bluuebunny/crossref_metadata_2025 huggingface dataset:
Relapse Following Electroconvulsive Therapy for Schizophrenia: A Systematic Review and Meta-analysis
Authors: Aoki Nobuatsu , Tajika Aran , Suwa Taro , Kawashima Hirotsugu , Yasuda Kazuyuki , Shimizu Toshiyuki , Uchinuma Niina , Tominaga Hirotaka , Tan Xiao Wei , Koh Azriel H K , Tor Phern Chern , Nikolin Stevan , Martin Donel , Kato Masaki , Loo Colleen , Kinoshita Toshihiko , Furukawa Toshi A , Takekita Yoshiteru
Published: October 2024

Background

Evidence regarding schizophrenia relapse following acute electroconvulsive therapy (ECT) is sparse compared with that for depression, and we have no clear consensus on relapse proportions. We aimed to provide longitudinal information on schizophrenia relapse following acute ECT.

Study Design

This systematic review and meta-analysis included randomised controlled trials (RCTs) and observational studies on post-acute ECT relapse and rehospitalization for schizophrenia and related disorders. For the primary outcome, we calculated the post-acute ECT pooled relapse estimates at each timepoint (3, 6, 12, and 24 months post-acute ECT) using a random effects model. For subgroup analyses, we investigated post-acute ECT relapse proportions by the type of maintenance therapy.

Study Results

Among a total of 6413 records, 29 studies (3876 patients) met our inclusion criteria. The risk of bias was consistently low for all included RCTs (4 studies), although it ranged from low to high for observational studies (25 studies). Pooled estimates of relapse proportions among patients with schizophrenia responding to acute ECT were 24% (95% CI: 15-35), 37% (27-47), 41% (34-49), and 55% (40-69) at 3, 6, 12, and 24 months, respectively. When continuation/maintenance ECT was added to antipsychotics post-acute ECT, the 6-month relapse proportion was 20% (11-32).

Conclusion

Relapse occurred mostly within 6 months post-acute ECT for schizophrenia, particularly within the first 3 months. Relapse proportions plateaued after 6 months, although more than half of all patients could be expected to relapse within 2 years. Further high-quality research is needed to optimise post-acute ECT treatment strategies in patients with schizophrenia.
Carcass cutting yields and meat quality of market gilts managed with immunological suppression of ovarian function and estrus
Authors: Bohrer Benjamin M , Edler Roy , Galina Pantoja Lucina , Amodie Deborah , Mellencamp Martha A , Vonnahme Kimberly A
Published: October 2024

The objective of this study was to analyze the effects of immunological suppression of ovarian function and estrus (Improvest®; Zoetis Inc.) on carcass cutting yields and meat quality. A total of 1,080 gilts were allocated by weight and assigned to pens of 27 pigs/pen. Pens were then randomly selected to be managed with or without immunological suppression of ovarian function and estrus (IMP vs. CON). Improvest was administered to each IMP gilt on days 7 and 67 of the study. Pigs were marketed on day 89 (n = 8 heaviest gilts per pen), 103 (n = 8 next heaviest gilts per pen), and 117 (remaining pigs/pen) of the study. The heaviest 47 to 50 carcasses for each treatment from each marketing group were selected for carcass cutting tests and evaluation of meat quality the day following slaughter (approximately 32-h postmortem). A smaller subset of 18 to 20 pork loins per treatment from each marketing group were selected for meat quality evaluation following 14 d of postmortem storage. Carcasses were fabricated according to institutional meat purchase specifications (IMPS) and meat quality analyses included pH and instrumental color at 32-h postmortem and purge loss, pH, instrumental color, intramuscular fat (IMF), cooking loss, and star probe following 14 d of postmortem storage. Live performance data were analyzed using the pen as the experimental unit, while carcass data were analyzed using the individual carcass as the experimental unit. During the post-second dose period (measured from days 70 to 85), IMP gilts consumed 10.8% more feed (P < 0.01) and grew 13.5% faster (P < 0.01) compared with CON gilts. Hot carcass weight (HCW), and the weights of many cuts, were significantly influenced by the interaction of Improvest management and marketing group. Therefore, the focus was directed toward primal weights and merchandized cut weights when expressed as a percentage of HCW. When expressed as a percentage of HCW, primal-cut yield and merchandized-cut yield calculations were not different (P = 0.33 and P = 0.65, respectively) between CON and IMP gilts. Meat quality traits did not differ (P > 0.05) between CON and IMP gilts, with the exception of instrumental a* at 32-h postmortem which was 0.32 units greater for CON gilts compared with IMP gilts. In summary, managing market gilts with immunological suppression of ovarian function and estrus improves the rate of weight gain through increased feed intake; however, carcass-cutting yields were not significantly changed.
Validity of Myobradypterygius hauthali von Huene, 1927 (Ichthyosauria: Ophthalmosauria) from the Early Cretaceous of Chile and Argentina
Authors: Pardo-Pérez Judith , Zambrano Patricio , Malkowski Matthew , Lomax Dean , Villa-Martínez Rodrigo , Stinnesbeck Wolfgang , Frey Eberhard , Scapini Francisca , Gascó Cristina , Maxwell Erin E
Published: October 2024

