bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing phenotypes and clinical and health utilization associations of young people with chronic pain: latent class analysis using the electronic Persistent Pain Outcomes Collaboration database
Authors: Slater Helen , Waller Robert , Briggs Andrew M. , Lord Susan M. , Smith Anne J.
Published: July 2024

Using the Australiasian electronic Persistent Pain Outcomes Collaboration, a binational pain registry collecting standardized clinical data from paediatric ePPOC (PaedsePPOC) and adult pain services (AdultePPOC), we explored and characterized nationally representative chronic pain phenotypes and associations with clinical and sociodemographic factors, health care utilization, and medicine use of young people. Young people ≥15.0 and <25.0 years captured in PaedePPOC and AdultePPOC Australian data registry were included. Data from 68 adult and 12 paediatric pain services for a 5-year period January 2018 to December 2022 (first episode, including treatment information) were analysed. Unsupervised latent class analysis was applied to explore the existence of distinct pain phenotypes, with separate models for both services. A 3-phenotype model was selected from both paediatric and adult ePPOC data, with 693 and 3518 young people included, respectively (at least one valid indicator variable). Indicator variables for paediatric models were as follows: pain severity, functional disability (quasisurrogate “pain interference”), pain count, pain duration, pain-related worry (quasisurrogate “catastrophizing”), and emotional functioning; and, for adult models: pain severity, pain interference, pain catastrophizing, emotional functioning, and pain self-efficacy. From both services, 3 similar phenotypes emerged (“low,” “moderate,” “high”), characterized by an increasing symptom-severity gradient in multidimensional pain-related variables, showing meaningful differences across clinical and sociodemographic factors, health service utilization, and medicines use. Derived phenotypes point to the need for novel care models that differentially respond to the needs of distinct groups of young people, providing timely, targeted, age-appropriate care. To effectively scale such care, digital technologies can be leveraged to augment phenotype-informed clinical care.
Treatment of Hip Cartilage Defects in Athletes
Authors: Alvero Alexander B. , Wright-Chisem Joshua , Vogel Michael J. , Wright-Chisem Adam , Mather Richard C. , Nho Shane J.
Published: July 2024

Chondral defects in the athlete’s hip are a relatively common occurrence, often presenting with debilitating pain and activity limitation. Preoperative identification of cartilage defects is challenging and there are many different modalities for treatment. Nonsurgical interventions, including activity modification, physical therapy, and injections, play a vital role, especially in less severe cases and as adjuncts to surgical intervention. Treating surgeons must be familiar with the cartilage restoration procedures available, including debridement, microfracture, and various implantation and transplantation options. Safe and effective management of cartilage defects is imperative to an athlete’s return to sport. It is also imperative that surgeons are aware of all these various treatment options to determine what modality is best for their patients. This review serves to outline these options, cover the published literature, and provide general guidelines for surgeons when they encounter chondral defects in the office and the operating room.
Novel Treatment Options for Knee Cartilage Defects in 2023
Authors: Ghisa Claudia , Zaslav Kenneth R.
Published: July 2024

Articular cartilage lesions are a common injury that have become increasingly treatable with joint preservation procedures. Well-documented allograft and cellular treatments for these lesions are detailed elsewhere in this volume. This article discusses three new unique options for addressing these defects taking three different paths to address these complex injuries. Agili-C is an existing FDA- and EMEA-approved option using an acellular aragonite-based scaffold to treat both chondral and osteochondral lesions, with or without concurrent arthritis. Cartistem is a stem-cell-based product composed of culture-expanded allogeneic human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel, which is in its final clinical trial stages in the United States, but already has regulatory approval in Korea. IMPACT and RECLAIM studies have shown the safety and efficacy of a new one-stage procedure utilizing autologous chondrons combined with allogeneic mesenchymal stem cells (MSCs) that can provide another effective single-stage treatment option.
Treatment of Shoulder Cartilage Defects in Athletes
Authors: Ganokroj Phob , Adriani Marco , Whalen Ryan J. , Provencher Matthew T.
Published: July 2024

Articular cartilage defects in the glenohumeral joint may be found in laborers, the elderly, and young athletes, among others. Various factors can contribute to cartilage damage, including prior surgery, trauma, avascular necrosis, inflammatory arthritis, joint instability, and osteoarthritis. There is a wide variety of treatment options, from conservative treatment, injections, and surgical options, including arthroscopic debridement, microfracture, osteochondral autograft transfer, osteochondral graft transplantation, autologous chondrocyte implantation, and the newly emerging techniques such as biologic augmentation. There is a challenge to determine the optimal treatment options, especially for young athletes, due to limited outcomes in the literature. However, there are many options which are viable to address osteochondral defects of the glenohumeral joint.
Snooze it or Lose it: Understanding Sleep Disturbance and Injuries in Soccer and Basketball Student-Athletes
Authors: Owoeye Oluwatoyosi B. A. , Breitbach Anthony , Esposito Flavio , Nguyen Natania , Bender Amy M. , Neme Jamil R.
Published: July 2024

Objectives:

To assess the sleep characteristics of collegiate soccer and basketball student-athletes and explore the associations between sleep and injury risk.

Design:

Cohort study.

Setting:

NCAA D1 and NAIA Tier 1.

Participants:

One hundred eighty-one collegiate soccer and basketball student-athletes (42% female; mean age: 20.0 ± 1.7 years).

