bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility and Acceptability of Mobile Phone-Based Surveys to Identify Mental Health Symptoms in Parents/Guardians of PICU Patients
Authors: Saju Leya , Smith Mallory B. , Ainsworth Elizabeth , Goldberg Jessica M. , Chertow Daniel J. , Hartman Mary E.
Published: July 2024

OBJECTIVE:

Parents experience psychologic distress during their child’s admission to a PICU, but effective screening for parental mental health symptoms is not the standard of care. We aimed to test the feasibility and acceptability of a mobile phone-based mental health survey for parents/guardians of PICU patients to facilitate their support by the PICU team.

DESIGN:

Post hoc analysis of a single-institution pilot study conducted in 2022. Mental health surveys were delivered by text message to parents/guardians of PICU patients over 1 month, beginning 3 days after their child’s PICU admission. In-person interviews 1 month after hospital discharge were used to solicit participants’ opinions on the survey platform and content.

SETTING:

A quaternary U.S. academic medical center.

PARTICIPANTS:

Parents/guardians of PICU patients.

INTERVENTIONS:

None.

MEASUREMENT AND MAIN RESULTS:

Of the 53 participants who consented, 31 (58%) completed the study. Symptoms of acute stress (ASS) were the most common and most severe: 21 participants screened positive for ASS, and 20 of those that screened positive had “moderate” or “severe” symptoms. Among the 23 participants who screened positive for one mental health condition, 10 met the thresholds for all three. Scoring of the protocol’s usability, acceptability, and feasibility showed a System Usability Scale equal to 82 of 100, an Acceptability of Intervention Measure score equal to 4.2 of 5, an Intervention Appropriateness Measure score equal to 4.5 of 5, and Feasibility of Intervention Measure score equal to 4.5 of 5.

CONCLUSIONS AND RELEVANCE:

Mobile phone-based screening for parental mental health symptoms is acceptable and may offer the advantage of privacy and flexibility.
Artificial Intelligence in Medical Education and Mentoring in Rehabilitation Medicine
Authors: Silver Julie K. , Dodurgali Mustafa Reha , Gavini Nara
Published: July 2024

Artificial intelligence emerges as a transformative force, offering novel solutions to enhance medical education and mentorship in the specialty of physical medicine and rehabilitation. Artificial intelligence is a transformative technology that is being adopted in nearly every industry. In medicine, the use of artificial intelligence in medical education is growing. Artificial intelligence may also assist with some of the challenges of mentorship, including the limited availability of experienced mentors, and the logistical difficulties of time and geography are some constraints of traditional mentorship. In this commentary, we discuss various models of artificial intelligence in medical education and mentoring, including expert systems, conversational agents, and hybrid models. These models enable tailored guidance, broaden outreach within the physical medicine and rehabilitation community, and support continuous learning and development. Balancing artificial intelligence’s technical advantages with the essential human elements while addressing ethical considerations, artificial intelligence integration into medical education and mentorship presents a paradigm shift toward a more accessible, responsive, and enriched experience in rehabilitation medicine.
Diagnostic Discrepancies in the Emergency Department: A Retrospective Study
Authors: Schols Laurens A. , Maranus Myrthe E. , Rood Pleunie P.M. , Zwaan Laura
Published: July 2024

Objectives

Diagnostic errors contribute substantially to preventable medical errors. Especially, the emergency department (ED) is a high-risk environment. Previous research showed that in 15%–30% of the ED patients, there is a difference between the primary diagnosis assigned by the emergency physician and the discharge diagnosis. This study aimed to determine the number and types of diagnostic discrepancies and to explore factors predicting discrepancies.

Methods

A retrospective record review was conducted in an academic medical center. The primary diagnosis assigned in the ED was compared with the discharge diagnosis after hospital admission. For each patient, we gathered additional information about the diagnostic process to identify possible predictors of diagnostic discrepancies.

Results

The electronic health records of 200 patients were reviewed. The primary diagnosis assigned in the ED was substantially different from the discharge diagnosis in 16.0%. These diagnostic discrepancies were associated with a higher number of additional diagnostics applied for (2.4 versus 2.0 diagnostics; P = 0.002) and longer stay in the ED (5.9 versus 4.7 hours; P = 0.008).

Conclusions

A difference between the diagnosis assigned by the emergency physician and the discharge diagnosis was found in almost 1 in 6 patients. The increased number of additional diagnostics and the longer stay at the ED in the group of patients with a diagnostic discrepancy suggests that these cases reflect the more difficult cases. More research should be done on predictive factors of diagnostic discrepancies.
Free Fibular Osteocutaneous Flap Combined With Simultaneous Tendon Reconstruction for Midfoot Restoration After Myoepithelial Carcinoma Resection
Authors: Kuo Yu-Chen , Lee Jian-Jr , Wee Shyun-Jing
Published: July 2024