Early Cretaceous ichthyosaurs were globally distributed pelagic marine reptiles, but many remains are fragmentary, creating a Northern Hemisphere diversity bias. A rich Hauterivian locality near the Tyndall Glacier inside Torres del Paine National Park in southern Chile yields important new data regarding ichthyosaurian diversity along the Pacific margin of Gondwana. These new data will contribute to clarifying questions regarding ichthyosaur taxonomy and the palaeobiogeographical relationships between the southern Gondwanan and Northern Hemisphere ichthyosaur groups during the Early Cretaceous. Here, we describe three new ichthyosaur specimens from this locality. Two of them are referred to Myobradypterygius hauthali, expanding the distribution of this species from the Barremian of Argentina to the Hauterivian of the Chilean Patagonia. This material shows that M. hauthali differs from Platypterygius platydactylus in forefin construction and scapular morphology, supporting its classification as a separate genus within Platypterygiinae. The third specimen is a large-bodied indeterminate ophthalmosaurine ichthyosaur. This record represents the southernmost record of Ophthalmosaurinae and the first occurrence of this group from the Cretaceous of the Southern Hemisphere. These discoveries show that ophthalmosaurines and platypterygiines continued to occur sympatrically in southernmost Gondwana during the Early Cretaceous, expanding the pattern documented in Europe to the Pacific region.
High retention rates of custom 3D printed titanium implants in complex pelvic reconstruction, a report on 106 consecutive cases over 10 years
Authors: Boyle Richard , Scholes Corey , Franks Daniel , Lodhia Amish , Harrison-Brown Meredith , Ebrahimi Milad , Guzman Maurice , Stalley Paul
Published: October 2024

Background

Access to custom 3D printed pelvic implants (3DPI) is improving for application in both arthroplasty revision and tumour reconstruction. There is limited evidence regarding the safety and outcomes of such implants for large bony defects of the pelvis.

Purpose

To report the incidence of complications, patient mortality and implant survival following pelvic reconstruction using custom 3Dprinted prostheses in the setting of extensive pelvic bone defects following pelvic tumour resection or failure of total hip arthroplasty (THA)

Methods

Patients who underwent reconstruction with a custom 3D printed pelvic prosthesis (3DPI) were identified from our clinical outcomes registry (Complex Reconstruction and Sarcoma Surgical Outcomes Registry; ANZCTRN 12621001421820). Indications for surgery, adverse events, reoperations and rates and modes of failure were recorded. Kaplan-Meier and multistate survival curves were generated for cumulative survival based on indication.

Results

One hundred and six procedures were completed(RevisionTHA = 33; TumourPelvis = 73) with a median follow up of 4.1 years, ranging from 0.6 to 10 years. Acetabular loosening was the most frequent indication for the RevisionTHA cohort, while indications for tumour varied across primary presentations, metastases and failures of previous resection/reconstruction. Intraoperative complications were observed in 4.1% (95%CI 1.1 - 12.3) of TumourPelvis cases. Overall implant retention was 96% (90 - 99). No mortality events were observed in the RevisionTHA cohort, with 5-year patient survival 79% (70-90) in the TumourPelvis cohort. Procedure-survival free from periprosthetic infection was 86% (74-100) in the RevisionTHA cohort and 85% (76 - 95) in the TumourPelvisCohort. Modelling adverse events using multistate survival models in both cohorts revealed complex time-varying presentation of adverse events, with a significant burden of reoperations and local tumour recurrence in the TumourPelvis cohort.

Conclusion

3DPIs are a safe and viable option for complex reconstruction of the pelvis across a range of oncological and non-oncological indications. The initial results of the present study provide important information to aid in counselling patients about such procedures and allocating healthcare resources for ongoing care. Further work is required to document functional and biomechanical outcomes in these patient populations.
ASSOCIATIONS OF AUTISTIC TRAITS AND AUTISM WITH INCONTINENCE AND CONSTIPATION IN A UK BIRTH COHORT
Authors: Gyamenah Prince , Burrows Kimberley , Rai Dheeraj , Joinson Carol
Published: October 2024

Background

There is evidence that children with autism/autistic traits have higher risks of incontinence and constipation, but no studies have examined this in a large community-based cohort.

Aim/Research question

are autistic traits and diagnosed autism prospectively associated with increased odds of incontinence and constipation in children and adolescents?

Methods

This was a population-based cohort study based on data from the Avon Longitudinal Study of Parents and Children (n=4233-4490 at age 9 years; n=3403-3697 at age 14). We used multivariable logistic regression to examine associations of parent-reported autistic traits (sociability, repetitive behaviours, social-communication, coherence) (at ages 3-9 years) and autism with incontinence (bedwetting, daytime-wetting, soiling) and constipation (parent-reported at age 9, self-reported at age 14). We adjusted for parity, maternal age at delivery, child’s sex and developmental level, maternal depression, and anxiety (antenatal and postnatal), and indicators of family socioeconomic status.

