bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of resistant cultivars for management of basil downy mildew in South Deerfield, MA, 2024
Authors: Scheufele Susan B. , Higgins Genevieve , Shokoohi Alireza
Published: January 2025

Basil downy mildew, caused by the oomycete pathogen Peronospora belbahrii, is among the most devastating diseases of basil worldwide. Symptoms include vein-trapped lesions on undersides of leaves that are initially water-soaked and develop fuzzy gray sporulation under humid conditions. Diseased foliage becomes quickly necrotic. This report evaluates the resistance to cucurbit downy mildew of 15 basil cultivars (Ocimum basilicum ‘Prospera Active® Mia’, ‘Prospera Active® Lihi’, ‘Prospera Active® Noga’, ‘BA159B’, ‘BA159C’, ‘BA160’, ‘Prospera® Red’, ‘Prospera® CRM CG1’, ‘Prospera® DRM PS5’, ‘Prospera® ILL2’, ‘Giuletta’, ‘Piamia’, ‘Evi’, ‘Eleonora’, and ‘Keira’). The trial was conducted in 2024 in South Deerfield, MA. Results from this trial will help basil growers select appropriate resistant cultivars for mid-summer production, when downy mildew pressure is high.
Pruritic Urticarial Papules and Plaques of Pregnancy Case Study
Authors: Ousley Lisa , Snuggs Barbora
Published: January 2025

A primiparous patient, 30 days postpartum, presented to the clinic with a chief complaint of an itchy red rash on her mid to lower abdomen. It started 2 days ago. The rash had spread to her upper thighs. Past medical history was negative for skin disease or atopy. Her examination exposed pruritic erythematous polymorphous papules, with subsequent coalescence of larger urticarial plaques on the mid to lower abdomen and upper thighs. The patient was diagnosed with pruritic urticarial papules and plaques of pregnancy (PUPPP). PUPPP is the most common dermatosis affecting about one in 200 pregnant women. It has no tendency to recur in subsequent pregnancies. The elevated differential diagnosis included pemphigoid gestationis and eczema. Drug eruptions, urticaria, and viral exanthems were also considered. The primary goal of PUPPP treatment is to alleviate pruritus and discomfort. Antihistamines and topical corticosteroids are often prescribed along with skin care recommendations. Patients frequently have limited relief from topical treatments or skin care strategies. The extent of patient discomfort mandates competent evaluation because treatment is symptomatic and PUPPP can be difficult to manage. Despite the discomfort related to severe pruritus, PUPPP is not harmful to the mother or baby.
Low Bone Mineral Density and Associated Factors Among People Living With HIV in Kerman, Iran: A Cross-Sectional Study in 2021–2022
Authors: Rashidi Hamidreza , Mehmandoost Soheil , Fahimfar Noushin , Aghaei Meybodi Hamid Reza , Hosseinian Seyed Mohammad , Shirzad Noushin , Hajivalizade Fatemeh , Sanjari Mahnaz , Shakibi Mohammad Reza , Hasan Aghaei Tarlan , Yazdi Yahaabadi Farzaneh , Salajegheh Pouriya , Shafiee Gita , Razi Farideh , Ranjbar Ebrahim , McFarland Willi , Ostovar Afshin , Sharifi Hamid
Published: January 2025

Chronic diseases such as osteoporosis and low bone mineral density (BMD) are significant public health concerns for people living with HIV (PLWH), especially with the increased life expectancy because of antiretroviral therapy (ART). This study evaluated the prevalence and associated factors of low BMD among 94 PLWH in Kerman, Iran, from September 2021 to February 2022. Using dual-energy X-ray absorptiometry, BMD was measured, with low BMD defined by specific T-scores and Z-scores. Predictors were assessed through interviews, medical records, and blood tests. Bivariable and multivariable logistic regression models identified associations between low BMD and various factors. The study found a 51.1% prevalence of low BMD, with significant associations with hypogonadism (adjusted odds ratio [aOR]: 3.19), longer ART duration (aOR per month: 1.02), and lower body mass index (aOR per unit: 0.83). The findings highlight the need for regular screening and timely intervention for low BMD among PLWH, particularly with prolonged ART use.
How people respond to their analgesic adverse drug event: A secondary data analysis
Authors: McDonald Deborah Dillon , Zhang Yiming , Almasri Batool
Published: January 2025

Background:

An individual's inability to self-identify or refusal to acknowledge an analgesic adverse drug event (ADE) lengthens the time to ADE treatment and resolution and may worsen the outcome.

Purpose:

The purpose was to describe how people who experienced an analgesic ADE during pain self-management respond to the event and to identify predictors of serious analgesic ADEs.

Methodology:

The design was a secondary data analysis. The sample consisted of 599 adult cases that had an analgesic ADE during pain self-management and reported their response to the ADE, the analgesic, a description of the ADE, demographic, and health data. Logistic regression was used to test predictors of serious versus nonserious analgesic ADEs.

Results:

Three-fourth (75.5%) of cases indicated the ADE was easy to connect to the analgesic. The majority (72.6%) stopped the medication. Most (71.9%) talked with their provider. Serious ADEs such as gastrointestinal bleeding occurred in 16.2% of cases. Significant predictors of serious analgesic ADEs included less than a baccalaureate degree, male gender, and a higher Analgesic Adverse Drug Event Measure score.