Myoepithelial carcinomas of soft tissue are rare, and most are malignant. The optimal treatment is surgical excision. The arches of the foot are a composite structure responsible for weight bearing and pressure distribution, so it is a vast challenge in reconstruction. We report a case of reconstruction of the midfoot with a free fibular bone flap and tendon graft. We review the literature to compare various options in foot reconstructions and sort out the outcomes of different bone flaps. The free fibula osteocutaneous flap is the superior choice for midfoot reconstruction owing to its sufficient length, strength, flexible skin paddles, easy-to-withstand osteotomy, and simultaneous tendon graft harvesting.
The Learning Curve of Total Breast Reconstruction With Autologous Fat Transfer
Authors: Rijkx Maud , Saelmans Alexander , Hommes Juliette , Brandts Lloyd , De Bruijn Daisy ,   Breast Reconstruction With External Preexpansion & autologous Fat Transfer vs Standard Therapy (BREAST) Trial Investigators, Piatkowski Andrzej , Heuts Esther
Published: July 2024

Introduction

Total breast reconstruction with autologous fat transfer (AFT) is a relatively new breast reconstruction method. Although AFT was predominantly used to correct postsurgical defects, the surgical skills of a total breast reconstruction with AFT are different and can be facilitated for novices to accelerate their learning process. This study aims to assess the learning curve of plastic surgeons in total breast reconstruction with AFT in the Netherlands.

Methods

A mixed-methods study was performed based on the multicenter randomized clinical BREAST trial data. For the qualitative analysis, semistructured interviews were conducted. To test hypotheses derived from the qualitative data, retrospective data analysis was performed using multilevel linear regression analysis of the patients undergoing AFT as a total breast reconstruction method.

Results

The interviews revealed that plastic surgeons need to perform the procedure several times to learn and experience the technical details of total breast reconstruction with AFT. Learning and improving this technique works best by scrubbing in with an expert. Before plastic surgeons learn the optimal volume of fat reinjection over time, they tend to inject too little fat and subsequently too much fat over multiple procedures. With more experience, the rigottomy technique becomes more important. Besides technical details, managing patient expectations before starting treatment is paramount. Multilevel linear regression revealed a significant decrease (P < 0.001) in the number of surgical procedures and the total injected volume (P = 0.002) to complete a total breast reconstruction with AFT.

Conclusions

This is the first study that explores the learning curve involved in using AFT as a total breast reconstruction method. The feeling of when fat transfer is sufficient, and how to release scars for a good result without causing seromas, is best learned by scrubbing in with experienced colleagues during several procedures, interchanged with starting one's own practice.
Snowflake Amniotic Membrane in Scalp Reconstruction for Pitbull Bite
Authors: Treger Dylan , Sturm Savanah , Thaller Seth R.
Published: July 2024

Amniotic membrane, derived from the innermost placenta, is widely employed in surgery to help regenerate soft tissue and promote re-epithelialization. The authors detail a case report of a 59-year-old female who presented with a large, full-thickness scalp avulsion injury (13 × 10 cm) after being attacked by her pet pitbull. Innovative application of “snowflake” or fragmented amniotic membrane to her wound bed was used during both stages of scalp reconstruction: irrigation and debridement with Integra biological membrane placement and later split-thickness skin grafting. The patient had an uncomplicated recovery with a satisfactory cosmetic outcome. The authors believe that the “snowflake” application of amniotic membrane played an important role in forming healthy granulation tissue and optimizing the wound bed for definitive coverage. “Snowflake” amniotic membrane may help maximize its mechanical and biological benefits and holds promise to be an important adjunctive treatment for surgical wound healing.
Late-onset myopathies
Authors: Salort-Campana Emmanuelle , Attarian Shahram
Published: July 2024

Purpose of review

Late-onset myopathies are defined as muscle diseases that begin after the age of 50 years. Some myopathies present classically in the elderly, whereas others may have a variable age of onset, including late-onset presentation. The purpose of this review is to summarize and comment on the most recent evidence regarding the main diagnosis of late-onset myopathies focusing on genetic causes.

Recent findings

Although late-onset myopathies (LOM) are expected to be predominantly acquired myopathies, some common genetic myopathies, such as facioscapulohumeral muscular dystrophy (FSHD), can present late in life, usually with an atypical presentation. In addition, metabolic myopathies, which are classically early-onset diseases, are also diagnoses to be considered, particularly as they may be treatable. Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) has recently been identified as a cause of subacute LOM with a dramatic response to riboflavin supplementation.

Inclusion body myositis is the most frequent of all LOM. Myotonic dystrophy type 2, FSHD and oculopharyngeal muscular dystrophy are the most frequent causes of genetic LOM. We summarize the major differential diagnoses and the clinical features on clinical examination that are suggestive of a genetic diagnosis to provide a diagnostic approach.
Linking discrete and continuous models of cell birth and migration
Authors: Martinson W. Duncan , Volkening Alexandria , Schmidtchen Markus , Venkataraman Chandrasekhar , Carrillo José A.
Published: July 2024