Results

Social-communication and speech coherence difficulties showed the strongest associations with incontinence, e.g. adjusted odds ratio (OR) and 95% confidence interval (CI) for the association between social-communication difficulties and daytime-wetting was 2.21 (1.47-3.32) and for coherence was 2.34 (1.60-3.43). The odds of soiling were also higher in children with social-communication (OR:1.88, 95%CI:1.28-2.75) and coherence difficulties (OR:2.04, 95%CI:1.43-2.93). Diagnosed autism was only associated with an increase in the odds of daytime-wetting (OR:3.18, 95%CI:1.44-7.02). At 14 years, there was less evidence of associations between autistic traits and incontinence but there was evidence of associations between autistic traits and constipation: social-communication (OR:1.68, 95%CI:1.13-2.49), coherence difficulties (OR:1.64, 95%CI:1.11-2.41). 5

Conclusions

Early assessment and treatment of incontinence/constipation should be considered for children with autistic traits.
Computational design of developable therapeutic antibodies: efficient traversal of binder landscapes and rescue of escape mutations
Authors: Dreyer Frédéric A. , Schneider Constantin , Kovaltsuk Aleksandr , Cutting Daniel , Byrne Matthew J. , Nissley Daniel A. , Wahome Newton , Kenlay Henry , Marks Claire , Errington David , Gildea Richard J. , Damerell David , Tizei Pedro , Bunjobpol Wilawan , Darby John F. , Drulyte Ieva , Hurdiss Daniel L. , Surade Sachin , Pires Douglas E. V. , Deane Charlotte M.
Published: October 2024

Developing therapeutic antibodies is a challenging endeavour, often requiring large-scale screening to produce initial binders, that still often require optimisation for developability. We present a computational pipeline for the discovery and design of therapeutic antibody candidates, which incorporates physics- and AI-based methods for the generation, assessment, and validation of developable candidate antibodies against diverse epitopes, via efficient few-shot experimental screens. We demonstrate that these orthogonal methods can lead to promising designs. We evaluated our approach by experimentally testing a small number of candidates against multiple SARS-CoV-2 variants in three different tasks: (i) traversing sequence landscapes of binders, we identify highly sequence dissimilar antibodies that retain binding to the Wuhan strain, (ii) rescuing binding from escape mutations, we show up to 54% of designs gain binding affinity to a new subvariant and (iii) improving developability characteristics of antibodies while retaining binding properties. These results together demonstrate an end-to-end antibody design pipeline with applicability across a wide range of antibody design tasks. We experimentally characterised binding against different antigen targets, developability profiles, and cryo-EM structures of designed antibodies. Our work demonstrates how combined AI and physics computational methods improve productivity and viability of antibody designs.
A curve fitting method for analysing starch granule size distributions in cereals
Authors: McNelly Rose , Briffa Amy , Yiasoumi Georgia , Uauy Cristobal , Matsushima Ryo , Seung David
Published: October 2024

Background and Objectives

The size distribution of starch granules is an important factor determining functional and nutritional properties of starch. However, a simple, standardised method for their analysis is lacking. Here, we developed an approach for estimating granule size parameters using a Python script that fits curves to volumetric granule size distributions generated using a Coulter counter.

Findings

The bimodal size distribution of starch from most wheat and barley cultivars could be best described with a mixed distribution curve. A log-normal distribution was fitted to the small B-type granules, and a normal distribution was fitted to the large A-type granules, allowing estimation of their relative abundance and size parameters, despite their overlapping size distributions. However, the optimal fitting is altered in wheat mutants with large perturbations in B-type granule content. In maize and rice, which have unimodal granule size distributions, size parameters were calculated by fitting a single normal distribution.

Conclusions

Curve fitting is an effective approach for estimating starch granule size parameters in diverse cereals, particularly the Triticeae with A- and B-type granules.

Significance and novelty

We provide new tools and guidelines for the quantitative analysis of granule size in cereals.
Aperiodic neural excitation of the prefrontal cortex offsets age-related decrease in hippocampal theta activity for spatial memory maintenance
Authors: Park Sang-Eon , Donoghue Thomas , Jacobs Joshua , Lee Sang Ah
Published: October 2024

Currently, there is a critical gap in age-related electrophysiological changes in the human brain and how they are correlated with individual decline and maintenance of spatial cognitive function. To characterize these complex neurocognitive changes using direct intracranial recordings, we isolated periodic band power from the aperiodic spectral slope from iEEG power spectra of 69 presurgical epilepsy patients between 19 and 61 years of age while they performed a virtual spatial navigation task. We found a flattening of aperiodic spectral slope in the prefrontal cortex, but also observed a steepening in the hippocampus, suggestive of region-specific changes in excitatory/inhibitory balance across aging. The hippocampus showed pronounced changes in periodic (oscillatory) activity, including a decrease in theta power that correlated with impaired spatial memory, potentially due to changes in the cholinergic system. Interestingly, individuals with the flatter spectral slope in DLPFC showed preserved performance despite lower hippocampal theta, indicating a potential compensatory mechanism for cognitive maintenance. These findings provide new evidence that individual age-related cognitive decline can be predicted by changes in hippocampal theta oscillation, in combination with concomitant prefrontal compensatory mechanisms.
Bilateral Symmetry and Asymmetry in the C. elegans Connectome: A Graph-Theoretic Analysis based on Redundancy Measures
Authors: Kim Pyeong Soo , Song Youngjo , Kralik Jerald D. , Jeong Jaeseung
Published: October 2024