Conclusions:

Adults who experience an analgesic ADE generally respond in an injury prevention way. A smaller group of individuals who experienced a serious analgesic ADE did not seem to differentiate between serious and nonserious ADEs.

Implications:

To promote safe pain management when prescribing new analgesics, providers should highlight common serious ADEs and instruct patients to contact them if an ADE emerges and to seek immediate care if they suspect a serious ADE.
Characterization of preclinical models to investigate spinal cord stimulation for neuropathic pain: a systematic review and meta-analysis
Authors: Mugan Dave , Vuong Quoc C. , Dietz Birte E. , Obara Ilona
Published: January 2025

Despite advancements in preclinical and clinical spinal cord stimulation (SCS) research, the mechanisms of SCS action remain unclear. This may result from challenges in translatability of findings between species. Our systematic review (PROSPERO: CRD42023457443) aimed to comprehensively characterize the important translational components of preclinical SCS models, including stimulating elements and stimulation specifications. Databases (Embase, PubMed, Web of Science, and WikiStim) were searched on October 5, 2023, identifying 78 studies meeting the search criteria. We conducted a post hoc meta-analysis, including subgroup analyses and meta-regression, to assess SCS efficacy on mechanical hypersensitivity in rats subjected to neuropathic pain. Although monopolar electrodes were predominantly used as stimulating elements until 2013, quadripolar paddle and cylindrical leads gained recent popularity. Most research was conducted using 50 Hz and 200 µs stimulation. Motor threshold (MT) estimation was the predominant strategy to determine SCS intensity, which was set to 71.9% of MT on average. Our analysis revealed a large effect size for SCS (Hedge g = 1.13, 95% CI: [0.93, 1.32]) with similar magnitudes of effect between conventional (≤100 Hz) and nonconventional SCS paradigms while sham SCS had nonsignificant effect size. In addition, different stimulation intensity, frequency, and electrode design did not affect effect size. The risk of bias was assessed using Systematic Review Centre for Laboratory animal Experimentation criteria and was unclear, and only the frequency subgroup analysis showed publication bias. In summary, our review characterizes the critical components of preclinical SCS models and provides recommendations to improve reproducibility and translatability, thereby advancing the scientific foundation for SCS research.
Current source density and functional connectivity extracted from resting-state electroencephalography as biomarkers for chronic low back pain
Authors: Ueno Keita , Yamada Keiko , Ueda Masaya , Naito Yasuo , Ishii Ryouhei
Published: January 2025

Introduction:

Chronic low back pain (CLBP) is a global health issue, and its nonspecific causes make treatment challenging. Understanding the neural mechanisms of CLBP should contribute to developing effective therapies.

Objectives:

To compare current source density (CSD) and functional connectivity (FC) extracted from resting electroencephalography (EEG) between patients with CLBP and healthy controls and to examine the correlations between EEG indices and symptoms.

Methods:

Thirty-four patients with CLBP and 34 healthy controls in an open data set were analyzed. Five-minute resting-state closed-eye EEG was acquired using the international 10-20 system. Current source density across frequency bands was calculated using exact low-resolution electromagnetic tomography. Functional connectivity was assessed between 24 cortical regions using lagged linear connectivity. Correlations between pain symptoms and CSD distribution and FC were examined in patients with CLBP.

Results:

Current source density analysis showed no significant differences between the groups. The CLBP group exhibited significantly reduced FC in the β3 band between the left middle temporal gyrus and the posterior cingulate cortex, and between the ventral medial prefrontal cortex and the left inferior parietal lobule. Prefrontal θ and δ activity positively correlated with pain symptoms. Increased β1 band FC between the right dorsolateral prefrontal cortex and right auditory cortex correlated with greater pain intensity.

Conclusions:

We found altered neural activity and connectivity in patients with CLBP, particularly in prefrontal and temporal regions. These results suggest potential targets for pain modulation through brain pathways and highlight the value of EEG biomarkers in understanding pain mechanisms and assessing treatment efficacy.
Role of bilevel erector spinae with high thoracic block vs conventional unilevel block in analgesia and reduction of pain in axilla in breast cancer surgeries: a randomized controlled trial
Authors: Elsabeeny Walaa Y. , Fahmy Reham M. , Elshamy Fatma H. , Shehab Nahla N. , Abed Sayed M. , Taha Walid S. , Ibrahim Mostafa A. , Gad Ahmed F.
Published: January 2025

Introduction:

Management of pain associated with breast cancer surgeries is crucial in reducing incidence of postmastectomy pain syndrome. The pain distribution involves the anterior chest wall, axillary area and ipsilateral upper limb.

Objective:

This study was designed to investigate the effect of bilevel erector spinae plane block (ESPB) with high thoracic block vs the conventional unilevel ESPB vs opioids in patients with cancer undergoing modified radical mastectomy regarding pain control and reducing pain in axilla.

Methods:

One hundred twenty-six female patients with cancer and American Society of Anesthesiology II, III were randomized into 3 groups: bilevel ESPB, unilevel ESPB, and control group. The primary outcome was total postoperative morphine consumption.