Self-organization of individuals within large collectives occurs throughout biology. Mathematical models can help elucidate the individual-level mechanisms behind these dynamics, but analytical tractability often comes at the cost of biological intuition. Discrete models provide straightforward interpretations by tracking each individual yet can be computationally expensive. Alternatively, continuous models supply a large-scale perspective by representing the ‘effective’ dynamics of infinite agents, but their results are often difficult to translate into experimentally relevant insights. We address this challenge by quantitatively linking spatio-temporal dynamics of continuous models and individual-based data in settings with biologically realistic, time-varying cell numbers. Specifically, we introduce and fit scaling parameters in continuous models to account for discrepancies that can arise from low cell numbers and localized interactions. We illustrate our approach on an example motivated by zebrafish-skin pattern formation, in which we create a continuous framework describing the movement and proliferation of a single cell population by upscaling rules from a discrete model. Our resulting continuous models accurately depict ensemble average agent-based solutions when migration or proliferation act alone. Interestingly, the same parameters are not optimal when both processes act simultaneously, highlighting a rich difference in how combining migration and proliferation affects discrete and continuous dynamics.
An agent-based modelling framework to study growth mechanisms in
EGFR-L858R
mutant cell alveolar type II cells
Authors: Coggan Helena , Weeden Clare E. , Pearce Philip , Dalwadi Mohit P. , Magness Alastair , Swanton Charles , Page Karen M.
Published: July 2024

Mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC), particularly in never-smoker patients. However, these mutations are not always carcinogenic, and have recently been reported in histologically normal lung tissue from patients with and without lung cancer. To investigate the outcome of EGFR mutation in healthy lung stem cells, we grow murine alveolar type II organoids monoclonally in a three-dimensional Matrigel. Our experiments show that the
EGFR-L858R
mutation induces a change in organoid structure: mutated organoids display more ‘budding’, in comparison with non-mutant controls, which are nearly spherical. We perform on-lattice computational simulations, which suggest that this can be explained by the concentration of division among a small number of cells on the surface of the mutated organoids. We are currently unable to distinguish the cell-based mechanisms that lead to this spatial heterogeneity in growth, but suggest a number of future experiments which could be used to do so. We suggest that the likelihood of L858R-fuelled tumorigenesis is affected by whether the mutation arises in a spatial environment that allows the development of these surface protrusions. These data may have implications for cancer prevention strategies and for understanding NSCLC progression.
Structure and composition of a canopy-beetle community (Coleoptera) in a Neotropical lowland rainforest in southern Venezuela
Authors: Kirmse Susan
Published: July 2024

Species richness, community structure and taxonomic composition are important characteristics of biodiversity. Beetle communities show distinct diversity patterns according to habitat attributes. Tropical rainforest canopies, which are well known for their richness in Coleoptera, represent such a conspicuous life zone. Here, I describe a canopy-inhabiting beetle community associated with 23 tree species in a Neotropical lowland rainforest. Adult beetles were sampled manually and in aerial traps using a large tower crane for a cumulative year. The sample revealed 6738 adult beetles, which were assigned to 862 (morpho-)species in 45 families. The most species-rich beetle families were Curculionidae (
n
= 246), Chrysomelidae (
n
= 121) and Cerambycidae (
n
= 89). The most abundant families were Curculionidae (
n
= 2746) and Chrysomelidae (
n
= 1409). Dominant beetle families were found in most assemblages. The beetle community consisted of 400 singletons (46.4%). A similar proportion was evident for assemblages of single tree species. I found that 74.5% of all beetle species were restricted in their occurrence on host trees to the phenological season and time of the day. This daily and seasonal migration causes patterns similar to mass effects and therefore accounts for the high proportion of singletons.
Enhanced interfacial capture with an elliptical cylinder
Authors: Tan Dongwen , Zhang Wanqiu , Zhang Qi , Zhou Xinping
Published: July 2024

Interfacial capture of particles and droplets is important in practical applications. Interfacial capture owing to the surface tension force occurs only when the target (particle or droplet) is close to the collector, leading to low efficiency with collector or collector arrays. An elliptical cylinder instead of a common circular cylinder is a method to enhance capture efficiency. We theoretically investigate this situation by modelling the motion of floating particles around a surface-piercing elliptical cylindrical collector at Reynolds numbers of 1–10. Results indicate that, despite a smaller capture width, elliptical cross-sections, especially with smaller aspect ratios, are more efficient in capturing owing to a much smaller contact line perimeter compared with circular cross-sections. The aligned orientation (the major axis is parallel to the flow) is better than the orthogonal orientation (the major axis is perpendicular to the flow) owing to a larger capture width. A larger collector is beneficial to capillary capture but a very large size is adverse. Smaller but heavier floating particles for smaller capillary numbers can be easily captured at lower Reynolds numbers. The aligned orientation has a greater advantage over the circular cross-section and the orthogonal orientation in the capillary capture. This provides a good method for enhancing the capture efficiency of floating particles in applications.
The impact of urbanization on health depends on the health metric, life stage and level of urbanization: a global meta-analysis on avian species
Authors: Reid Rachel , Capilla-Lasheras Pablo , Haddou Yacob , Boonekamp Jelle , Dominoni Davide M.
Published: July 2024