Understanding the balance between symmetry and asymmetry in animal nervous systems is crucial for unraveling the complexities of neural architectures and their functions. Previous studies have primarily focused on morphological symmetry, such as neuron placement, leaving the symmetry in the functional architecture largely unexplored. The current study investigates this aspect within theCaenorhabditis elegansconnectomes by introducing a graph-theoretic approach. By defining a ‘mirror-symmetry index,’ we quantitatively assess the symmetry in these connectomes, revealing a significant level of bilateral symmetry alongside notable asymmetry. Our approach also incorporates measures including connectivity similarity, motif-fingerprint differences, and path-compensation index to evaluate the network’s functional redundancy and its capacity to compensate for unilateral disturbances. Here we show the C. elegans connectomes’ robust bilateral symmetry, which not only facilitates similar functions across neuron pairs but also ensures resilience against disruptions. This redundancy is not confined to symmetrical connections; it also includes asymmetric ones, adding to the neural network’s complexity. An in-depth analysis into different neuron types shows varied redundancy levels: high in interneurons, moderate in motor neurons, and low in sensory neurons. This pattern suggests a strategic neural design where diverse inputs from sensory neurons, coupled with the stable integration by interneurons, lead to coordinated actions through motor neurons. This study advances our understanding of neural connectomes, offering insights into the intricate balance of symmetry and asymmetry in neural systems and their implications for complex, adaptive behaviors.
Reducing spatial heterogeneity in coverage improves the effectiveness of dog vaccination campaigns against rabies
Authors: Ferguson Elaine A , Lugelo Ahmed , Czupryna Anna , Anderson Danni , Lankester Felix , Sikana Lwitiko , Dushoff Jonathan , Hampson Katie
Published: October 2024

Vaccination programs are the mainstay of control for many infectious diseases. Heterogeneous coverage is hypothesised to reduce vaccination programme effectiveness, but this impact has not been quantified in real systems. We address this gap using fine-scale data from two decades of rabies contact tracing and dog vaccination campaigns in Serengeti district, Tanzania. We also aimed to identify drivers of continued circulation of rabies in the district despite annual vaccination campaigns. Using generalised linear mixed models, we find that current focal (village-level) dog rabies incidence decreases with increasing recent focal vaccination coverage. However, current focal incidence depends most on recent incidence, both focally and in the wider district, consistent with high population connectivity. Removing the masking effects of prior non-focal incidence shows that, for the same average prior non-focal (wider-district) vaccination coverage, increased heterogeneity in coverage among the non-focal villages leads to increased focal incidence. These effects led to outbreaks following years when vaccination campaigns missed many villages, whereas when heterogeneity in coverage was reduced, incidence declined to low levels (<0.4 cases/1,000 dogs annually and no human deaths) and short vaccination lapses thereafter did not lead to resurgence. Through transmission-tree reconstruction, we inferred frequent incursions into the district each year (mean of 7). Inferred incursions substantially increased as a percentage of all cases in recent years, reaching 50% in 2022, suggesting regional connectivity is driving residual transmission. Overall, we empirically demonstrate how population connectivity and spatial heterogeneity in vaccination can impact disease outcomes, highlighting the importance of fine-scale monitoring in managing vaccination programs.
k-mer-based GWAS in a wheat collection reveals novel and diverse sources of powdery mildew resistance
Authors: Jaegle Benjamin , Voicheck Yoav , Haupt Max , Sotiropoulos Alexandros G. , Gauthier Kevin , Heuberger Matthias , Jung Esther , Herren Gerhard , Widrig Victoria , Leber Rebecca , Li Yipu , Schierscher Beate , Serex Sarah , Boczkowska Maja , Jasińska Marta-Puchta , Bolc Paulina , Chalhoub Boulos , Stein Nils , Keller Beat , Sanchez Martin Javier
Published: October 2024

Background

Wheat landraces and cultivars stored in gene banks worldwide represent a valuable source of genetic diversity for discovering genes critical for agriculture, which is increasingly constrained by climate change and inputs reduction. We assembled and genotyped, using DArTseq technology, a panel of 461 accessions representative of the genetic diversity of Swiss wheat material. The collection was evaluated for powdery mildew resistance under field conditions for two consecutive years and at the seedling stage with 10 different wheat powdery mildew isolates.

Results

To identify the genetic basis of mildew resistance in wheat, we developed ak-mer-based GWAS approach using multiple fully-assembled genomes includingTriticum aestivumas well as four progenitor genomes. Compared to approaches based on single reference genomes, we unambiguously mapped an additional 25% resistance-associatedk-mers. Our approach outperformed SNP-based GWAS in terms of number of loci identified and precision of mapping. In total, we detected 34 (Pm) powdery mildew resistance loci, including seven previously-described and more importantly 27 novel loci active at the seedling stage. Furthermore, we identified a region associated with adult plant resistance, which was not detected with SNP-based approaches.