Results:

Total postoperative morphine consumption was higher for the control group compared with the bilevel and unilevel groups (5.5 ± 1.8 vs 3.0 ± 0.0 and 4.3 ± 1.6 mg, P = 0.038). First time to receive morphine was longer for bilevel and unilevel groups compared with the control group (20.7 ± 3.1 and 17.7 ± 4.1 vs 8.2 ± 5 hours, P < 0.001). There was 96.1% and 90.3% reduction in morphine intake with odds ratio 25.6 (95% confidence interval [CI]: 6.6–100) and 10.3 (95% CI: 3.7–28.6) for the bilevel and unilevel groups compared with the control group. There was 98.5% and 65.4% reduction in the incidence of pain in axilla with odds ratio 66.6 (95% CI: 16.9–250) and 21.7 (95% CI: 6.75–66.6) for the bilevel and unilevel groups compared with the control group. Postoperative visual analog scale was lower for the bilevel group after 2, 4, and 24 hours compared with both the control group and the unilevel groups, P < 0.005.

Conclusion:

Both conventional unilevel and high thoracic bilevel ESPB had better analgesic profile when compared with opioids. Although the bilevel ESPB had additional merits to the unilevel ESPB in analgesic effects, both can be used effectively.
A Prospective Comparison of Patient Reported Outcomes After Facial Laser Resurfacing
Authors: Arias Fernando , Gala Zachary , Stetz Laura , Elfanagely Omar , Greco Gregory
Published: January 2025

Introduction:

Laser resurfacing provides a minimally invasive method for addressing facial/neck skin rejuvenation neglected by modern surgical approaches. Despite its popularity, there is a paucity of outcome data. Herein, we present patient reported outcomes (PROs) to assess the effectiveness of a single surgeon’s approach to skin rejuvenation.

Methods:

Adult patients undergoing first-time facial laser resurfacing (with broadband light and hybrid Er:YAG/thulium laser or hybrid thulium fractional laser alone) between March 2023 - February 2024, performed by the senior author (GG) and laser specialist (Registered Nurse: RN (LS)), were prospectively analyzed. Patient demographics, laser technique/settings, prophylactic medication, and post-procedure management were collected. PROs were assessed during early and late recovery periods, using 10 FACE-Q surveys related to appearance, health-related quality of life (HRQOL), and adverse effects. A paired student’s t-test compared pre- and post-treatment responses.

Results:

A total of 71 (69 female, two male) patients were identified. The mean age was 56 years [40-78]. Most (>50%) patients experienced tightness, swelling, tenderness, discomfort, and burning in the early recovery period, that dissipated over time. Post-procedure facial (p < 0.001) and skin (p < 0.001) appearance scores improved significantly, whereas that of facial lines insignificantly improved (p = 0.053). Overall, most patients were satisfied with the treatment outcome and their decision to undergo laser resurfacing.

Conclusion:

Patients were highly satisfied with both the decision to undergo the procedure and the outcome, particularly in facial appearance and HRQOL. They experienced minimal adverse effects in the early recovery period that dissipated over time.
“MINIMIZING THIGHPLASTY COMPLICATIONS: A COMBINED APPROACH OF J MEDIAL PATTERN AND HELIUM-PLASMA ASSISTED LIPOSCULPTURE”
Authors: Tambasco Damiano , Albanese Roberta , Tomaselli Federica , Pinto Valentina , Pinelli Massimo , De Santis Giorgio
Published: January 2025

Thighplasty is a widely performed body contouring procedure, utilizing various surgical techniques for thigh lifting, including medial scar positioning, vertical and horizontal procedures, and liposuction. Despite its popularity, thighplasty is associated with high complication rates and suboptimal postoperative outcomes.

This article presents a novel technique: the J medial thighplasty combined with helium plasma radiofrequency technology (HPRF) to address moderate skin and soft-tissue laxity and ptosis in the inner thighs. Between 2020 and 2023, 21 patients underwent this combined procedure. The surgical approach involved selective liposuction in targeted areas, skin resection, and preservation of deep tissue layers, coupled with the application of HPRF in the lower third of the medial thigh.

Results demonstrated significant reductions in thigh laxity, correction of skin overhang, and fat reduction, yielding improved functional and aesthetic outcomes in the lower thigh region. By strategically avoiding lymphatic vessels in superficial areas, the risk of secondary lymphedema was minimized. Patient satisfaction was notably high, with both patients and surgeons reporting favorable results.

In conclusion, the J medial thighplasty combined with HPRF offers an effective and straightforward method for enhancing the lower thigh area with minimal complications. This innovative technique provides a promising solution for patients seeking improved thigh contouring while ensuring high levels of patient satisfaction.
Operating on the Oldest-Old: Vaginal Prolapse Surgery Outcomes in Women Over 90
Authors: Zuo Stephanie W. , Warner Kristina , Zyczynski Halina , Ackenbom Mary F.
Published: January 2025

Importance

Women aged 90 years and older (“oldest-old”) represent a small but growing population who may experience bothersome pelvic organ prolapse and opt for surgical repair.

Objective

This study aimed to compare perioperative adverse events (AEs) within 8 weeks of prolapse surgery between women ≥90 years and younger patients.

Study Design

We performed a secondary analysis of a dual-center retrospective cohort study of women ≥61 years old undergoing major prolapse surgery from January 2016 to May 2023. We identified all women ≥90 years and matched them to women <90 years in a 1:4 fashion based on Charlson Comorbidity Index score and surgery type. Matching was performed without replacement. The primary outcome was a composite AE outcome, defined as all intraoperative and postoperative complications within 8 weeks of surgery.