Stressors associated with urban habitats have been linked to poor wildlife health but whether a general negative relationship between urbanization and animal health can be affirmed is unclear. We conducted a meta-analysis of avian literature to test whether health biomarkers differed on average between urban and non-urban environments, and whether there are systematic differences across species, biomarkers, life stages and species traits. Our dataset included 644 effect sizes derived from 112 articles published between 1989 and 2022, on 51 bird species. First, we showed that there was no clear impact of urbanization on health when we categorized the sampling locations as urban or non-urban. However, we did find a small negative effect of urbanization on health when this dichotomous variable was replaced by a quantitative variable representing the degree of urbanization at each location. Second, we showed that the effect of urbanization on avian health was dependent on the type of health biomarker measured as well as the individual life stage, with young individuals being more negatively affected. Our comprehensive analysis calls for future studies to disentangle specific urban-related drivers of health that might be obscured in categorical urban versus non-urban comparisons.
IFNγ initiates TLR9-dependent autoimmune hepatitis in DNase II deficient mice
Authors: Hao Kaiyuan , Gao Kevin MingJie , Strauss Melissa , Subramanian Sharon , Marshak-Rothstein Ann
Published: July 2024

Patients with biallelic hypomorphic mutation inDNASE2develop systemic autoinflammation and early-onset liver fibrosis. Prior studies showed that Dnase2-/-Ifnar-/-double knockout (DKO) mice develop Type I IFN-independent liver inflammation, but immune mechanisms were unclear. We now show that DKO mice recapitulate many features of human autoimmune hepatitis (AIH), including periportal and interstitial inflammation and fibrosis and elevated ALT. Infiltrating cells include CD8+ tissue resident memory T cells, type I innate lymphoid cells, and inflammatory monocyte/macrophage cells that replace the Kupffer cell pool. Importantly, TLR9 expression by bone marrow-derived cells is required for the the development of AIH. TLR9 is highly expressed by inflammatory myeloid cells but not long-lived Kupffer cells. Furthermore, the initial recruitment of TLR9 expressing monocytes and subsequent activation of lymphocytes requires IFNγ signaling. These findings highlight a critical role of feed forward loop between TLR9 expressing monocyte-lineage cells and IFNg producing lymphocytes in autoimmune hepatitis.
The longitudinal growth of the embryo of the kelpSaccharinadepends on actin filaments that control the formation of an alginate corset in the cell wall
Authors: Boscq Samuel , Theodorou Ioannis , Milstein Roman , Le Bail Aude , Chenivesse Sabine , Billoud Bernard , Charrier Bénédicte
Published: July 2024

The initiation of embryogenesis in the kelpSaccharina latissimais accompanied by significant anisotropy in cell shape. Using monoclonal antibodies, we show that this anisotropy coincides with a spatio-temporal pattern of accumulation of alginates in the cell wall of the zygote and embryo. Alginates rich in guluronates as well as sulphated fucans show a homogeneous distribution in the embryo throughout Phase I of embryogenesis, but mannuronate alginates accumulate mainly on the sides of the zygote and embryo, disappearing as the embryo enlarges at the start of Phase II. This pattern depends on the presence of cortical actin filaments. In contrast, within the embryo lamina, the alginate composition of the walls newly formed by cytokinesis is not affected by the depolymerisation of actin filaments. Thus, in addition to revealing the existence of a mannuronate-rich alginate corset that may restrict the enlargement of the zygote and the embryo, thereby promoting the formation of the apico-basal growth axis, we demonstrate stage- and cytoskeleton-dependent differences in cell wall deposition inSaccharinaembryos.
Resident memory T cells in dirty mice suppress innate cell activation and infiltration into the skin following stimulation with alarmins
Authors: Story Meaghan E. , Ferris Laura K. , Mathers Alicia R.
Published: July 2024

Trm cells are sequestered at barrier tissues as a swift first line defense against peripheral reinfections in both antigen dependent and antigen independent bystander modes. Trm cells are also capable of mediating autoimmune diseases, such as psoriasis, wherein autoreactive Trm cells are aberrantly activated. To quickly combat infections, activated Trm cells can stimulate the influx and activation of memory T cells and innate immune cells. However, there is significant heterogeneity in the inflammatory responses that Trm cell populations can induce, specifically in the activation of the innate profile. Most studies to date have utilized a reductionist approach to examine single Trm populations, specific pathogens, and defined tissues. Herein, we adopted a more holistic approach utilizing barrier-free ‘dirty’ mice to profile activated innate cells attracted to the skin in the presence of quiescent cutaneous Trm cells. Notably, dirty mice are a more human predictive model due to having a diverse microbial experience that leads to the development of a complete complement of Trm cells in the skin. We demonstrate that in the dirty mouse model mice have a significant reduction in cutaneous neutrophils and monocytes compared to SPF mice following local treatment with two separate innate stimuli. These findings reveal that cutaneous Trm cells have the capacity to temper the innate immune response and further substantiate the implication that Trm cells are heterogenous in their functions depending in large part on their tissue residency. However, in an autoimmune microenvironment Trm cells are capable of recruiting innate cells to the site of an exposure to a damage-associated molecular pattern. Likely due to the imbalance of IL-17 and IFN-γ.
The Once and Future Fish: 1300 years of Atlantic herring population structure and demography revealed through ancient DNA and mixed-stock analysis
Authors: Atmore Lane M. , van der Jagt Inge , Boilard Aurélie , Häberle Simone , Blevis Rachel , Dierickx Katrien , Quinlan Liz M. , Orton David C. , Hufthammer Anne Karin , Barrett James H. , Star Bastiaan
Published: July 2024