Conclusions

The described non-reference-based approach highlights the potential of integrating multiple wheat reference genomes withk-mer GWAS to harness the untapped genetic diversity present in germplasm collections.
Conserved chromatin regulators control the transcriptional immune response to intracellular pathogens inCaenorhabditis elegans
Authors: Tecle Eillen , Li Samuel , Blanchard Michael J. , Bui Theresa , Chhan Crystal B. , Underwood Ryan S. , Bakowski Malina A. , Troemel Emily R. , Lažetić Vladimir
Published: October 2024

Robust transcriptional responses are critical for defense against infection. However, unrestrained immune responses can cause negative impacts such as damaging inflammation and slowed development. Here we find that a class of transcriptional regulators previously associated with regulation of development inCaenorhabditis elegans, is also involved in immune responses. Specifically, through forward genetics, we find that loss oflin-15Bleads to constitutive expression of Intracellular Pathogen Response (IPR) genes.lin-15Bencodes a transcriptional repressor with a conserved THAP domain that is associated with the DRM chromatin remodeling complex that regulatesC. elegansdevelopment. We show thatlin-15Bmutants have increased resistance to natural intracellular pathogens, and the induction of IPR genes inlin-15Bmutants relies on the MES-4 histone methyltransferase. We extend our analyses to other DRM and NuRD chromatin remodeling factors, as well as SUMOylation histone modifiers, showing that a broad range of chromatin-related factors can repress IPR gene expression. Altogether these findings suggest that conserved chromatin regulators may facilitate development in part by repressing damaging immune responses against intracellular pathogens.

AUTHOR SUMMARY

In this study, we show that transcriptional regulators, previously linked to development inC. elegans, also control immune responses. Through forward genetic screens, we found that loss of LIN-15B leads to constitutive activation of Intracellular Pathogen Response (IPR) genes. LIN-15B is part of the DREAM chromatin remodeling complex, and its loss enhances resistance to intracellular pathogens. This immune response depends on the MES-4 histone methyltransferase. We also discovered that other chromatin regulators, including NuRD and SUMOylation factors, similarly repress IPR gene expression, highlighting a new role in immunity for these conserved regulators of development.
VAPA mediates lipid exchange betweenLeishmania amazonensisand host macrophages
Authors: Gdovinova Ilona , Descoteaux Albert
Published: October 2024

Leishmaniais a vacuolar pathogen that replicates within parasitophorous vacuoles inside host phagocytes. To promote its replication,Leishmaniarelies on a panoply of strategies to acquire macromolecules such as lipids from host macrophages. In this study, we have evaluated the role of VAPA, an endoplasmic reticulum-resident membrane protein involved in inter-organellar lipid transport, in macrophages infected withL. amazonensis. Following infection of bone marrow-derived macrophages with metacyclicL. amazonensispromastigotes, we observed that VAPA gradually associates with communal parasitophorous vacuoles. Knockdown of VAPA prevented the replication ofL. amazonensis, which was accompanied by an impaired parasitophorous vacuole expansion. Using fluorescent ceramide, we established that VAPA is required for the transport of sphingolipids to the parasitophorous vacuoles and for its acquisition byL. amazonensisamastigotes. Proximity-ligation and immunoprecipitation assays revealed thatL. amazonensishijacks VAPA by disrupting its interactions with the lipid transfer proteins CERT and ORP1L. Finally, we found that VAPA is essential for the transfer of theLeishmaniavirulence glycolipid lipophosphoglycan from the parasitophorous vacuoles to the host cell endoplasmic reticulum. We propose that VAPA contributes to the ability ofL. amazonensisto colonize macrophages by mediating bi-directional transfer of lipids essential for parasite replication and virulence between the parasitophorous vacuoles and the host cell endoplasmic reticulum.

AUTHOR SUMMARY

The protozoan parasiteLeishmania amazonensisreplicates in macrophages, within communal parasitophorous vacuoles. To satisfy its various auxotrophies, this parasite must obtain macronutrients and metabolites from its host cell, including lipids. To salvage host sphingolipids, we obtained evidence thatL. amazonensisexploits a macrophage nonvesicular lipid transport mechanism that requires the endoplasmic reticulum membrane protein VAPA. Moreover, we found that VAPA is also required for the transfer of theLeishmaniavirulence glycolipid lipophosphoglycan from the parasitophorous vacuole to the macrophage endoplasmic reticulum. The fact that VAPA is essential forL. amazonensisto colonize macrophages is consistent with the central role that VAPA plays in mediating bi-directional transfer of lipids and illustrates the importance of the host cell endoplasmic reticulum in this host-parasite interaction.
De novo design of ATPase based on the blueprint optimized for harboring the P-loop motif
Authors: Kosugi Takahiro , Tanabe Mikio , Koga Nobuyasu
Published: October 2024