Results

There were 24 oldest-old undergoing prolapse surgery who were matched to 96 women with mean ± standard deviation age of 77.2 ± 5.7 years. Women ≥90 years were more likely to have a lower body mass index (P < 0.01), greater preoperative prolapse stage (P = 0.049), and were less likely to have general anesthesia (P < 0.01). Patients did not differ in medical comorbidities, frailty status, concomitant hysterectomy or incontinence procedure, or length of postoperative stay. The oldest-old did not experience any intraoperative complications and had low rates of readmission (8.3%) and discharge to skilled nursing facilities (4.2%). Age ≥90 was not associated with composite AEs on multivariable analysis (adjusted odds ratio 1.60, 95% confidence interval [0.39–6.55]).

Conclusions

Age ≥90 years does not appear to increase the risk of perioperative AEs in women with similar comorbidities.
Integrated Multi-Omics Analyses of Synaptosomes Revealed Synapse-Centered Novel Targets in Alzheimer’s Disease
Authors: Kumar Subodh , Ramos Enrique , Hidalgo Axel , Rodarte Daniela , Sharma Bhupender , Torres Melissa M. , Devara Davin , Gadad Shrikanth S.
Published: January 2025

Abstract

Synapse dysfunction is an early event in Alzheimer’s disease (AD) caused by various factors such as Amyloid beta, p-tau, inflammation, and aging. However, the exact molecular mechanism of synapse dysfunction in AD is largely unknown. To understand this, we comprehensively analyzed the synaptosome fraction in postmortem brain samples from AD patients and cognitively normal individuals. We conducted high-throughput transcriptomic analyses to identify changes in microRNA (miRNA) and mRNA levels in synaptosomes extracted from the brains of both unaffected individuals and those with Alzheimer’s disease (AD). Additionally, we performed mass spectrometry analysis of synaptosomal proteins in the same sample group. These analyses revealed significant differences in the levels of miRNAs, mRNAs, and proteins between the groups. To further understand the pathways or molecules involved, we used an integrated omics approach and studied the molecular interactions of deregulated synapse miRNAs, mRNAs, and proteins in the samples from individuals with AD and the control group, which demonstrated the impact of deregulated miRNAs on their target mRNAs and proteins. Furthermore, the DIABLO analysis highlighted complex relationships between mRNAs, miRNAs, and proteins that could be key in understanding the pathophysiology of AD. Our study identified synapse-centered novel candidates that could be critical in restoring synapse dysfunction in AD.
Neuronal cell adhesion molecule (NRCAM) variant defined by microexon skipping is an essential, antigenically distinct, and targetable proteoform in high-grade glioma
Authors: Sehgal Priyanka , Naqvi Ammar S. , Higgins Makenna , Liu Jiageng , Harvey Kyra , Jarroux Julien , Kim Taewoo , Mankaliye Berk , Mishra Pamela , Watterson Grace , Fine Justyn , Davis Jacinta , Hayer Katharina E. , Castro Annette , Mogbo Adanna , Drummer Charles , Martinez Daniel , Koptyra Mateusz P. , Ang Zhiwei , Wang Kai , Farrel Alvin , Quesnel-Vallieres Mathieu , Barash Yoseph , Spangler Jamie B. , Rokita Jo Lynne , Resnick Adam C. , Tilgner Hagen U. , DeRaedt Thomas , Powell Daniel J , Thomas-Tikhonenko Andrei
Published: January 2025

To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30 nucleotide-long microexons. Several of these skipped microexons mapped to L1-IgCAM family members, such asNRCAM. Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping ofNRCAMmicroexons 5 and 19 in virtually every pHGG sample. Importantly, the Δex5Δex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo. We developed a monoclonal antibody selective for Δex5Δex19 NRCAM and demonstrated that “painting” of pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor. Thus, pHGG-specific NRCAM and possibly other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.

Statement of significance

Existing targets for chimeric antigen receptors (CAR)-armed T cells are often shared by CNS tumors and normal tissues, creating the potential for on-target/off-tumor toxicities. Here we demonstrate that in CNS tumors of glial origin, cell adhesion molecules have alternatively spliced proteoforms, which could be targeted by highly selective therapeutic antibodies.
Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging
Authors: Runyan Constance E. , Luo Lucy , Welch Lynn C. , Lu Ziyan , Chen Fei , Schleck Maxwell J. , Nafikova Radmila A. , Grant Rogan A. , Aillon Raul Piseaux , Senkow Karolina J. , Bunyan Elsie G. , Plodzeen William T. , Abdala-Valencia Hiam , Weiss Craig , Dada Laura A. , Thorp Edward B. , Sznajder Jacob I. , Chandel Navdeep S. , Misharin Alexander V. , Budinger G.R. Scott
Published: January 2025

Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.
Spatiotemporal temperature control by holographic heating microscopy unveils cellular thermosensitive calcium signaling
Authors: Oyama Kotaro , Ishii Ayumi , Matsumura Shuhei , Oyama Tomoko Gowa , Taguchi Mitsumasa , Suzuki Madoka
Published: January 2025