Atlantic herring populations have been the target of highly profitable coastal and pelagic fisheries in northern Europe for well over a thousand years. Their complex and intermingled population dynamics have sparked extensive debate over the impacts of historical overfishing and have complicated their sustainable management today. Recently developed tools – including diagnostic SNP panels for mixed-stock analysis – aim to improve population assignment for fisheries management, however, the biological relevance of such tools over long periods of time remains unknown. Here, we demonstrate the millennium-long applicability of diagnostic SNP panels and identify population perturbations associated with increasing exploitation pressure and climate change by analyzing whole genome data from modern and ancient herring specimens. We find that herring demographic cycles were likely within healthy ecosystem boundaries until the dramatic disruption of these cycles in the 20th century. We find only autumn-spawning herring in our archaeological remains spanning 900 years from 8 sites across Europe, supporting observations that the numerical dominance of specific spawning populations can demographically outcompete other herring types. We also obtain pre-archival aDNA evidence for the famous, cyclical “Bohuslän periods,” during which mass quantities of North Sea autumn-spawning herring congregated in the Skagerrak. Finally, the long-term applicability of diagnostic SNP panels underscores their highly cost-effective application for the genetic monitoring of herring stocks. Our results highlight the utility of ancient DNA and genomic analysis to obtain historical and natural insights in herring ecology and population dynamics with relevance for sustainable fisheries management.
Big Data in Myoelectric Control: Large Multi-User Models Enable Robust Zero-Shot EMG-based Discrete Gesture Recognition
Authors: Eddy Ethan , Campbell Evan , Bateman Scott , Scheme Erik
Published: July 2024

Myoelectric control, the use of electromyogram (EMG) signals generated during muscle contractions to control a system or device, is a promising modality for enabling always-available control of emerging ubiquitous computing applications. However, its widespread use has historically been limited by the need for user-specific machine learning models because of behavioural and physiological differences between users. Leveraging the publicly available 612-user EMG-EPN612 dataset, this work dispels this notion, showing that true zero-shot cross-user myoelectric control is achievable without user-specific training. By taking a discrete approach to classification (i.e., recognizing the entire dynamic gesture as a single event), a classification accuracy of 93.0% for six gestures was achieved on a set of 306 unseen users (who provided no training data), showing that big data approaches (compared to most EMG studies, which typically employ only 10-20 users) can enable robust cross-user myoelectric control. By organizing the results into a series of mini-studies, this work provides an in-depth analysis of discrete cross-user models to answer unknown questions and uncover new research directions. In particular, this work explores the number of participants required to build cross-user models, the impact of transfer learning for fine-tuning these models, and the effects of under-represented end-user demographics in the training data, among other issues. Additionally, in order to further evaluate the performance of the created cross-user models, a completely new data set was created (using the same recording device) that includes known covariate factors such as cross-day use and limb-position variability. The results show that the large data models can effectively generalize to new datasets and mitigate the impact of common confounding factors that have historically limited the adoption of EMG-based inputs.
Trichoderma afroharzianumT22 induces rhizobia and flavonoid-driven symbiosis to promote iron deficiency tolerance in garden pea
Authors: Thapa Asha , Hasan Md Rokibul , Kabir Ahmad H.
Published: July 2024

Iron (Fe) deficiency is a limiting factor for legumes, yet the role of beneficial fungi in mitigating Fe deficiency in garden pea is understudied. In this study,Trichoderma afroharzianumT22 colonized the roots of garden pea cultivars exposed to alkali-mediated Fe-deficiency in a host- specific manner. In Fe-deficient Sugar Snap, T22 improved growth parameters consistent with increased tissue Fe and rhizosphere siderophore. The split-root assay demonstrated that the beneficial effects of T22 on Fe deficiency mitigation are the result of a whole-plant association rather than localized root-specific effects. RNA-seq analysis showed 575 and 818 differentially expressed genes upregulated and downregulated in the roots inoculated with T22 under Fe deficiency. The upregulated genes were mostly involved in the flavonoid biosynthetic pathway (monooxygenase activity, ammonia-lyase activity, 4-coumarate-CoA ligase), along with genes related to mineral transport and redox homeostasis. Further, a flavonoid precursor restored plant health even in the absence of T22, confirming the role of microbial symbiosis in mitigating Fe deficiency. Interestingly, T22 restored the abundance of rhizobia, particularlyRhizobium leguminosarumandRhizobium indicum, along with the induction ofNifA,NifD, andNifHin nodules, suggesting a connection between T22 and rhizobia under Fe-starvation. Further, the elevated rhizosphere siderophore, root flavonoid, expression ofPsCoA(4-coumarate-CoA ligase) as well as the relative abundance ofTaAOX1andR. leguminosarumdiminished when T22 was substituted with exogenous Fe. This suggests that exogenous Fe eliminates the need for microbiome-driven Fe mobilization, while T22-mediated Fe mitigation depends on flavonoid- driven symbiosis andR. leguminosarumabundance. It was further supported by the positive interaction of T22 onR. leguminosarumgrowth in Fe-deficient media. Thus, the beneficial effect of T22 on rhizobia likely stems from their interactions, not just improved Fe status in plants. This study provides the first mechanistic insights into T22 interactions with host and rhizobia, advancing microbiome strategies to alleviate Fe deficiency in peas and other legumes.
Extracellular Vesicles from hiPSC-derived NSCs Protect Human Neurons against Aβ-42 Oligomers Induced Neurodegeneration, Mitochondrial Dysfunction and Tau Phosphorylation
Authors: Rao Shama , Madhu Leelavathi N , Babu Roshni Sara , Nagarajan Advaidhaa , Upadhya Raghavendra , Narvekar Esha , Shetty Ashok K
Published: July 2024