Independent Variables:

Questionnaires were administered during the 2020/2021 and 2021/2022 preseason, collecting demographic, injury history, medical history, and sleep information, including sleep difficulty category scores of 0 to 4 (none), 5 to 7 (mild), and ≥8 (moderate/severe) and other sleep disturbance measures derived from the Athlete Sleep Screening Questionnaire (ASSQ), including insufficient sleep duration (<7 hours of sleep) and poor subjective sleep quality.

Main Outcome Measures:

All-complaint knee and ankle injuries.

Results:

According to the ASSQ, 25.4% (95% confidence interval [CI], 17.9-34.3) of the student-athletes had mild sleep difficulty and 12.7% (95% CI, 7.3-20.1) had moderate/severe sleep difficulty. 36.1% (95% CI, 29.1-43.6) had insufficient sleep duration. 17.1% (95% CI, 11.7-23.7) were not satisfied with the quality of their sleep (poor sleep quality), and 13.8% (95% CI, 9.1-19.7) had an “eveningness” chronotype. Based on multivariable logistic regression models, student-athletes with poor sleep quality had significantly higher odds for injury (OR: 2.2, 95% CI, 1.04-4.79, P = 0.039).

Conclusions:

Clinically relevant dysfunctional sleep patterns are prevalent among collegiate soccer and basketball student-athletes. Poor sleep quality was significantly associated with injury risk among student-athletes. Findings suggest a substantial sleep problem in collegiate soccer and basketball student-athletes and warrant that student-athletes are regularly screened and timely interventions applied.
Implementation of High-Value Care for Physical Therapy Residents Through Systems-Based Practice Curriculum Development: Case Report
Authors: Pak Sang S. , Scheid Alison , Hoang Cathy , Fitzsimmons Amber , Topp Kimberly S.
Published: July 2024

Background and Purpose.

Systems-based practice is a core competency for physical therapy residents, best acquired through experiential learning. Peer health professions are further along than physical therapy in implementing curricula that support systems-based practice. Clinical and practice data in residency programs could provide for education in high-value care (HVC) as a foundation for systems-based practice. Our purpose was to develop and assess a HVC curriculum incorporating reflective practice to help residents achieve competency in systems-based practice.

Case Description.

The Logic Model, which evaluates key components needed for success and sustainability, was used to identify resources for a curriculum in HVC. Two orthopedic physical therapy residents and 5 faculty mentors participated in didactic and mentoring sessions. A practice dashboard for each clinician was developed to facilitate resident–mentor discussions. Focus group input was used to refine the curriculum. The validated Systems Thinking Scale, the Quality Improvement Knowledge Application Tool Rubric, and the American Physical Therapy Association Residency Core Competency Score were used to assess residents' progress and to make comparisons to prior years' residents.

Outcomes.

The residents demonstrated increases in systems thinking and quality-improvement knowledge and improvements in clinical outcomes and practice efficiencies. Three themes emerged from semistructured interviews: challenges to HVC, current approach in HVC, and future-oriented thinking in HVC in practice.

Discussion and Conclusion.

This study demonstrates that HVC activities and a personalized clinical dashboard in a physical therapy residency program can facilitate experiential learning of systems-based practice, a core competency for value-centered, inclusive practice.
Simultaneous Presentation of B-Acute Lymphoblastic Leukemia and Streptococcus agalactiae Meningitis in a 3-Year-old Girl
Authors: Purvis Katelyn , Hiskey Lisa , Khanlari Mahsa , Mead Paul E. , Holland Ashley C. , Bag Asim K. , Adderson Elisabeth , Inaba Hiroto
Published: July 2024

Infection is a major cause of treatment-related morbidity and mortality in pediatric acute lymphoblastic leukemia (ALL). Most children with ALL who develop life-threatening bacterial infections do so during induction therapy. We describe a rare case of ALL presenting simultaneously with Streptococcus agalactiae group B Streptococcus bacteremia and meningitis in a 3-year-old girl. She received appropriate antimicrobial therapy and a 2-drug early induction regimen consisting of vincristine and dexamethasone, leading to slow neurologic recovery and a favorable initial response to anti-neoplastic therapy as evidenced by minimal residual disease of 1.12% on day 15 of induction.
Cytoplasmic Lipid Droplets Predict Worse Prognosis in Diffuse Large B-Cell Lymphoma
Authors: Wang Shu-Hsien , Chiang Po-Min , Su Yung-Yeh , Yu Yu-Ting , Chen Ya-Ping , Chen Tsai-Yun , Medeiros L. Jeffrey , Chu Chang-Yao , Chen Peng-Chieh , Chang Kung-Chao
Published: July 2024