Optical microheating technologies have revealed how biological systems sense heating and cooling at the microscopic scale. Sensing is based on thermosensitive biochemical reactions that frequently engage membrane proteins, Ca2+channels, and pumps to convert sensing information as the Ca2+signaling in cells. These findings highlight the feasibility of thermally manipulating intracellular Ca2+signaling. However, how the thermosensitive Ca2+signaling would behave, particularly in multicellular systems, remains elusive. In this study, to extend the ability of the spatiotemporal temperature control by optical microheating technologies, we propose holographic heating microscopy. Water-absorbable infrared (IR) laser light is modulated by a reflective liquid crystal on a silicon spatial light modulator (LCOS-SLM). A computer-generated hologram displayed on the LCOS-SLM modulates the spatial phase pattern of the IR laser light to generate predesigned temperature gradients at the microscope focal plane. The holographic heating microscopy visualizes how thermosensitive Ca2+signaling is generated and propagated in MDCK cells, rat hippocampal neurons, and rat neonatal cardiomyocytes. Moreover, the optical control of the temporal temperature gradient reveals the cooling-rate dependency of Ca2+signaling in HeLa cells. These findings demonstrate the extended ability of holographic heating microscopy in investigating cellular thermosensitivities and thermally manipulating cellular functions.
Signed motif analysis of theCaenorhabditis elegansneuronal network reveals positive feedforward and negative feedback loops
Authors: Szilagyi Gabor S. , Gulyas Attila , Vassy Zsolt , Csermely Peter , Fenyves Bank G.
Published: January 2025

Nervous systems are complex biological networks with largely unknown structural and functional characteristics. Motif analysis is a robust tool that can reveal unique aspects of connectivity of a complex network. An ideal candidate for motif analysis is the connectome of the nematodeCaenorhabditis eleganswhich is the only fully reconstructed nervous system. Utilizing recent data on the connection signs of this network and a novel structure-preserving randomization method, we performed signed motif analysis on theC. elegansconnectome for the first time, to our knowledge. We identified 56 significantly over- and 1 underrepresented three-node signed motifs and revealed that certain motifs (e.g. positive feedforward, negative feedback, disinhibitory feedback, and incoherent feedforward loops) are overabundant in theC. elegansconnectome. We further distinguished (coloured) nodes by corresponding neuron modalities (e.g. sensory vs. motor neurons) and found that there is characteristic neuronal layout for each significant feedforward and feedback loop. Our findings demonstrate the importance and potential of signed motif analysis in understanding biological networks. Our motif enumerating tool and definition system can be utilized in signed motif analysis of other complex networks.
A proteo-transcriptomic investigation of toxin evolution in planarians and their role in flatworm terrestrialization
Authors: García-Vernet Raquel , Benítez-Álvarez Lisandra , Palma-Guerrero Javier , Chiva Cristina , Eleftheriadi Klara , Rojo Iñaki , Sabidó Eduard , Fernández Rosa
Published: January 2025

The transition from aquatic to terrestrial environments represents a major evolutionary transition in animals, requiring significant adaptations in physiology and defense mechanisms to the challenges presented by the harsh terrestrial environment. Platyhelminthes, which include both aquatic and terrestrial species with a single terrestrialization event in the family Geoplaniidae, serve as excellent model organisms for studying the evolutionary adaptations required for terrestrialization. This study investigates the evolutionary dynamics of toxin orthologous groups (as a proxy to gene families) in aquatic and terrestrial flatworms, together with mucus composition, focusing on their role in terrestrialization from a molecular ecology perspective. Using a proteo-transcriptomic approach, we predicted and identified a broader toxin gene repertoire in terrestrial flatworms compared to freshwater ones. Although most toxins in flatworms arose before terrestrial planarian diversification—gaining a novel evolutionary origin at the Tricladida and Continenticola nodes—the mucus protein repertoire appears to have a far older evolutionary origin in both species. Moreover, distinct orthologous groups underpin the toxin gene repertoire and mucus composition in each lineage, highlighting the contrasting evolutionary trajectories of these two functional components. While toxin families in both aquatic and terrestrial flatworms revealed overall common functions, including cytokine modulation and ion channel regulation, terrestrial flatworms exhibited specific expansions of lectin-like proteins and pro-inflammatory responses, highlighting their potential key role to respond to land-based threats. This study provides new insights into the differential evolutionary trajectories of toxin and mucus proteins in planarians, offering a deeper understanding of the genetic innovations that facilitated flatworm terrestrialization.
The Role of Genetic Variation in Shaping Phenotypic Responses to Diet in AgingDrosophila melanogaster
Authors: Bak Nikolaj Klausholt , Mackay Trudy F. C. , Morgante Fabio , Nielsen Kåre Lehmann , Nielsen Jeppe Lund , Kristensen Torsten Nygaard , Rohde Palle Duun
Published: January 2025

