bluuebunny/crossref_metadata_2025 huggingface dataset:
Sinonasal Squamous Cell Carcinoma with DEK::AFF2 Rearrangement
Authors: Trinquet Aude , Laé Marick , Lépine Charles , Lanic Marie-Delphine , Lacheretz-Szablewski Vanessa , Shaar Chneker Caroline , Goujon Jean-Michel , Favier Valentin , Costes-Martineau Valérie
Published: August 2024

Aims: DEK::AFF2 squamous cell carcinoma is a recently described cancer entity, with 29 cases reported to date. Occasionally, these carcinomas appear deceptively indistinguishable; however, specific morphological and phenotypic features suggest the presence of this rearrangement. However, the prognostic value of this diagnosis remains unclear. We aimed to report a new case series with histological, molecular, and clinical features. Methods: We collected data from 15 patients and investigated their phenotypes, including the expression profiles of CK7, P63/P40, PDL1, AFF2, and P16, morphological features, and associated prognostic data. We analyzed these data along with the previously published data. Results: Most of these cases exhibited indicative morphological features, such as exophytic and endophytic papillary growth, nuclear monomorphism, and abundant neutrophil-rich inflammatory infiltrates. Immunohistochemical analysis revealed the expression of AFF2 and squamous cell markers in all the patients. Overexpression of P16 was not detected, whereas CK7 and PDL1 were expressed variably. In our study cohort, a 50% progression or recurrence rate, 25% lymph node metastasis, 17% distant metastasis, and 18% disease-related death were identified, with a short follow-up time. Conclusion: DEK::AFF2 squamous cell carcinoma incidence is probably underestimated. The low-grade appearance of these tumors sometimes limits their detection. The rates of recurrence and metastasis seem to be high despite an often bland morphology. We propose AFF2 immunohistochemistry as an effective tool, and a diagnostic algorithm has been established to support accurate diagnosis of these tumors.
No longer stuck in the past: new advances in artificial intelligence and molecular assays for parasitology screening and diagnosis
Authors: Attaway Christopher , Mathison Blaine A. , Misra Anisha
Published: August 2024

Purpose of review

Emerging technologies are revolutionizing parasitology diagnostics and challenging traditional methods reliant on microscopic analysis or serological confirmation, which are known for their limitations in sensitivity and specificity. This article sheds light on the transformative potential of artificial intelligence and molecular assays in the field, promising more accurate and efficient detection methods.

Recent findings

Artificial intelligence has emerged as a promising tool for blood and stool parasite review, when paired with comprehensive databases and expert oversight result in heightened specificity and sensitivity of diagnoses while also increasing efficiency. Significant strides have been made in nucleic acid testing for multiplex panels for enteric pathogen. Both multiplex and single target panels for Plasmodium, Babesia, filaria, and kinetoplastids have been developed and garnered regulatory approval, notably for blood donor screening in the United States. Additional technologies such as MALDI-TOF, metagenomics, flow cytometry, and CRISPR-Cas are under investigation for their diagnostic utility and are currently in the preliminary stages of research and feasibility assessment.

Recent implementation of artificial intelligence and digital microscopy has enabled swift smear screening and diagnosis, although widespread implementation remains limited. Simultaneously, molecular assays – both targeted and multiplex panels are promising and have demonstrated promise in numerous studies with some assays securing regulatory approval recently. Additional technologies are under investigation for their diagnostic utility and are compelling avenues for future proof-of-concept diagnostics.
7 T Lumbosacral Plexus Neurography
Authors: Marth Adrian A. , Feuerriegel Georg Constantin , Wanivenhaus Florian , Nanz Daniel , Sutter Reto
Published: August 2024

Objectives

7 T magnetic resonance (MR) imaging can offer superior spatial resolution compared with lower field strengths. However, its use for imaging of the lumbosacral plexus has been constrained by technical challenges and therefore remained relatively unexplored. Therefore, this study investigated the feasibility of 7 T MR neurography by means of comparing the visibility of the spinal nerves and image quality to 3 T MR neurography.