Burkitt lymphoma is characterized by high cell turnover and numerous cytoplasmic vacuoles that are demonstrated to be lipid droplets (LDs) decorated by adipophilin. By contrast, cytoplasmic vacuoles are variably observed in diffuse large B-cell lymphoma (DLBCL) and less well characterized. In this study, we first validated in DLBCL that cytoplasmic vacuoles are indeed LDs by Oil-red-O stain, Bodipy fluorescent stain, and electron microscopy. Second, in a cohort of DLBCL patients (n=52) we showed that LDs in effusional lymphoma cells were associated with a poorer prognosis (P=0.029, log-rank test) and higher International Prognostic Index (IPI) score (94% vs. 66%, P=0.026) than those without. Moreover, using adipophilin as a surrogate marker for LDs, we found in another cohort of biopsy specimen (n=85) that expression of adipophilin by lymphoma cells predicted a poorer prognosis (P=0.007, log-rank test) and higher IPI score (63% vs. 30%, P=0.005). In addition, whole exome sequencing of effusional DLBCL cells showed LD-positive DLBCL shared genetic features with the MCD (MYD88 and CD79B mutations) subtype and highlighted OSBPL10 and CUBN as the most frequently mutated genes involved in lipogenesis. Whole transcriptome analysis by comparing effusional DLBCL cells with versus without LDs showed upregulation of EHHADH, SLC1A1, CD96, INPP4B, and RNF183 relevant for lymphoma lipogenesis and upregulation of epithelial-mesenchymal transition and KRAS signaling pathways. Higher expression of EHHADH and CD96 were validated in LD-positive clinical samples and LD-rich cell lines than LD-poor cells along with the known lipogenic gene, FASN. Our findings highlight the roles of LDs and adipophilin expression in DLBCL, suggest that these markers may predict prognosis and show that lipogenic genes may be potential therapeutic targets.
ALK-rearranged Mesenchymal Neoplasms With Prominent Foamy/Pseudolipogenic Cell Morphology
Authors: Agaimy Abbas , Stoehr Robert , Fisher Cyril , Chrisinger John S.A. , Demicco Elizabeth G. , Tögel Lars , Michal Michal , Michal Michael
Published: July 2024

The category of ALK-rearranged mesenchymal neoplasms has been evolving rapidly, with reports of morphologically diverse lesions of cutaneous, soft tissue, and visceral origin. While some of these represent morphologically defined entities harboring recurrent ALK fusions (inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma), others are unclassified by morphology with variable overlap with the tyrosine kinase family of neoplasia and their underlying ALK fusions cannot be suspected based on morphology. We herein report 3 cases that expand the anatomic, morphologic, and genotypic spectrum of ALK-rearranged unclassified neoplasms. Patients were all adults aged 46 to 69 (median: 63) who presented with a mass located in the gingiva, subcutis of the back, and submucosal posterior pharyngeal wall. The tumor size ranged from 1 to 2.7 cm (median: 1.6). Conservative surgery was the treatment in all patients. Follow-up was available for one patient who remained disease-free at 14 months. Histologically, all tumors displayed large polygonal cells with foamy to granular and lipogenic-like microvacuolated copious cytoplasm and medium-sized round nuclei with 1 or 2 prominent nucleoli. Mitoses and necrosis were not seen. The initial diagnostic impression was PEComa, inflammatory rhabdomyoblastic tumor and unclassified pseudolipogenic neoplasm. Strong cytoplasmic ALK was detected by immunohistochemistry in all cases. Other positive markers include Cathepsin K (2/2), desmin (1/3), focal MyoD1 (1/1), focal SMA (1/3), and focal EMA (1/2). Targeted RNA sequencing revealed ALK fusions with exon 20 (2 cases) and exon 19 (one case) of ALK fused to RND3 (exon 3), SQSTM1 (exon 6), and desmin (intron 6). Methylation profiling in the desmin-fused case (initially diagnosed as inflammatory rhabdomyoblastic tumor) revealed an inflammatory myofibroblastic tumor match with a low confidence score of 0.5 and a flat copy number variation (CNV) profile. No NF1 mutation was detected in this case, altogether excluding an inflammatory rhabdomyoblastic tumor. Our study highlights and expands the morphologic and anatomic diversity of ALK-fused neoplasms and documents novel fusion partners (RND3 and desmin).
Patient and carer experiences of cancer cachexia and its management
Authors: Bowers Megan , Higginson Irene J. , Maddocks Matthew
Published: July 2024

Purpose of review

To explore the contributions of recent qualitative literature in progressing understanding of the experiences of cancer cachexia, and its management, from the perspectives of patients and unpaid/family carers.

Recent findings

Challenges with conducting everyday activities, maintaining independence, and continuing usual roles within the family are sources of distress. Patients and carers value individualization, flexibility, and carer involvement in physical activity/exercise interventions. In psychosocial/educational interventions that were positively perceived, the opportunity to talk about cachexia was appreciated, leading to improved health literacy, awareness about nutrition, and relationships with food. However, the general patient and carer experience around clinical acknowledgement and management of cachexia remains poor.

Eating-related distress and conflicts, lack of understanding about cachexia, and the visibility of weight loss remain recurring themes amongst literature on experiences of cancer cachexia. Studies exploring preferences for, and experiences of, interventions have primarily focused on physical activity or exercise. Psychosocial/educational and physical activity/exercise interventions are valued and perceived to alleviate some of the key quality of life issues amongst patients with cancer cachexia and their unpaid/family carers.
Resolving a “W-Shaped” P100 Waveform: Is It Normal or Abnormal?
Authors: Martin-Gonzalez Maya , Husain Aatif M.
Published: July 2024