Nutrition plays a central role in healthy living, however, extensive variability in individual responses to dietary interventions complicates our understanding of its effects. Here we present a comprehensive study utilizing theDrosophilaGenetic Reference Panel (DGRP), investigating how genetic variation influences responses to diet and aging. Quantitative genetic analyses of the impact of dietary restriction on lifespan, locomotor activity, dry weight, and heat knockdown time were performed. Locomotor activity, dry weight and heat knockdown time were measured on the same individual flies. We found significant genotype-by-diet interaction (GDI) and genotype-by-age interaction (GAI) for all traits. Therefore, environmental factors play a crucial role in shaping trait variation at different ages and diets, and/or distinct genetic variation influences these traits at different ages and diets. Our genome wide association study also identified a quantitative trait locus for age-dependent dietary response. The observed GDI and GAI indicates that susceptibility to environmental influences changes as organisms age, which could have significant implications for dietary recommendations and interventions aimed at promoting healthy aging in humans. The identification of associations between DNA sequence variation and age-dependent dietary responses opens new avenues for research into the genetic mechanisms underlying these interactions.
Microscopy Nodes: versatile 3D microscopy visualization with Blender
Authors: Gros Oane , Bhickta Chandni , Lokaj Granita , Schwab Yannick , Köhler Simone , Banterle Niccolò
Published: January 2025

Effective visualization of 3D microscopy data is essential for communicating biological results. While scientific 3D rendering software is specifically designed for this purpose, it often lacks the flexibility found in non-scientific software like Blender, which is a free and open-source 3D graphics platform. However, loading microscopy data in Blender is not trivial. To bridge this gap, we introduce Microscopy Nodes, an extension for Blender that enables the seamless integration of large microscopy data. Microscopy Nodes provides efficient loading and visualization of up to 5D microscopy data from Tif and OME-Zarr files. Microscopy Nodes supports various visualization modes including volumetric, isosurface, and label-mask representations, and offers additional tools for slicing, annotation, and dynamic adjustments. By leveraging Blender’s advanced rendering capabilities, users can create high-quality visualizations that accommodate both light and electron microscopy. Microscopy Nodes makes powerful, clear data visualization available to all researchers, regardless of their computational experience, and is available through the Blender extensions platform with comprehensive tutorials.
Precision mRNA Nanomedicine for Targeted Vascular Therapies in ARDS and Atherosclerosis
Authors: Zhou Zhengjie , Zhu Jiayu , Yeh Chih-Fan , Meliton Angelo , Wu David , Huang Ru-Ting , Shentu Tzu-Pin , Ray Aleepta Guha , Wiseman Destini , Budina Erica , Alpar Aaron , Yang Kai-Chien , Hubbell Jeffrey A , Weinstock Ada , Mutlu Gokhan M , Tirrell Matthew V , Fang Yun
Published: January 2025

Vascular diseases, including acute respiratory distress syndrome (ARDS) and atherosclerosis, are leading causes of global morbidity and mortality, underscoring the critical need for innovative therapies. While human genetics has uncovered specific molecular mechanisms in endothelial cells that drive acute and chronic vascular inflammation central to these conditions, effectivein vivostrategies to spatiotemporally target these disease-causing pathways using therapeutic mRNAs remain limited. Here, we present a modular and tunable nanoparticle platform (PROGRAMMED nanoparticles) engineered to selectively deliver therapeutic mRNAs to target cells with distinct molecular signatures, such as inflamed endothelial cells expressing vascular cell adhesion molecule 1 (VCAM1). This approach restores key genetics-informed endothelial pathways implicated in disease, including the loss of Krüppel-like factor 2 (KLF2) in acute inflammation underlying ARDS and the suppression of phospholipid phosphatase 3 (PLPP3) in chronic inflammation driving atherosclerosis. In multiple preclinical models, these precision mRNA nanomedicine strategies demonstrated compelling therapeutic efficacy. VCAM1-targeting PROGRAMMED nanoparticles delivering KLF2 mRNA to inflamed lung microvascular endothelial cells significantly improved microvascular health and alleviated virus-induced ARDS. Similarly, PLPP3 mRNA delivery by VCAM1-targeting PROGRAMMED nanoparticles attenuated arterial inflammation, slowed atherosclerosis progression, and promoted regression of advanced plaques. This innovative platform offers a transformative approach for spatiotemporal mRNA therapies targeting inflamed endothelial cells, providing a minimally invasive and highly specific strategy to address acute and chronic vascular diseases. Moreover, the modularity of PROGRAMMED nanoparticles, particularly their ability to display diverse targeting motifs, holds substantial potential for addressing a broad spectrum of vascular complications and other diseases that require precise spatiotemporal correction of dysregulated genes.
Effector-triggered processing body formation attenuates host translation via ER stress responses and autophagy upon bacterial infection
Authors: González-Fuente Manuel , Schulz Nico , Abdrakhmanov Alibek , Izzati Gaiea , Zhu Shanshuo , Langin Gautier , Gouguet Paul , Franz-Wachtel Mirita , Macek Boris , Hafrén Anders , Dagdas Yasin , Üstün Suayib
Published: January 2025