Materials and Methods

In this monocentric, institutional review board–approved, prospective study, 30 healthy subjects underwent acquisition time–matched 7 T MR neurography and 3 T MR neurography of the lumbar spine using a 3-dimensional dual-echo steady-state sequence. Visibility of the nerve root, dorsal root ganglia, and spinal nerve fascicles of L1–S1, along with image artifacts and overall image quality, were compared between the different field strengths by 2 radiologists using 4-point Likert scales (1 = poor, 4 = excellent). Comparisons between field strengths were made using the Wilcoxon signed rank test, and interobserver agreement was assessed.

Results

7 T MR neurography enabled significantly improved visualization of the lumbar nerve roots, dorsal root ganglia, and spinal nerve fascicles (P ≤ 0.002). Compared with 3 T MR neurography, no difference in overall image quality was observed (P = 0.211), although 7 T MR imaging exhibited significantly increased image artifacts (P < 0.001). Interobserver agreement (κ) for qualitative measures ranged from 0.71 to 0.88 for 7 T, and from 0.75 to 0.91 for 3 T.

Conclusions

7 T MR neurography allowed for improved visualization of lumbar spinal nerves, whereas overall image quality was comparable to 3 T MR neurography. This supports the feasibility of 7 T MR neurography of the lumbosacral plexus, even though image artifacts at 7 T were significantly increased.
Can We Predict Gastric Leaks After Laparoscopic Sleeve Gastrectomy by Evaluating the Complete Blood Count on Postoperative Day 1?
Authors: Seyit Hakan , Gokcal Fahri , Alis Halil
Published: August 2024

Introduction:

We assessed whether postoperative day-1 (POD-1) complete blood count (CBC) test parameters, including red cell distribution width (RDW), mean platelet volume (MPV), plateletcrit (PCT), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR), could identify patients with gastric leaks after laparoscopic sleeve gastrectomy (LSG).

Methods:

Patients with postoperative gastric leaks (n=36) and patients with no complications who were selected by age-sex-BMI matching (n=254) were included in the study. The levels of RDW, MPW, PCT, PLR, and NLR were compared between groups in univariate analyses. Receiver operating characteristic (ROC) curve analysis was run for CBC parameters with a P-value<0.05 in univariate analyses. The area under the curve (AUC) was evaluated, and a cutoff value was determined. Sensitivity, specificity, likelihood ratio (LR), positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated.

Results:

The level of PCT was significantly lower, while levels of PLR and NLR were significantly higher in patients with postoperative gastric leaks as compared with those without (P<0.05). The AUC of both PCT and PLR was <0.750, while the AUC of NLR was 0.911. NLR cutoff at 3.6 yielded 80% sensitivity, 92% specificity, and an LR of 10. In the study cohort, PPV of 59%, NPV of 97%, and an accuracy of 90% were found.

Conclusions:

Our results suggest that NLR at POD-1, with a cutoff value of 3.6, is a useful indicator of postoperative gastric leak who underwent LSG. We recommend the use of this easily calculated parameter in clinical practice.
The perpendicular gyroscope: modal analysis of plate, beam and gyroscope multistructures
Authors: Madine K. H. , Colquitt D. J.
Published: August 2024

This paper presents a study of the perpendicular gyroscope, which is formed of two orthogonal beams, a flexural plate and a gyroscope. Two sets of chiral-torsional boundary conditions are derived to analytically model the dynamic effects of the gyroscope while taking into account the broken symmetries of the system. The perpendicular junction causes the coupling of the compressional, flexural and torsional displacements in the system. This complex behaviour is accounted for with a comprehensive set of kinematic and dynamic junction conditions. Modal analysis demonstrates the fully coupled system and reveals how the spinning gyroscope induces dynamic chiral Chladni patterns in the plate.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
A study of antigen selection by extracellular vesicles as vaccine candidates against Mycobacterium tuberculosis infection
Authors: Ji Lin , Ruan Hang , Fu Yuxuan , Xiong Sidong
Published: August 2024

Introduction. Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tb), remains a significant global public health concern. It is crucial to develop more effective vaccines for TB in order to achieve global control of the disease. Extracellular vesicles (EVs) are spherical membrane-bound structures released by pathogens and host cells. During the course of an infection, both pathogen- and host-derived EVs are produced and play important roles in determining the course of the infection. EVs offer intriguing tools as potential vaccines due to their ability to deliver multiple pathogen or host antigens.