Background

One of the hallmarks of Alzheimer’s disease (AD) is the buildup of amyloid beta-42 (Aβ-42) in the brain, which leads to various adverse effects. Therefore, therapeutic interventions proficient in reducing Aβ-42-induced toxicity in AD are of great interest. One promising approach is to use extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) because they carry multiple therapeutic miRNAs and proteins capable of protecting neurons against Aβ-42-induced pathological changes. Therefore, thisin vitrostudy investigated the proficiency of hiPSC-NSC-EVs to protect human neurons derived from two distinct hiPSC lines from Aβ-42o-induced neurodegeneration.

Methods

We isolated hiPSC-NSC-EVs using chromatographic methods and characterized their size, ultrastructure, expression of EV-specific markers and proficiency in getting incorporated into mature human neurons. Next, mature human neurons differentiated from two different hiPSC lines were exposed to 1 µM Aβ-42 oligomers (Aβ-42o) alone or with varying concentrations of hiPSC-NSC-EVs. The protective effects of hiPSC-NSC-EVs against Aβ-42o-induced neurodegeneration, increased oxidative stress, mitochondrial dysfunction, impaired autophagy, and tau phosphorylation were ascertained using multiple measures and one-way ANOVA with Newman-Keuls multiple comparisons post hoc tests.

Results

Significant neurodegeneration was observed when human neurons were exposed to Aβ-42o alone. Notably, neurodegeneration was associated with elevated levels of oxidative stress markers malondialdehyde (MDA) and protein carbonyls (PCs), increased expression of proapoptotic Bax and Bad genes and proteins, reduced expression of the antiapoptotic gene and protein Bcl-2, increased expression of genes encoding mitochondrial complex proteins, decreased expression of autophagy-related proteins Beclin-1 and microtubule-associated protein 1 light chain 3B, and increased phosphorylation of tau. However, the addition of an optimal dose of hiPSC-NSC-EVs (6 x 109EVs) to human neuronal cultures exposed to Aβ-42o significantly reduced the extent of neurodegeneration, along with diminished levels of MDA and PCs, normalized expressions of Bax, Bad, and Bcl-2, and genes linked to mitochondrial complex proteins, and reduced tau phosphorylation.

Conclusions

The findings demonstrate that an optimal dose of hiPSC-NSC-EVs could significantly decrease the degeneration of human neurons induced by Aβ-42o. The results also support further research into the effectiveness of hiPSC-NSC-EVs in AD, particularly their proficiency in preserving neurons and slowing disease progression.
AoUPRS: A Cost-Effective and Versatile PRS Calculator for theAll of UsProgram
Authors: Khattab Ahmed , Chen Shang-Fu , Wineinger Nathan , Torkamani Ali
Published: July 2024

Background

The All of Us (AoU) Research Program provides a comprehensive genomic dataset to accelerate health research and medical breakthroughs. Despite its potential, researchers face significant challenges, including high costs and inefficiencies associated with data extraction and analysis. AoUPRS addresses these challenges by offering a versatile and cost-effective tool for calculating polygenic risk scores (PRS), enabling both experienced and novice researchers to leverage the AoU dataset for significant genomic discoveries.

Results

AoUPRS is implemented in Python and utilizes the Hail framework for genomic data analysis. It offers two distinct approaches for PRS calculation: the Hail MatrixTable (MT) and the Hail Variant Dataset (VDS). The MT approach provides a dense representation of genotype data, while the VDS approach offers a sparse representation, significantly reducing computational costs. In performance evaluations, the VDS approach demonstrated a cost reduction of up to 99.51% for smaller scores and 85% for larger scores compared to the MT approach. Both approaches yielded similar predictive power, as shown by logistic regression analyses of PRS for coronary artery disease, atrial fibrillation, and type 2 diabetes. The empirical cumulative distribution functions (ECDFs) for PRS values further confirmed the consistency between the two methods.