De novo design of proteins has seen remarkable recent progress and has provided understanding of folding and functional expression. However, rationally creating enzymes with high activity comparable to most naturally occurring enzymes remains challenging. Here, we attempted to design an ATPase de novo, through the exploration of an optimal backbone blueprint to incorporate a conserved phosphate binding motif, the P-loop, into designed structures. The designed protein, based on the identified blueprint, was found to be a monomer with high thermal stability, and exhibited the ATPase ability. The crystal structure was closely matched to the design model, both at the overall structure level and within the P-loop motif. Interestingly, AlphaFold was not able to predict the designed structure accurately, indicating the difficulties of predicting folded structures for novel protein sequences. Remarkably, the designed protein exhibited ATPase ability even at temperatures around 100 °C, with significantly increased activity. However, the ATPase activity was still not comparable to those of naturally occurring enzymes. This suggests that the P-loop motif alone is insufficient to achieve the high ATPase activity seen in naturally occurring enzymes, indicating that other structural components are necessary to reach such activity levels.
3D mechanical confinement directs muscle stem cell fate and function
Authors: Park GaYoung , Grey Josh A. , Mourkioti Foteini , Han Woojin M.
Published: October 2024

Muscle stem cells (MuSCs) play a crucial role in skeletal muscle regeneration, residing in a niche that undergoes dimensional and mechanical changes throughout the regeneration process. This study investigates how three-dimensional (3D) confinement and stiffness encountered by MuSCs during the later stages of regeneration regulate their function, including stemness, activation, proliferation, and differentiation. We engineered an asymmetric 3D hydrogel bilayer platform with tunable physical constraints to mimic the regenerating MuSC niche. Our results demonstrate that increased 3D confinement maintainsPax7expression, reduces MuSC activation and proliferation, inhibits differentiation, and is associated with smaller nuclear size and decreased H4K16ac levels, suggesting that mechanical confinement modulates both nuclear architecture and epigenetic regulation. MuSCs in unconfined two-dimensional (2D) environments exhibited larger nuclei and higher H4K16ac expression compared to those in more confined 3D conditions, leading to progressive activation, expansion, and myogenic commitment. This study highlights the importance of 3D mechanical cues in MuSC fate regulation, with 3D confinement acting as a mechanical brake on myogenic commitment, offering novel insights into the mechano-epigenetic mechanisms that govern MuSC behavior during muscle regeneration.
Population history of Swedish cattle breeds: estimates and model checking
Authors: Adepoju Dolapo , Ohlsson J Ingemar , Klingström Tomas , Rius-Vilarrasa Elisenda , Johansson Anna M , Johnsson Martin
Published: October 2024

In this work, we use linkage disequilibrium-based methods to estimate recent population history from genotype data in Swedish cattle breeds, as well as international Holstein and Jersey cattle data for comparison. Our results suggest that these breeds have been effectively large up until recently, when they declined around the onset of systematic breeding. The inferred trajectories were qualitatively similar, with a large historical population and one decline. We used population genetic simulation to check the inferences. When comparing simulations from the inferred population histories to real data, the proportion low-frequency variants in real data was different than was implied by the inferred population histories, and there was somewhat higher genomic inbreeding in real data than implied by the inferred histories. The inferred population histories imply that much of the variation we see today is transient, and it will be lost as the populations settle into a new equilibrium, even if efforts to maintain effective population size at current levels are successful.
APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer
Authors: Cramer Zvi , Monaghan Keara , Petroni Ricardo , Wang Xin , Adams-Tzivelekidis Stephanie , Durning Kayla , Kim Melissa S. , Tian Yuhua , Johnson Nicolette M. , Leu Nicolae A. , Sidoli Simone , Li Ning O. , Andres Blanco M. , Lengner Christopher J.
Published: October 2024

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths with increasing incidence globally. Mutations in the tumor suppressor APC initiate CRC at least in part by preventing the GSK3 kinase from phosphorylating β-CATENIN, leading to its constitutive stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well-established, APC regulation of GSK3 activity upon other targets with potential oncogenic relevance are not understood. Here, we identify the H4K20 methyltransferase SETD8 as target of APC-coordinated GSK3 phosphorylation in the intestinal epithelium. We found that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, phosphorylation alters the role of SETD8 in transcriptional regulation, most notably by preventing it from activating oncogenic YAP signaling and a fetal-like transcriptional program. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN -independent oncogenic consequence of APC loss.

Significance

GSK3 is thought to restrain colorectal cancer primarily by phosphorylation of β-CATENIN. We show that GSK3 also phosphorylates SETD8, preventing SETD8 activation of oncogenic programs including YAP-driven fetal-like gene expression.
Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in male mice with Down Syndrome
Authors: Islam Md Rezaul , Jackson Brennan , Naomi Maeesha Tasnim , Schatz Brooke , Tan Noah , Murdock Mitchell , Park Dong Shin , Amorim Daniela Rodrigues , Jiang Fred , Sebastian Pineda S. , Adaikkan Chinnakkaruppan , Fernandez Vanesa , Geigenmuller Ute , Firenze Rosalind Mott , Kellis Manolis , Boyden Edward S. , Tsai Li-Huei
Published: October 2024