Hypothesis /Gap Statement. We hypothesized that EVs derived from M. tb and EVs from M. tb-infected macrophages may serve as potential vaccine candidates against M. tb infection.

Aim. This study aims to compare the immunogenicity and immune protection between M. tb EVs and M. tb-infected macrophage-derived EVs.

Methodology. In this study, EVs were extracted from culture supernatants of M. tb and M. tb-infected macrophages, respectively. Mass spectrometry was employed to explore the antigen composition of H37Rv-Mφ-EVs and H37Rv-EVs. Cytokine profiling and antibody response assays were used to analyse the immunogenicity offered by EVs. Additionally, we used histological examination to evaluate and protective efficacy of the EVs.

Results. Our results demonstrated that mice immunized by EVs released from M. tb-infected macrophages induced stronger inflammatory cytokine response than M. tb. Moreover, EVs from M. tb-infected macrophages reinforced T-cell activation and antibody response compared to M. tb EVs. Proteomic analysis revealed that EVs from M. tb-infected macrophages containing immunodominant cargos have stronger binding ability with major histocompatibility complex molecules, which may contribute to the protection from M. tb infection. Indeed, immunization of EVs released from M. tb-infected macrophages significantly reduced the bacterial load and better protection against M. tb infection than EVs from M. tb. Importantly, the selected antigens (Ag85B, ESAT-6 and the Rv0580c) from EVs of M. tb-infected macrophages exhibited effective immunogenicity.

Conclusion. Our results suggested that EVs derived from M. tb-infected macrophages might serve as a proper antigenic library for vaccine candidates against M. tb challenge.
Time trends in cardiac doses in 10,000 patients receiving curative thoracic radiation therapy between 2009 and 2020
Authors: Forbes Nora , Terrones-Campos Cynthia , Smith Abraham , Reekie Joanne , Darkner Sune , Maraldo Maja , Pøhl Mette , Risumlund Signe , Specht Lena , Bentzen Soren M. , Petersen Jens , Vogelius Ivan R.
Published: August 2024

Background and purpose

In the last 20 years, it has become well-documented that incidental cardiac exposure to ionizing radiation is associated with a clinically relevant increased risk of cardiovascular morbidity. In parallel, radiation therapy technologies have been developed to provide target dose coverage with less exposure to adjacent organs at risk. In the current work, we investigate trends in cardiac exposure among patients treated with curative intent radiotherapy from a single institution between 2009 to 2020.

Materials and methods

10,215 treatment courses were analyzed from 9,966 patients treated with curative intent for intrathoracic or breast cancers in the period 2009-2020. All hearts were re-delineated using an AI model to ensure consistency over time. Cardiac doses were extracted in 3D from the record-and-verify system and converted, voxel-by-voxel, to equi-effective doses in 2 Gy fractions (EQD2) using α/β=2 Gy. Mean heart dose (in EQD2) and volume exposed to 5 and 40 Gy (V5 and V40Gy), respectively, were extracted. Time trends in these cardiac dose-volume metrics were investigated for each diagnosis.

Results

Patients with esophageal cancer had the highest mean heart dose (median = 11.67 Gy; IQR = 2.85, 18.18), while the lowest was observed in patients with breast cancer (median = 0.60 Gy; IQR = 0.30, 1.08) and lymphoma (median = 0.01 Gy; IQR = 0.00, 0.38). A decreasing trend over time was seen most clearly for patients with esophageal and lung cancers (p<0.05). Among patients with breast cancer, V40 decreased from 2009-2015 after which we observed an increase.

Conclusion

There has been a significant reduction in radiation exposure to the heart in patients treated in the period 2009-2020, likely due to increased awareness of cardiovascular toxicity and technological developments. The study also found a significant increase in V40 from 2015 to 2020 for patients with breast cancers, possibly related to increased prioritization of target coverage.