Compartmentalization of transcripts in biomolecular condensates allows rapid and cost-efficient responses to environmental stimuli. Processing bodies (P-bodies) are dynamic ribonucleoprotein condensates formed by phase separation in the cytosol. P-bodies are involved in translational arrest and mRNA decay and regulate several developmental processes and stress responses. Pathogens have evolved strategies to exploit host degradation pathways for their own benefit, however little is known about how they impact translation. Here we show that upon infection with pathogenic bacteriaPseudomonas syringaepathovartomato(Pst), P-body assembly is enhanced in an effector-dependent manner. Moreover, a P-body-defective mutant is more tolerant to bacterial infection due to altered endoplasmic reticulum (ER) stress responses, suggesting a role of P-bodies as novel susceptibility hubs.Pstinfection is accompanied by a general host translation attenuation, which is both effector-dependent, and deregulated in the P-body-defective mutant. This indicates that P-bodies are required for the bacterial modulation of the plant translation, probably to hinder the defense responses. Additionally, host autophagy is also exploited by the bacteria to modulate P-body dynamics and its subsequent translation attenuation, revealing a complex interplay between P-body formation and disassembly during infection. Altogether, our discoveries provide novel insights on how host translation is targeted by bacteria via effector-triggered P-body formation to promote disease and uncover unknown connections between ER stress responses and autophagy with P-body dynamics.
Improved Functional Classification of Hydrolases through Pairwise Structural Similarity of Reaction Cores
Authors: Ferdous Sakib , Gupta Priyanshu , Teoh Yee Chuen , Sajeevan Karuna Anna , Vaishnavey SR , Hainlin Kaelie , Reuel Nigel , Qamhiyah Abir , Aluru Narayana R. , Kumar Manish , Chowdhury Ratul
Published: January 2025

We report a systematic pipeline is for extracting the catalytically relevant reactive site in addition to the surrounding allosterically linked residue shells around the reaction site of the most diverse enzyme class - hydrolases, with known experimental structures. We first successfully extract 40196 such hydrolase reaction cores (RC) and collates them into a publicly accessible reaction core collection (RC-Hydrolase). We perform 128M pairwise shape comparison across RC-Hydrolase using a three-dimensional search engine and present 155,329 pair instances clustering them by 60% or higher similarities in a publicly available, visually interactive dataset. Robustness of defined RCs is shown to successfully capture experimentally known function-enhancing mutations distal to the active site in PETases. Allowing comparisons of enzyme reaction centers across functional spaces (ligands bound, EC classification numbers, and expression hosts) enables identification of enzyme backbones which can be minimally mutated to accommodate more than one type of catalytic activity thereby aiding rational design of multifunctional enzymes. We also demonstrate how such versatile enzyme backbones could be leveraged by the latest diffusion-based protein design models to design bespoke libraries of small molecule inhibitors, and structurally stable multifunctional enzyme pockets. With only sporadic successes in multifunctional enzyme design thus far, we provide strong structural priors for machine-learning-guided advanced enzyme engineering in the future.
Constructing Biologically Constrained RNNs via Dale’s Backprop and Topologically-Informed Pruning
Authors: Balwani Aishwarya H. , Wang Alex Q. , Najafi Farzaneh , Choi Hannah
Published: January 2025

Abstract

Recurrent neural networks (RNNs) have emerged as a prominent tool for modeling cortical function, and yet their conventional architecture is lacking in physiological and anatomical fidelity. In particular, these models often fail to incorporate two crucial biological constraints: i) Dale’s law, i.e., sign constraints that preserve the “type” of projections from individual neurons, and ii) Structured connectivity motifs, i.e., highly sparse yet defined connections amongst various neuronal populations. Both constraints are known to impair learning performance in artificial neural networks, especially when trained to perform complicated tasks; but as modern experimental methodologies allow us to record from diverse neuronal populations spanning multiple brain regions, using RNN models to study neuronal interactions without incorporating these fundamental biological properties raises questions regarding the validity of the insights gleaned from them. To address these concerns, our work develops methods that let us train RNNs which respect Dale’s law whilst simultaneously maintaining a specific sparse connectivity pattern across the entire network. We provide mathematical grounding and guarantees for our approaches incorporating both types of constraints, and show empirically that our models match the performance of RNNs trained without any constraints. Finally, we demonstrate the utility of our methods for inferring multi-regional interactions by training RNN models of the cortical network to reconstruct 2-photon calcium imaging data during visual behaviour in mice, whilst enforcing data-driven, cell-type specific connectivity constraints between various neuronal populations spread across multiple cortical layers and brain areas. In doing so, we find that the interactions inferred by our model corroborate experimental findings in agreement with the theory of predictive coding, thus validating the applicability of our methods.
Macroevolution of fly wings proceeds along developmental lines of least resistance
Authors: Rohner Patrick T. , Berger David
Published: January 2025

Evolutionary change necessitates genetic variation, and a reigning paradigm in biology is that rates of microevolution can be predicted from estimates of available genetic variation within populations. However, the accuracy of such predictions should decay on longer evolutionary timescales, as the influence of genetic constraints diminishes. Here, we show that intrinsic developmental variability and standing genetic variation in wing shape in two distantly related flies,Drosophila melanogasterandSepsis punctum, are aligned and predict deep divergence in the dipteran phylogeny, spanning >900 taxa and 185 My. This alignment cannot easily be explained by constraint hypotheses unless most of the quantified standing genetic variation is associated with deleterious side-effects and effectively unusable for evolution. However, phenotyping of 71 genetic lines ofS. punctumrevealed no covariation between wing shape and fitness, lending no support to this hypothesis. We also find little evidence for genetic constraints on the pace of wing shape evolution along the dipteran phylogeny. Instead, correlational selection related to allometric scaling, simultaneously shaping developmental bias and deep divergence in fly wings, emerges as a potential explanation for the observed alignment. This suggests that pervasive natural selection has the potential to shape developmental architectures of some morphological characters such that their intrinsic variability predicts their long-term evolution.
BDNF in Ventrolateral Orbitofrontal Cortex to Dorsolateral Striatum Circuit Moderates Alcohol Consumption and Gates Alcohol Habit
Authors: Gunasekaran Sowmya , Moffat Jeffrey J. , Epstein Joshua D. , Phamluong Khanhky , Ehinger Yann , Ron Dorit
Published: January 2025

