.Nucleic acidCircular-dichroismDataBank (NuCDB)https://project.iith.ac.in/nucdb/, a repository of nucleic acid secondary structure CD spectra published during 1964-2012, is created. Besides acting as the repository for the nucleic acids CD spectra,NuCDBalso has the facility to upload recently published CD spectra to keep the repository up-to-date. This repository provides the sequence-structure-environmental relationship of different nucleic acid fragments in one platform. Until today, CD is used for studying the secondary structure of smaller nucleic acid fragments. Since different parts of the genome and transcriptome of an organism have combinations of various secondary structures and play a crucial role in regulating the biological processes, the CD spectra of longer nucleic acid sequences would be more realistic. Thus, this bioinformatics repository would be helpful in training machine learning models to predict the presence of multiple secondary structures in a given CD spectra.
Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia
Authors: Barneh Farnaz , Koedijk Joost B. , Wijnen Noa E. , Meulendijks Tom , Ashtiani Minoo , Dunnebach Ester , Dautzenberg Noël , Cornel Annelisa M. , Krippner-Heidenreich Anja , Klein Kim , Zwaan C. Michel , Kuball Jürgen , Nierkens Stefan , Cloos Jacqueline , Kaspers Gertjan J.L. , Heidenreich Olaf
Published: April 2024

In contrast to patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL), patients with acute myeloid leukemia (AML) have not yet benefited from recent advances in targeted immunotherapy. Repurposing immunotherapies that have been successfully used to target other hematological malignancies could, in case of a shared target antigen, represent a promising opportunity to expand the immunotherapeutic options for AML. Here, we evaluated the expression of CD19 in a large pediatric AML cohort, assessed theex vivoAML killing efficacy of CD19-directed immunotherapies, and characterized the bone marrow immune microenvironment in pediatric AML, BCP-ALL, and non-leukemic controls. Out of 167 newly diagnosedde novopediatric AML patients, 18 patients (11%) had CD19+AML, with 61% carrying the translocation t(8;21)(q22;q22). Among CD19+samples, we observed a continuum of CD19 expression levels on AML cells. In individuals exhibiting unimodal and high CD19 expression, the antigen was consistently present on nearly all CD34+CD38-and CD34+CD38+subpopulations. Inex vivoAML-T cell co-cultures, blinatumomab demonstrated substantial AML killing, with an efficacy similar to BCP-ALL. In addition, CAR T cells could effectively eliminate CD19+AML cellsex vivo. Furthermore, our immunogenomic assessment of the bone marrow immune microenvironment of newly diagnosed pediatric t(8;21) AML revealed that T- and NK cells had a less exhausted and senescent phenotype in comparison to pediatric BCP-ALL. Altogether, our study underscores the promise of CD19-directed immunotherapies for the treatment of pediatric CD19+AML.
The selective 5-HT2Areceptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents
Authors: Jensen Anders A. , Cecchi Claudia R. , Hibicke Meghan , Bach Astrid H. , Kaadt Erik , Märcher-Rørsted Emil , Nichols Charles D. , Elfving Betina , Kristensen Jesper L.
Published: April 2024

Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the results of an elaborate preclinical characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2Areceptor (5-HT2AR) and to exhibit pronounced selectivity for this receptor over the related 5-HT2Band 5-HT2Creceptors in a range of functional assays. LPH-5 (0.375 – 12.0 mg/kg,i.p.) dose-dependently induced head-twitch responses (HTR) in Sprague Dawley rats, with substantial 5-HT2AR engagement being observed at 0.5-1.0 mg/kg. Acute administration of LPH-5 (1.5 mg/kg,i.p.) induced robust antidepressant-like effects in Flinders Sensitive Line rats and adrenocorticotropic hormone-treated Sprague Dawley rats, and LPH-5 (0.3 and 1.5 mg/kg,i.p.) induced significant effects in a recently developed Wistar Kyoto rat model proposed to reflect the long-term antidepressant-like effects produced by psychedelics in humans. In conclusion, selective 5-HT2AR activation, as mediated here by LPH- 5, seems to hold antidepressant potential, suggesting that this activity component is key for the beneficial effects of classical psychedelics. Hence, we propose that LPH-5 and other 5-HT2AR- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.