Pattern-reversal visual evoked potentials are used to assess the visual pathways. The main waveform of interest is the P100, which is best recorded with electrodes over the mid-occipital region. Most often, the P100 waveform has negative–positive–negative components. Occasionally, it is “W-shaped,” with positive–negative–positive components. Although most often a W-shaped P100 waveform indicates an abnormality in the visual pathway, occasionally, it can be normal. A case is presented in which a W-shaped P100 waveform is seen after monocular full-field stimulation of both eyes with 30′ checks. To resolve this finding, the pattern-reversal visual evoked potentials is repeated with 60′ and 15′ checks. With 15′ checks a single typical single-peak P100 waveform is seen with normal latency. Evaluation of a W-shaped P100 waveform should involve analysis of various montages, stimulation with different check sizes, and hemifield stimulation to confirm whether the W-shaped waveform is normal or abnormal.
Evidence Review for the American College of Surgeons Quality Verification Part III: Standardization, Protocols, and Achieving Better Outcomes for Patient Care
Authors: Cardell Chelsea F , Peters Xane D , Hu Q Lina , Robinson-Gerace Amy , Mistretta Stephanie , Wescott Annie B , Maggard-Gibbons Melinda , Hoyt David B , Ko Clifford Y
Published: July 2024

BACKGROUND:

After decades of experience supporting surgical quality and safety by the American College of Surgeons (ACS), the ACS Quality Verification Program (ACS QVP) was developed to help hospitals improve surgical quality and safety. This review is the final installment of a 3-part review aimed to synthesize evidence supporting the main principles of the ACS QVP.

STUDY DESIGN:

Evidence was systematically reviewed for 3 principles: standardized team-based care across 5 phases of surgical care, disease-based management, and external regulatory review. MEDLINE was searched for articles published from inception to January 2019 and 2 reviewers independently screened studies for inclusion in a hierarchical manner, extracted data, and summarized results in a narrative fashion. A total of 5,237 studies across these 3 topics were identified. Studies were included if they evaluated the relationship between the standard of interest and patient-level or organization measures within the last 20 years.

RESULTS:

After applying inclusion criteria, a total of 150 studies in systematic reviews and primary studies were included for assessment. Despite institutional variation in standardized clinical pathways, evidence demonstrated improved outcomes such as reduced length of stay, costs, and complications. Evidence for multidisciplinary disease-based care protocols was mixed, though trended toward improving patient outcomes such as reduced length of stay and readmissions. Similarly, the evidence for accreditation and adherence to external process measures was also mixed, though several studies demonstrated the benefit of accreditation programs on patient outcomes.

CONCLUSIONS:

The identified literature supports the importance of standardized multidisciplinary and disease-based processes and external regulatory systems to improve quality of care.
Inference on spatiotemporal dynamics for coupled biological populations
Authors: Li Jifan , Ionides Edward L. , King Aaron A. , Pascual Mercedes , Ning Ning
Published: July 2024

Mathematical models in ecology and epidemiology must be consistent with observed data in order to generate reliable knowledge and evidence-based policy. Metapopulation systems, which consist of a network of connected sub-populations, pose technical challenges in statistical inference owing to nonlinear, stochastic interactions. Numerical difficulties encountered in conducting inference can obstruct the core scientific questions concerning the link between the mathematical models and the data. Recently, an algorithm has been proposed that enables computationally tractable likelihood-based inference for high-dimensional partially observed stochastic dynamic models of metapopulation systems. We use this algorithm to build a statistically principled data analysis workflow for metapopulation systems. Via a case study of COVID-19, we show how this workflow addresses the limitations of previous approaches. The COVID-19 pandemic provides a situation where mathematical models and their policy implications are widely visible, and we revisit an influential metapopulation model used to inform basic epidemiological understanding early in the pandemic. Our methods support self-critical data analysis, enabling us to identify and address model weaknesses, leading to a new model with substantially improved statistical fit and parameter identifiability. Our results suggest that the lockdown initiated on 23 January 2020 in China was more effective than previously thought.
Oxidation-induced structural changes in actin and myosin evaluated by computational simulation, machine learning modeling and high-speed AFM
Authors: Matusovsky Oleg S. , Elkrief Daren , Cheng Yu-Shu , Rassier Dilson E.
Published: July 2024

High levels of reactive oxygen species produced during muscle oxidative stress are implicated in the development of several muscle diseases. To better understand the mechanism behind a reduced myosin force generation under oxidizing conditions, we analyzed the structural and functional changes in the actin and actin-myosin complex using high-speed atomic force microscopy (HS-AFM), simulated HS-AFM, and molecular dynamics (MD) simulation. Computational oxidative nitration of tyrosine residues demonstrated instability in the molecular structure of the F-actin subunit. Cross-section analysis of the simulated HS-AFM images revealed a shift in the height values (∼0.2-1.5 nm in magnitude) between the non-oxidized and oxidized actin, which correspond to the height differences observed in HS-AFM experiments with in vitro oxidized F-actin. The oxidation-induced structural alterations in actin impact myosin molecule displacement on the single-molecule level. The displacements of myosin heads along the F-actin filaments in the presence of ATP involve the binding of the myosin molecule to a specific site on the F-actin filament, followed by the rotation of the myosin lever arm, which triggers the release of inorganic phosphate (Pi). Subsequently, the myosin head detaches from the F-actin and re-binds to a new site on the filament. The formation of the SIN-1-treated F-actin-myosin complex in the presence of ATP resulted in a change in myosin head displacement size, with a significant decrease in the frequency of long displacements (≥ 4 nm). These results suggest that oxidation decreases the pool of the weak-bound myosin molecules and shortens the long displacements related to the Pi release step, reducing the force generation by myosin motors.
Knee Biomechanics during Walking in Individuals with Anterior Cruciate Ligament Repair: The Role of a Custom 3D Printed Knee Brace
Authors: Mougin Florian , Begon Mickaël , Desmyttere Gauthier , Bleau Jacinte , Nault Marie-Lyne , Cherni Yosra
Published: July 2024