BDNF plays a crucial role in shaping the structure and function of neurons. BDNF signaling in the dorsolateral striatum (DLS) is part of an endogenous pathway that protects against the development of alcohol use disorder (AUD). Dysregulation of BDNF levels in the cortex or dysfunction of BDNF/TrkB signaling in the DLS results in the escalation of alcohol drinking and compulsive alcohol use. The major source of BDNF in the striatum is the prefrontal cortex. We identified a small ensemble of BDNF-positive neurons in the ventrolateral orbitofrontal cortex (vlOFC), a region involved in AUD, that extend axonal projections to the DLS. We speculated that BDNF in vlOFC-to-DLS circuit may play a role in limiting alcohol drinking and that heavy alcohol use disrupts this protective pathway. We found thatBDNFexpression is reduced in the vlOFC of male but not female mice after long-term cycles of binge alcohol drinking and withdrawal. We discovered that overexpression of BDNF in vlOFC-to-DLS but not in vlOFC-to-dorsomedial striatum (DMS) or M2 motor cortex-to-DLS circuit reduces alcohol but not sucrose intake and preference. The DLS plays a major role in habitual behaviors. We hypothesized that BDNF in vlOFC-to-DLS circuitry controls alcohol intake by gating habitual alcohol seeking. We found that BDNF over-expression in vlOFC-to-DLS circuit and systemic administration of BDNF receptor TrkB agonist, LM22A-4, biases habitually trained mice towards goal-directed alcohol seeking. Together, our data suggest that BDNF in a small ensemble of vlOFC-to-DLS neurons gates alcohol intake by attenuating habitual alcohol seeking.
Cleanet: robust doublet detection in cytometry data based on protein expression patterns
Authors: Ionita Matei , McKeague Michelle L. , Painter Mark M. , Mathew Divij , Pattekar Ajinkya , Maseda Damian , Wherry E. John , Greenplate Allison R.
Published: January 2025

Flow and mass cytometry experiments are essential for profiling immune cells at single cell resolution. Better understanding of human immunology increasingly involves analyzing studies at the scale of hundreds or thousands of samples, with data analysis a significant bottleneck. This trend increases the demand for automated analysis methods. In particular, a common preprocessing step in cytometry data analysis is distinguishing single cells from doublets (or multiplets), events in which two (or more) cells pass simultaneously through the detector. Typically, doublets are identified on two-dimensional density plots, using their high measured values for DNA intercalators (mass cytometry) or scattering channels (flow cytometry). Despite its popularity, this bivariate gating method is sometimes imprecise: for example, we show that bivariate gating of mass cytometry data can mistake single eosinophils for doublets, due to their high DNA content. Taking inspiration from methods already used in single cell transcriptomics, but not in the cytometry community, we propose an alternative approach. Our method, called Cleanet, first simulates doublet events, then identifies true events with protein expression similar to the simulated doublets. This simple method is completely automated and detects both homotypic and heterotypic doublets. We validate it in datasets acquired with mass and flow cytometry; moreover, we verify with imaging flow cytometry that events predicted to be doublets truly consist of multiple cells. Cleanet can also classify doublets based on their component cell types, which potentially enables the study of cell-cell interactions, mining extra information out of doublet events that would otherwise be discarded. As a proof of concept, we demonstrate that Cleanet can detect a treatment-specific increase in interactions between two cell lines. By automating doublet detection and classification, we aim to streamline the data analysis in large cytometry studies and provide a more accurate picture of both immune cell populations and cell-cell interactions.
Rosace-AA: Enhancing Interpretation of Deep Mutational Scanning Data with Amino Acid Substitution and Position-Specific Insights
Authors: Rao Jingyou , Wang Mingsen , Howard Matthew K , Macdonald Christian , Fraser James S. , Coyote-Maestas Willow , Pimentel Harold
Published: January 2025

Proteins are dynamic systems whose function and behavior are sensitive to environmental conditions and often involve multiple cellular roles. Deep mutational scanning (DMS) experiments generate extensive datasets to capture the functional consequences of mutations. However, the sheer volume of data presents challenges in visualization and interpretation. Current approaches often rely on heatmaps, but these methods fail to capture the nuanced effects of amino acid (AA) substitutions, which are essential for understanding mutational impact. To address this, we extend the Rosace framework withRosace-AA, a model that incorporates both position-specific information and AA substitution trends. Using substitution matrices like BLOSUM90,Rosace-AAoffers a flexible and interpretable approach to summarize DMS data oil both protein-level and position-level. We demonstrate its utility across datasets, including OCTI and MET kinase, showing thatRosace-AAhighlights key positions where mutations deviate from expected substitution patterns and captures functionally relevant variation in protein behavior across multiple DMS screens. These results suggest thatRosace-AAenables more robust and interpretable analysis of complex DMS datasets.