Down syndrome (DS) has been linked with deficits in hippocampal dependent cognitive tasks and adult neurogenesis, yet treatment options are still very limited. We and others previously showed that a non-invasive multisensory gamma stimulation using light and sound at 40 Hz ameliorated Alzheimer’s disease pathology and symptoms in mouse models. In this study, we tested the effects of 40 Hz multisensory stimulation in the Ts65Dn mice, a mouse model of DS. For three weeks, mice were exposed daily to one hour of stimulation or one hour of ambient light and sound. Mice receiving the stimulation showed improved object recognition and spatial working memory. Using single nuclei RNA-seq and experimental validations in mouse hippocampal samples, we identified underlying expression changes in gene regulatory networks and demonstrated increased adult neurogenesis and reorganization of synapses as potential mechanisms for these improved cognitive phenotypes. Together, our data reveal a novel effect of multisensory gamma stimulation on adult neurogenesis and beneficial effects of 40 Hz treatment on cognitive function in DS model mice.

Significance Statement

We present strong evidence, using a well-characterized mouse model, that the cognitive and neurogenesis deficits in Down syndrome can be improved through non-invasive multi-sensory gamma stimulation. Employing a systems biology approach, we provide extensive hippocampal single-cell resolution gene expression signatures and changes in gene regulatory networks in response to sensory gamma stimulation.
Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity
Authors: Avelar Roberto A. , Duffield Thomas , Lagger Cyril , Krstevska Nikita , Breuer Marian , de Magalhães João Pedro
Published: October 2024

Cellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity (β-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells.

Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples.

Genes regulating stress responses – including transcription factors and genes controlling chromatin accessibility – are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner.

We propose that ‘senescence’ cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, TFs, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.
An electrophysiological study about the pharmacological manipulation of the immediate consequences of a spinal trauma reveals a crucial role for TRPV4 antagonism
Authors: Mohammadshirazi Atiyeh , Taccola Giuliano
Published: October 2024

A physical trauma to the spinal cord produces an immediate massive depolarizing injury potential accompanied both by a transient episode of spinal hypoxia, and an extensive cell loss at the level of injury, which interrupts conduction of longitudinal input along white matter tracts. Afterwards, the transient hypotonia and areflexia characterize the following spinal shock phase. The relationship between the extent of injury potentials and spinal cord injury (SCI) progression, as well as the potential pharmacological modulation of the immediate consequences of a trauma, have not yet been explored. To limit the peak of injury potentials and speed up recovery of reflex motor responses, we serially applied selective neurochemicals in the exact moment of an experimental physical trauma delivered through a calibrated device impacting the mid-thoracic cord of an entire CNS preparation of neonatal rats. Continuous lumbar root recordings monitored baseline DC-levels and reflex responses elicited by trains of electric pulses applied to sacrocaudal afferents. In uninjured preparations, each agent showed distinct effects on baseline polarization, modulation of synaptic responses, and appearance of bursting activity. Interestingly, neurochemicals acting on glutamatergic-, adenosinergic-, glycinergic- or GABAergic receptors, did not affect the monitored outcome when each parameter was normalized against pre-injury values. Conversely, the selective TRPV4 antagonist, RN1734, unlike the TRPA1 antagonist, AP18, reduced peak of injury potentials and speeded up full recovery of reflex responses within 1 min from trauma. Similarly, blockage of gap junctions quickly, yet partially, restored motor reflexes, while antagonism of GABAAreceptors restored full reflexes, though slightly later. The current study indicates that both mechanosensitive TRPV4 receptors and GABAergic transmission reduce the immediate pathological consequences of a trauma when applied at the moment of impact, envisaging a clinical translation for preventing accidental spinal lesions during the most delicate spinal surgeries.
Disruption of the Novel Nested Gene Aff3ir Mediates Disturbed Flow-Induced Atherosclerosis in Mice
Authors: He Shuo , Huang Lei , Chen Zhuozheng , Yuan Ze , Zhao Yue , Zeng Lingfang , Zhu Yi , He Jinlong
Published: October 2024

Disturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of Aff3ir-ORF2, a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces Aff3ir-ORF2 expression in athero-prone regions. Using three distinct mouse models with manipulated AFF3ir-ORF2 expression, we demonstrate that AFF3ir-ORF2 exerts potent anti-inflammatory and anti-atherosclerotic effects in ApoE-/-mice. RNA sequencing revealed that interferon regulatory factor 5 (IRF5), a key regulator of inflammatory processes, mediates inflammatory responses associated with AFF3ir-ORF2 deficiency. AFF3ir-ORF2 interacts with IRF5, promoting its retention in the cytoplasm, thereby inhibiting the IRF5-dependent inflammatory pathways. Notably, IRF5 knockdown in AFF3ir-ORF2 deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific AFF3ir-ORF2 supplementation using the CRISPR/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for AFF3ir-ORF2 in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of IRF5, highlighting its potential as a valuable therapeutic approach for treating atherosclerosis.
ENDOTHELIAL PROX1 INDUCES BLOOD-BRAIN BARRIER DISRUPTION IN THE CENTRAL NERVOUS SYSTEM
Authors: González-Hernández Sara , Sato Ryo , Sato Yuya , Liu Chang , Li Wenling , Liu Chengyu , Jackson Sadhana , Kubota Yoshiaki , Mukouyama Yoh-suke
Published: October 2024