Background

Anterior cruciate ligament (ACL) injuries frequently lead to altered gait biomechanics and muscle activation patterns, increasing the risk of osteoarthritis. Knee braces are commonly used to address these issues although a lack of consensus remains regarding their clinical benefits. The recent emergence of 3D-printed braces, lighter and personalized, could improve rehabilitation.

Objectives

To evaluate the effect of a novel custom-made 3D-printed knee brace (Provoke™) in individuals after unilateral ACL reconstruction during walking. The brace incorporates an asymmetrical hinge system aimed at stabilizing the knee joint while minimizing compensatory movements.

Methods

Fourteen participants with unilateral ACL reconstruction wore the Provoke™ brace while walking at comfortable and fast paces. Knee kinematics and kinetics, and muscular activity (rectus femoris, vastus medialis, and semitendinosus) were assessed with and without the brace. Two-tailed non-parametric paired T-tests were used to assess the biomechanical effect of the brace.

Results and conclusions

The Provoke™ brace improved knee kinematics, facilitating a more neutral knee position by reducing valgus angles (-1.95°), and increasing flexion angles (+1.14°). Additionally, it enhanced muscle activation, particularly of the rectus femoris, suggesting improved quadriceps function. Overall, the Provoke™ brace effectively improves knee function and reduces muscle imbalances in individuals undergoing ACL reconstruction. It may help prevent further injury and reduce the risk of post-traumatic osteoarthritis development. The long-term effects of brace use in ACL rehabilitation must be investigated.

Key Points

Walking while wearing Provoke™ brace allow to reduce knee valgus angles which could counteract the development of post-traumatic osteoarthritis.

Braced walking may mitigate the stiffened knee gait strategy by increasing the peak knee flexion angle during the stance phase of the gait.

Increased rectus femoris activation during early stance phase could improve knee function and stability, acting against quadriceps weakness often observed after anterior cruciate ligament reconstruction.
Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets
Authors: Vijay Vindhya , Karisani Negin , Shi Lei , Hung Yu-Han , Vu Phuong , Kattel Prabhat , Kenney Lauren , Merritt Joshua , Adil Ramzi , Wu Qibiao , Zhen Yuanli , Morris Robert , Kreuzer Johannes , Kathiresan Meena , Herrera Lopez Xcanda Ixchel , Ellis Haley , Gritti Ilaria , Lecorgne Lilian , Farag Ines , Popa Alexandra , Shen William , Kato Hiroyuki , Xu Qin , Balasooriya Eranga R. , Wu Meng-Ju , Chaturantabut Saireudee , Kelley Robin K. , Cleary James M. , Lawrence Michael S. , Root David , Benes Cyril H. , Deshpande Vikram , Juric Dejan , Sellers William R. , Ferrone Cristina R. , Haas Wilhelm , Vazquez Francisca , Getz Gad , Bardeesy Nabeel
Published: July 2024

Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.
Time-resolved functional connectivity during visuomotor graph learning
Authors: Loman Sophie , Caciagli Lorenzo , Kahn Ari E. , Szymula Karol P. , Nyema Nathaniel , Bassett Dani S.
Published: July 2024

1

Humans naturally attend to patterns that emerge in our perceptual environments, building mental models that allow for future experiences to be processed more effectively and efficiently. Perceptual events and statistical relations can be represented as nodes and edges in a graph, respectively. Recent work in the field of graph learning has shown that human behavior is sensitive to graph topology, but less is known about how that topology might elicit distinct neural responses during learning. Here, we address this gap in knowledge by applying time-resolved network analyses to fMRI data collected during a visuomotor graph learning task to assess neural signatures of learning modular graphs and non-modular lattice graphs. We found that performance on this task was supported by a highly flexible visual system and otherwise relatively stable brain-wide community structure, cohesiveness within the dorsal attention, limbic, default mode, and subcortical systems, and an increasing degree of integration between the visual and ventral attention systems. Additionally, we found that the time-resolved connectivity of the limbic, default mode, temporoparietal, and subcortical systems was associated with enhanced performance for the modular group but not the lattice group. These findings provide evidence for the differential neural processing of statistical structures with distinct topologies and highlight similarities between the neural correlates of graph learning and statistical learning more broadly.
Functional traits explain growth resistance to successive hotter droughts across a wide set of common and future tree species in Europe
Authors: Kretz Lena , Schnabel Florian , Richter Ronny , Raabgrund Anika , Kattge Jens , Andraczek Karl , Kahl Anja , Künne Tom , Wirth Christian
Published: July 2024

In many regions worldwide, forests suffer from climate change-induced droughts. The ‘hotter drought’ in Europe in 2018 with the consecutive drought years 2019 and 2020 caused large-scale growth declines and forest dieback. We investigated if tree growth responses to the 2018–2020 drought can be explained by tree functional traits related to drought tolerance, growth, and resource acquisition.