Conclusions

AoUPRS is a versatile and cost-effective tool that addresses the high costs and inefficiencies associated with PRS calculations using the AoU dataset. By offering both dense and sparse data processing approaches, AoUPRS allows researchers to choose the approach best suited to their needs, facilitating genomic discoveries. The tool’s open-source availability on GitHub, coupled with detailed documentation and tutorials, ensures accessibility and ease of use for the scientific community.
Pulsatile dynamics propagate crystalline order in the developingDrosophila eye
Authors: Couturier Lydie , Luna-Escalante Juan , Mazouni Khallil , Mestdagh Claire , Phan Minh-Son , Tinevez Jean-Yves , Schweisguth François , Corson Francis
Published: July 2024

Pattern formation in developing tissues often involves self-organization guided by positional information. In most tissues, however, its dynamics, and therefore the underlying logic, remain unknown. Examining self-organized patterning of the fly eye, we combine experiments and modeling to elucidate how rows of light-receiving units emerge in the wake of a traveling differentiation front to form a crystal-like array. Live imaging of the proneural factor Atonal reveals unanticipated oscillations at the front, which are produced by the successive activation of two distinct enhancers and associated with pulsatile Notch signaling. Our observations are inconsistent with current models of eye patterning, whereby each row of differentiating cells provides a negative template for the next. Instead, they inform a new relay model in which transient Notch signaling from differentiating cells provides a positive template for the onset of differentiation two rows ahead, conveying both temporal and spatial information to propagate oscillations and crystal-like order.
Parallel HIV-1 fitness landscapes shape viral dynamics in humans and macaques that develop broadly neutralizing antibodies
Authors: Shimagaki Kai S. , Lynch Rebecca M. , Barton John P.
Published: July 2024

Human immunodeficiency virus (HIV)-1 exhibits remarkable genetic diversity. An effective HIV-1 vaccine must therefore elicit antibodies that can neutralize many variants of the virus. While broadly neutralizing antibodies (bnAbs) have been isolated from HIV-1 infected individuals, a general understanding of the virus-antibody coevolutionary processes that lead to their development remains incomplete. We performed a quantitative study of HIV-1 evolution in humans and rhesus macaques, including individuals who developed bnAbs. We observed strong selection early in infection for mutations affecting HIV-1 envelope glycosylation and escape from autologous strain-specific antibodies, followed by weaker selection for bnAb resistance. The inferred fitness effects of HIV-1 mutations in humans and macaques were remarkably similar. Moreover, we observed a striking pattern of rapid HIV-1 fitness gains that precedes the development of bnAbs. Our work highlights strong parallels between infection in rhesus macaques and humans, and it reveals a quantitative evolutionary signature of bnAb development.
Composite Hedges Nanopores: A High INDEL-Correcting Codec System for Rapid and Portable DNA Data Readout
Authors: Zhao Xuyang , Li Junyao , Fan Qingyuan , Dai Jing , Long Yanping , Liu Ronghui , Zhai Jixian , Pan Qing , Li Yi
Published: July 2024

DNA, as the origin for the genetic information flow, has also been a compelling alternative to non-volatile information storage medium. Reading digital information from this highly dense but lightweighted medium nowadays relied on conventional next-generation sequencing (NGS), which involves ‘wash and read’ cycles for synchronization and the indel (insertion and deletion) errors rarely occur. However, these time-consuming cycles hinder the future of real-time data retrieval. Nanopore sequencing holds the promise to overcome the efficiency problem, but high indel error rates lead to the requirement of large amount of high-quality data for accurate readout using emerging NGS-based codec systems. Here we introduce Composite Hedges Nanopores (CHN), a nanopore-based codec scheme tailored for real-time data retrieval, capable of handling indel rates up to 15.9% and substitution rates up to 7.8%. The overall information density can be doubled from 0.59 to 1.17 by utilizing a degenerated eight-letter alphabet, where one composite strand will be projected into eight normal strands. We demonstrate that sequencing times of 20 and 120 minutes were sufficient for processing representative text and image files (7 and 115 composite strands), respectively. The time-diminishing deviations are mainly originated from the extremely uneven abundance among the composite strands (cross-group variation) as well as the huge inequality among the normal strands (in-group variation). Moreover, to achieve complete data recovery, it is estimated that text and image data require 4× and 8× physical redundancy (coverage) of composite strands, respectively. Our CHN codec system excels on both molecular design and equalized dictionary usage, laying a solid foundation for nucleic acid-based data retrieval and encoding approaching to real-time, applicable in both cloud and edge computing systems.
Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina
Authors: Wu Zhifei , Liao Baoshan , Ying Julia , Keung Jan , Zheng Zongli , Ahola Virpi , Xiong Wenjun
Published: July 2024

Harnessing the regenerative potential of endogenous stem cells to restore lost neurons is a promising strategy for treating neurodegenerative disorders. Müller glia (MG), the primary glial cell type in the retina, exhibit extraordinary regenerative abilities in zebrafish, proliferating and differentiating into neurons post-injury. However, the regenerative potential of mouse MG is limited by their inherent inability to re-enter the cell cycle, constrained by high levels of the cell cycle inhibitor p27Kip1 and low levels of cyclin D1. Here, we report a method to drive robust MG proliferation by adeno-associated virus (AAV)-mediated cyclin D1 overexpression and p27Kip1 knockdown. MG proliferation induced by this dual targeting vector was self-limiting, as MG did not undergo uncontrolled proliferation. As shown by single-cell RNA-sequencing, cell cycle reactivation led to suppression of interferon signaling, activation of reactive gliosis, and downregulation of glial genes in MG. Over time, the majority of the MG daughter cells retained the glial fate, resulting in an expanded MG pool. Interestingly, about 1% MG daughter cells expressed markers for retinal interneurons, suggesting latent neurogenic potential in a small MG subset. By establishing a safe, controlled method to promote MG proliferation in vivo while preserving retinal integrity, this work provides a valuable tool for combinatorial therapies integrating neurogenic stimuli to promote neuron regeneration.
Direct non-transcriptional link between brassinosteroid perception and cortical microtubule reorientation drives hypocotyl growth
Authors: Delesalle Charlotte , Montiel-Jorda Alvaro , Neveu Julie , Fujita Satoshi , Vert Grégory
Published: July 2024