The central nervous system (CNS) parenchyma has conventionally been believed to lack lymphatic vasculature, likely due to a non-permissive microenvironment that hinders the formation and growth of lymphatic endothelial cells (LECs). Recent findings of ectopic expression of LEC markers including Prospero Homeobox 1 (PROX1), a master regulator of lymphatic differentiation, and the vascular permeability marker Plasmalemma Vesicle Associated Protein (PLVAP), in certain glioblastoma and brain arteriovenous malformations (AVMs), has prompted investigation into their roles in cerebrovascular malformations, tumor environments, and blood-brain barrier (BBB) abnormalities. To explore the relationship between ectopic LEC properties and BBB disruption, we utilized endothelial cell-specificProx1overexpression mutants. When induced during embryonic stages of BBB formation, endothelialProx1expression induces hybrid blood-lymphatic phenotypes in the developing CNS vasculature. This effect is not observed whenProx1is overexpressed during postnatal BBB maturation. EctopicProx1expression leads to significant vascular malformations and enhanced vascular leakage, resulting in BBB disruption when induced during both embryonic and postnatal stages. Mechanistically, PROX1 downregulates critical BBB-associated genes, includingß-cateninandClaudin-5, which are essential for BBB development and maintenance. These findings suggest that PROX1 compromises BBB integrity by negatively regulating BBB-associated gene expression and Wnt/ß-catenin signaling.
A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer
Authors: Wang Shuo , Diao Shiqi , Kim Hyungdong , Zou Jia Yi , Li Ke Ke , Koromilas Antonis E.
Published: October 2024

In tumorous conditions, the transcription factor STAT1, traditionally recognized for its anti-tumor role in immunology, exhibits pro-survival characteristics, though the underlying mechanisms remain unclear. Investigating STAT1’s function in isogenic colorectal tumor cells with wild-type or mutant KRAS, we found that STAT1 specifically promotes the survival and proliferation of cells with mutant KRAS. Through gene expression profiling, we discovered a previously unknown role of STAT1 in upregulating sterol and lipid biosynthetic genes specifically in mutant KRAS cells. This effect is driven by STAT1’s phosphorylation at serine 727 and its cooperation with STAT3 and STAT5 for the transcriptional upregulation of sterol regulatory element-binding proteins (SREBP) 1 and 2, which boostde novosterol and lipid biosynthesis. In mutant KRAS cells, STAT1 amplifies the mevalonate pathway, maintaining its serine 727 phosphorylation through RHO GTPase signaling and establishing a positive feedback loop through the transcription factors YAP1 and TEAD4, further driving lipid biosynthesis and tumor growth. Through xenograft tumor assays in mice, we discovered that the STAT1-YAP1 axis plays a role in mutant KRAS tumor cells’ resistance to mevalonate pathway inhibitors, which can be overcome by pharmacologically targeting the YAP1-TEAD interaction. Additionally, the STAT1-YAP1 arm is essential for the intrinsic resistance to EGFR-targeting therapy in the mutant KRAS colon cancer cells. These findings indicate that the STAT1-YAP1 pathway plays a significant role in therapy resistance and presents a potential therapeutic target in mutant KRAS colorectal cancer.
Disruptive effect of rainfalls on the diurnal periodicity of airborne wheat rust spore under field conditions
Authors: Suffert Frederic
Published: October 2024

Stripe rust and leaf rust, caused byPuccinia striiformisf. sp.tritici(Pst) andPuccinia triticina(Pt), respectively, are major threats to wheat production. Forecasting epidemics requires a deeper understanding of the mechanisms driving spore dispersal. Many studies have either employed field data for purely correlative approaches without incorporating established knowledge on physical mechanisms or, conversely, relied on specific physical approaches in controlled environments focusing on only a few mechanisms or factors. Little emphasis has been placed on holistic field-based studies, where wind and rain play crucial roles. This study fills that gap by attempting to unravel the processes by which rainfall affects airborne spore concentrations over a wheat canopy during active rust epidemics. Over more than two months, bi-hourly spore counts from Burkard traps were integrated with detailed meteorological data, revealing both seasonal and diurnal trends. Diurnal peaks in airborne spore concentrations, typically driven by cyclic changes in wind and humidity, were dramatically altered by rain. Rain events either amplified spore concentrations by up to 25-fold through ‘rain-puff’ and/or depletes them via ‘wash-out’ and ‘wash-off’. Rains events from the dataset were classified into categories with distinct impacts: ‘precursor’ rains often trigger spore release, while ‘follower’ (and prolonged rains) reduce airborne spore concentrations. Moreover, differences in the dispersal dynamics ofPstandPtwere observed, and some were linked to how humidity and wind influence spore clustering. These results provide valuable insights for a more integrated understanding of the effect of rain and in order to enhance forecasting models.