We assessed growth resistance, that is, growth during drought compared to pre-drought-conditions, in 71 planted tree species using branch shoot increments. We leveraged gap-filled trait data related to drought tolerance (P50, stomata density and conductivity), growth and resource acquisition (SLA, LNC, C:N, Amax) and wood density from the TRY database to explain growth resistance for gymnosperms and angiosperms.

We found significantly reduced growth during drought across all species. Legacy effects further decreased growth resistance in 2019 and 2020. Gymnosperms showed decreasing growth resistance with increasing P50 and acquisitiveness, such as high SLA, LNC, and Amax. Similar results were found for angiosperms, however, with less clear pattern. Four distinct response types emerged: ‘Sufferer’, ‘Late sufferer’, ‘Recoverer’ and ‘Resisters’, with gymnosperms predominately falling into the ‘Sufferer’ and ‘Late sufferer’ categories.

Our study provides evidence for significant growth reductions and legacy effects in response to consecutive hotter droughts, which can be explained by functional traits across a wide set of tree species. The a posteriori classification into response types revealed the diversity of temporal responses to a prolonged drought. We conclude that high drought tolerance bolsters growth resistance, while acquisitive species suffer stronger under drought.
Microglial low-affinity FcγR mediates the phagocytic elimination of dopaminergic neurons in Parkinson’s disease degeneration
Authors: Casanova P.V. , Saavedra-López E. , Freitag-Berenguel I. , Usandizaga M. , Martínez-Remedios P. , Giménez-Montes C. , Clinton E. , Roig-Martínez M. , Cribaro G.P. , Barcia C
Published: July 2024

Microglia-mediated neuroinflammation contributes to dopaminergic (DA) neurodegeneration in Parkinson’s disease (PD). It is thought that microglial cells interact with DA neurons of the substantia nigra pars compacta (SNpc), the most vulnerable region in parkinsonian neuropathology, playing a critical role through the process of neuronal loss. However, the specific mechanisms by which microglial reactivity is triggered and exerts such a deleterious effect remains unclear. Experimental models of PD in mice have shown that phagocytosis plays an essential role in the elimination of degenerating neurons, suggesting that blocking this microglial function could be beneficial to preserve remaining DA neurons. In the present work, we pinpoint the role of the Fcγ receptor (FcγR) as a potential trigger of microglial phagocytosis in PD. We found that the FcγR is overexpressed in the degenerating SNpc in postmortem samples of PD patients, alongside histological indications of phagocytic microglia. Likewise, experimental models of PD also show increased FcγR expression, together with evidence of similar phagocytosis events. Most importantly, blocking FcγRin vitro, by using neutralizing antibodies, reduced the microglial-mediated elimination of DA cells. High resolution imaging revealed that the FcγR is involved in phagocytic synapse formation, and appeared polarized, and segregated to actin-rich protruding cups, when interacting one-on-one towards single target DA cells. Additionally, by inhibiting FcγR downstream actin-polymerizing signaling Cdc42, microglia were unable to eliminate DA cells. Finally, experimentsin vivo, using an experimental model of PD in mouse, revealed that passive immunotherapy with FcγR neutralizing monoclonal antibodies, as well as inhibiting its downstream signaling Cdc42, protect DA neurons from elimination. These results indicate that the FcγR may be a critical factor inducing DA neuron phagocytosis in PD and suggest a novel immunotherapeutic strategy targeting microglia to preserve neuronal loss.
A pilot study for deciphering post-translational modifications and proteoforms of tau protein by capillary electrophoresis-mass spectrometry
Authors: Fang Fei , Xu Tian , Hagar Hsiao-Tien Chien , Hovde Stacy , Kuo Min-Hao , Sun Liangliang
Published: July 2024

Abnormal accumulation of tau proteins is one pathological hallmark of Alzheimer□s disease (AD). Many tau protein post-translational modifications (PTMs) are associated with the development of AD, such as phosphorylation, acetylation, and methylation. Therefore, a complete picture of PTM landscape of tau is critical for understanding the molecular mechanisms of AD progression. Here, we offered a pilot study of combining two complementary analytical techniques, capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) and reversed-phase liquid chromatography (RPLC)-MS/MS, for bottom-up proteomics of recombinant human tau-0N3R. We identified 53 phosphorylation sites of tau-0N3R in total, which is about 30% higher than that from RPLC-MS/MS alone. CZE-MS/MS provided more PTM sites (i.e., phosphorylation) and modified peptides of tau-0N3R than RPLC-MS/MS, and its predicted electrophoretic mobility helped improve the confidence of the identified modified peptides. We developed a highly efficient capillary isoelectric focusing (cIEF)-MS technique to offer a bird’s-eye view of tau-0N3R proteoforms, with 11 putative tau-0N3R proteoforms carrying up to nine phosphorylation sites and lower pI values from more phosphorylated proteoforms detected. Interestingly, under a native-like cIEF-MS condition, we observed three putative tau-0N3R dimers carrying phosphate groups. The findings demonstrate that CE-MS is a valuable analytical technique for the characterization of tau PTMs, proteoforms, and even oligomerization.
Assessing nutritional pigment content and plant health status of green and red leafy vegetables by image analysis: Catching the “red herring” of plant digital color processing
Authors: Agarwal Avinash , Colwell Filipe de Jesus , Galvis Viviana Andrea Correa , Hill Tom , Boonham Neil , Prashar Ankush
Published: July 2024