Brassinosteroids (BRs) are steroid-type phytohormones that are essential for plant growth, development and adaptation to environmental stresses. BRs promote cell wall remodelling through extensive reprogramming of gene expression, thus impacting on cell elongation and hypocotyl growth. The existence of non-genomic responses to BRs is however still unclear. Here we identified and characterized a new family of BRI1-interacting proteins identified by yeast two hybrid named MBAPs. We confirmed using several complementary approaches that MBAPs are genuine BRI1 partners in plant cells. We demonstrated that MBAPs are localized to cortical microtubules (CMTs) underlying the plasma membrane using a short conserved helix and where they contact with and are phosphorylated by BRI1. Combinations ofmbaploss-of-function mutants showed hypersensitivity to BRs and establish MBAPs as negative regulators of BR responses. Surprisingly,mbapmutants showed unaffected typical downstream BR signaling readouts and BR target gene expression. Rather,mbapmutants displayed disordered CMT network and enhanced CMT reorganization upon BR perception. Altogether, our work shed light on the direct non-transcriptional connection between BR perception at the cell surface and CMT organization in the control of hypocotyl elongation.
Caenorhabditis elegansSynMuv B gene activity is down-regulated during a viral infection to enhance RNA interference
Authors: Seetharaman Ashwin , Galagali Himani , Linarte Elizabeth , Liu Mona H.X. , Cohen Jennifer D. , Chetal Kashish , Sadreyev Ruslan , Tate Alex J. , Montgomery Taiowa A. , Ruvkun Gary
Published: July 2024

Small RNA pathways regulate eukaryotic antiviral defense. Many of theCaenorhabditis elegansmutations that were identified based on their enhanced RNAi, the synMuv B genes, also emerged from unrelated genetic screens for increased growth factor signaling. The dozen synMuv B genes encode homologues of the mammalian dREAM complex found in nearly all animals and plants, which includes thelin-35/retinoblastoma oncogene. We show that a set of highly induced mRNAs in synMuv B mutants is congruent with mRNAs induced by Orsay RNA virus infection ofC. elegans. In wild type animals, a combination of a synMuv A mutation and a synMuv B mutation are required for the Muv phenotype of increased growth factor signaling. But we show that Orsay virus infection of a single synMuv A mutant can induce a Muv phenotype, unlike the uninfected single synMuv A mutant. This suggests that decreased synMuv B activity, which activates the antiviral RNAi pathway, is a defense response to viral infection. Small RNA deep sequencing analysis of various dREAM complex mutants uncovers distinct siRNA profiles indicative of such an siRNA response. We conclude that the synMuv B mutants maintain an antiviral readiness state even in the absence of actual infection. The enhanced RNAi and conservation of the dREAM complex mutants suggests new therapeutic avenues to boost antiviral defenses.
Spatial Transcriptomics and Single-Nucleus Multi-omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development
Authors: Xu Xiguang , Lin Yu , Yin Liduo , Serpa Priscila da Silva , Conacher Benjamin , Pacholac Christina , Carvallo Francisco , Hrubec Terry , Farris Shannon , Zimmerman Kurt , Wang Xiaobin , Xie Hehuang
Published: July 2024

Folate, an essential vitamin B9, is crucial for diverse biological processes including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Here, we employed mouse model and spatial transcriptomics and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.
Denoising, Deblurring, and optical Deconvolution for cryo-ET and light microscopy with a physics-informed deep neural network DeBCR
Authors: Li Rui , Yushkevich Artsemi , Chu Xiaofeng , Kudryashev Mikhail , Yakimovich Artur
Published: July 2024

Computational image-quality enhancement for microscopy (deblurring, denoising, and optical deconvolution) provides researchers with detailed information on samples. Recent general-purpose deep learning solutions advanced in this task. Yet, without consideration of the underlying physics, they may yield unrealistic and non-existent details and distortions during image restoration, requiring domain expertise to discern true features from artifacts. Furthermore, the large expressive capacity of general-purpose deep learning models requires more resources to train and use in applications. We introduce DeBCR, a physics-informed deep learning model based on wavelet theory to enhance microscopy images. DeBCR is a light model with a fast runtime and without hallucinations. We evaluated the image restoration performance of DeBCR and 12 current state-of-the-art models over 6 datasets spanning crucial modalities in advanced light microscopy and cryo-electron tomography. Leveraging optic models, DeBCR demonstrates superior performance in denoising, optical deconvolution, and deblurring tasks across both LM and cryo-ET modalities.