Estimating pigment content in leafy vegetables via digital image analysis is a reliable method for real-time assessment of plant health status and nutritive value. However, the present leaf color analysis models developed using green-leafed plants do not perform reliably while analyzing images of anthocyanin-rich leaves, often giving misleading or “red herring” trends. Hence, the present study investigates variations in different digital color features for six types of leafy vegetables with varying levels of laminar anthocyanin to identify holistic digital color analysis models that could be implemented for real-time assessment of health status as well as nutritional pigment contents of leafy vegetables irrespective of laminar anthocyanin status. For this, datasets from three digital color spaces, viz., RGB (red, green, blue), HSI (hue, saturation, intensity), andL*a*b*(lightness, redness-greenness, yellowness-blueness), were compared with pigment contents ofn= 320 leaf samples, and were analyzed via linear and non-linear regression using single variables, multiple linear regression, Support Vector regression, and Random Forest regression to predict chlorophyll and anthocyanin contents. While most digital color features presented abrupt shifts between anthocyanin-rich and low-anthocyanin samples, the R digital color feature did not show any deviation due to leaf anthocyanin content and was found to have the best correlation with SPAD chlorophyll meter readings (R2= 0.83). Concomitantly, H (R2= 0.82) anda*(R2= 0.79) features correlated most strongly with leaf anthocyanin content. In general, prediction of pigment contents was more accurate when data from all channels within a color space was analyzed simultaneously. Further, most reliable estimates of pigment content were provided by Support Vector and Random Forest regression models (0.7 <R2< 0.85). Thus, the present findings demonstrate how digital color analysis of green as well as anthocyanin-rich leafy vegetables could be implemented for assessing plant health status and nutritional pigment content non-invasively.
Astroglial atrophy associates with loss of nuclear S100A10 in the hippocampus of aged male tree shrews
Authors: Rodriguez-Callejas Juan D. , Irene-Fierro Mariangel , Aguilar-Navarro Sara , Fuchs Eberhard , Perez-Cruz Claudia
Published: July 2024

Astrocytes are glial cells that participate in multiple physiological functions, such as protecting neurons against all types of damage. However, astrocytes develop morphological alterations during aging, such as decreased length, volume, and branch points of their processes, also known as astrocytic atrophy. Until now, the exact mechanism associated with the onset of atrophy is unknown. Tree shrew (Tupaia belangeri) is a long-lived animal from the Scadentia order that develops several age-dependent brain alterations. In this study, we analyzed the morphology of GFAP+ astrocytes in the hippocampal region of adult, old, and aged male tree shrews. Aged animals presented more GFAP+ astrocytes in the proximal subiculum, CA3, and CA2-CA1 subregions than younger animals, being significantly higher only in CA3. However, in aged subjects, the number of atrophic astrocytes was significantly higher in the dentate gyrus and CA2 subregion compared to old animals. Interestingly, in the proximal subiculum, astrocytes had a reduced arborization at all ages evaluated. S100A10, a protein overexpressed by neuroprotective-type astrocytes, was mainly found in the nucleus of astrocytes of adult and old subjects. However, in old and aged animals, S100A10 was located in the cytoplasmic compartment of atrophic astrocytes. Furthermore, in astrocytes of aged tree shrews, cytoplasmic inclusions of S100A10 colocalized with the nuclear export protein, Crm-1. These results suggest that the transport of S100A10 from the nucleus to the cytoplasmic compartment of astrocytes could be a process related to astroglial atrophy during the aging process in the hippocampus of three shrews.
Enhancing Perceptual, Attentional, and Working Memory Demands through Variable Practice Schedules: Insights from High-Density EEG Multi-Scale Analyses
Authors: Cretton Alexandre , Schipper Kate , Hassan Mahmoud , Ruggeri Paolo , Barral Jérôme
Published: July 2024

Contextual interference (CI) enhances learning by practicing motor tasks in a random order rather than a blocked order. One hypothesis suggests that the benefits arise from enhanced early perceptual/attentional processes, while another posits that better learning is due to highly activated mnemonic processes. We propose to harness high-density electroencephalography in a multi-scale analysis approach, including topographic analyses, source estimations, and functional connectivity, to examine the intertwined dynamics of attentional and mnemonic processes within short time windows. We recorded scalp activity from 35 participants as they performed an aiming task at three different distances, under both random and blocked conditions using a crossover design. Our results showed that topographies associated with processes related to perception/attention (N1, P3a) and working memory (P3b) were more pronounced in the random condition. Source estimation analyses supported these findings, revealing greater involvement of the perceptual ventral pathway and the anterior cingulate and parietal cortices, along with increased functional connectivity in ventral alpha and frontoparietal theta band networks during random practice. Our results suggest that CI is driven, in the random compared to the blocked condition, by enhanced specific processes such as perceptual, attentional, and mnemonic, as well as large-scale general processes.
Delayed accumulation of inhibitory input explains gamma frequency variation with changing contrast in an Inhibition Stabilized Network
Authors: Krishnakumaran R , Pavuluri Abhimanyu , Ray Supratim
Published: July 2024

Gamma rhythm (30-70 Hz), thought to represent the push-pull activity of excitatory and inhibitory population, can be induced by presenting achromatic gratings in the primary visual cortex (V1) and is sensitive to stimulus properties such as size and contrast. In addition, gamma occurs in short bursts, and shows a “frequency-falloff” effect where its peak frequency is high after stimulus onset and slowly decreases to a steady state. Recently, these size-contrast properties and temporal characteristics were replicated in a self-oscillating Wilson-Cowan (WC) model operating as an Inhibition stabilized network (ISN), stimulated by Ornstein-Uhlenbeck (OU)-type inputs. In particular, frequency-falloff was explained by delayed and slowly accumulated inputs arriving at local inhibitory populations. We hypothesized that if the stimulus is preceded by another higher contrast stimulus, frequency-falloff could be abolished or reversed, since the excessive inhibition will now take more time to dissipate. We presented gratings at different contrasts consecutively to two female monkeys while recording gamma using microelectrode arrays in V1 and confirmed this prediction. Further, this model also replicated a characteristic pattern of gamma frequency modulation to counter-phasing stimuli as reported previously. Thus, the ISN model with delayed surround input replicates gamma frequency responses to time-varying contrasts.

Significance statement

Gamma rhythms represent sustained push-pull dynamics between excitatory and inhibitory populations during visual stimulation. Gamma power and centre frequency varies depending on stimulus features, and onset of stimulus produces a “frequency-fall” trend where onset frequency is higher and subsequently plateaus to a lower value. In an earlier work, we argued, using a noisy rate-model of V1, that a delayed onset of inhibition-drive from the surround populations produced the gamma ‘frequency-falloff’. We tested a key prediction of this hypothesis that the frequency-falloff can be abolished or reversed if the stimulus is preceded by a higher contrast stimulus, and confirmed the same by recording from primate primary visual cortex while presenting multiple stimuli consecutively at varying contrasts.
Exploring Effector Protein Dynamics and Natural Fungicidal Potential in Rice Blast PathogenMagnaporthe oryzae
Authors: Ferdausi Jannatul , Robin Tanjin Barketullah , Nasrin Sanjida , Ahmed Istiak , Hossain Tawsif , Hasan Md Mehedi , Soaeb Mehrab Hassan , Tamim Md. Ahsanul , Yeasmin Nusrat Jahan , Habiba Ummay , Ahmed Nadim , Rani Nurul Amin , Bhuyian Md Shishir , Vakare Suvarna N. , Moin Abu Tayab , Patil Rajesh B. , Hossain Mohammad Shahadat
Published: July 2024

Rice blast, caused byMagnaporthe oryzae, is a severe agricultural disease leading to significant global economic losses. Genetic and genomic investigations have identified crucial genes and pathways involved in its pathogenesis, particularly highlighting effector proteins like AvrPik variants and MAX proteins. These proteins interact with specific Pik alleles on rice chromosome 11, influencing host immune responses. This study focused on 35 plant-derived metabolites known for their antifungal properties, evaluating their potential as fungicidal agents against M. oryzae. Molecular docking analyses identified Hecogenin and Cucurbitacin E as highly effective binders to MAX40 and APIKL2A proteins, respectively, which are pivotal for fungal virulence and immune evasion. Molecular dynamics simulations further validated strong and stable interactions, affirming the therapeutic potential of these compounds. Additional assessments including Lipinski’s rule of five criteria and toxicity predictions indicated their suitability for agricultural use. These findings underscore the promise of Hecogenin and Cucurbitacin E as lead candidates in developing novel fungicidal strategies against rice blast, offering prospects for enhanced crop protection and agricultural sustainability.
eLemur: A cellular-resolution 3D atlas of the mouse lemur brain
Authors: Jeon Hyungju , Kim Jiwon , Kim Jayoung , Choi Yoon Kyoung , Ho Andy Chun Lum , Pifferi Fabien , Huber Daniel , Feng Linqing , Kim Jinhyun
Published: July 2024

The gray mouse lemur (Microcebus murinus), one of the smallest living primates, emerges as a promising model organism for neuroscience research. This is due to its genetic similarity to humans, its evolutionary position between rodents and humans, and its primate-like features encapsulated within a rodent-sized brain. Despite its potential, the absence of a comprehensive reference brain atlas impedes the progress of research endeavors in this species, particularly at the microscopic level. Existing references have largely been confined to the macroscopic scale, lacking detailed anatomical information. Here, we present eLemur, a new resource, comprising a repository of high-resolution brain-wide images immunostained with multiple cell type and structural markers, elucidating the cyto- and chemoarchitecture of the mouse lemur brain. Additionally, it encompasses a segmented two-dimensional (2D) reference and 3D anatomical brain atlas delineated into cortical, subcortical, and other vital regions. Furthermore, eLemur includes a comprehensive 3D cell atlas, providing densities and spatial distributions of non-neuronal and neuronal cells across the mouse lemur brain. Accessible via a web-based viewer (https://eeum-brain.com/#/lemurdatasets), the eLemur resource streamlines data sharing and integration, fostering the exploration of new hypotheses and experimental designs using the mouse lemur as a model organism. Moreover, in conjunction with the growing 3D datasets for rodents, non-human primates, and humans, our eLemur 3D digital framework enhances the potential for comparative analysis and translation research, facilitating the integration of extensive rodent study data into human studies.