Highlights

10,215 radiation therapy plans extracted and analyzed

Hearts were re-delineated with machine learning on the therapy CT-scan to ensure time-independent delineations

Cardiac doses were found to decrease over time, especially high dose exposure of intrathoracic lesions

An unexpected increase in cardiac high dose volume (V40Gy) for breast cancer treatment plans in recent years was observed
Nearly complete genome assembly of a critically endangered pine illuminates evolution and conservation of conifers
Authors: Zhang Ren-Gang , Liu Hui , Shu Heng , Liu De-Tuan , Shang Hong-Yun , Jia Kai-Hua , Wang Xiao-Quan , Sun Wei-Bang , Zhao Wei , Ma Yong-Peng
Published: August 2024

Conifers are dominant in most temperate and boreal forest ecosystems, and are the most widely distributed of the gymnosperms. Despite this, many conifer species are threatened with extinction, and in particular the genetic mechanisms underlying their endangerment remain largely unknown.Pinus squamata, which harbors an extremely large diploid genome and conservation significance, is among the 100 most endangered species (plants and animals) globally, and has been designated as ‘Critically Endangered’ on the IUCN Red List. In this study, we report an almost complete genome sequence forP. squamatagenerated by a suite of sequencing technologies, with an assembly of 29.2 Gb, a scaffold N50 length of 2.5 Gb, and a remarkable contig N50 length of 915.4 Mb. This represents the largest and most high-quality gymnosperm genome sequenced to date. The genome is characterized by an ultra-low rate of heterozygosity, is dominated by transposable elements, and contains 55,413 protein-coding genes. Our study provides the first detailed examination of chromosome organization inP. squamata, revealing Rabl configurations and distinctive centromere signatures. This genomic milestone not only deepens our understanding of gymnosperm genetics and evolution but also lays a solid foundation for the development of effective conservation measures, ensuring the survival of this rare species in the face of environmental challenges.
Weak Relationship Between Divergence and Selection in a North American Toad Hybrid Zone
Authors: Cobb Kerry A , Oaks Jamie R
Published: August 2024

Hybrid zones present an excellent opportunity to study the evolution of reproductive isolation between divergent evolutionary lineages as generations of interbreeding and backcrossing produce many different recombinant genotypes. We can then observe patterns of genetic variation within a hybrid zone to understand how selection is acting on these recombinant genotypes. Using genome-wide sequence data, we characterized patterns of introgression within a putative hybrid zone between two species of North American toads (Anaxyrus americanus and Anaxyrus terrestris) to better understand reproductive isolation between these species. Both model based and non-parametric approaches to population structure inference showed that there is likely a substantial level of interbreeding and successful backcrossing at this hybrid zone with admixed individuals located quite far from the center of the hybrid zone. Bayesian genomic cline analysis revealed loci with extreme patterns of introgression relative to other loci which would be expected if these sites were linked to sites under negative selection in a hybrid genomic background. A site-based measure of genetic divergence was found to be weakly correlated with cline parameter estimates. We argue that this weak correlation is consistent with a history of secondary contact following a period of geographic isolation as many highly divergent sites do not have correspondingly high cline parameter estimates consistent with strong selection against introgression. Our findings substantiate previous claims of the existence of a hybrid zone between A. americanus and A. terrestris and highlight the potential for this hybrid zone to further our understanding of the evolution of reproductive incompatibly.
Modeling collagen fibril degradation as a function of matrix microarchitecture
Authors: Debnath B. , Narasimhan B. N. , Fraley S. I. , Rangamani P.
Published: August 2024

Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability.In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our model predictions were tested usingin vitroexperiments with synthesized collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.
Oligomerization-Mediated Phase-Separation in the Nucleoid-Associated Sensory Protein H-NS is Controlled by Ambient Cues
Authors: Lukose Bincy , Goyal Saloni , Naganathan Athi N.
Published: August 2024

H-NS, a nucleoid-associated protein (NAP) from enterobacteria, regulates gene expression by dynamically transducing environmental cues to conformational assembly and DNA binding. In this work, we show that H-NS fromEscherichia coli, which can assemble into octameric and tetrameric oligomerization states, forms spontaneous micron-sized liquid-like condensates with DNA at sub-physiological concentrationsin vitro. The heterotypic condensates are metastable at 298 K, partially solubilizing with time, while still retaining their liquid-like properties. The condensates display UCST-like phase behavior solubilizing at higher temperatures, but with a large decrease in droplet-assembly propensities at 310 K and also at higher ionic strength. Condensate formation can be tuned in a cyclic manner between 298 and 310 K with the extent of reversibility determined by the incubation time, highlighting strong hysteresis. An engineered phospho-mimetic variant (Y61E) of H-NS, which is dimeric and only weakly binds DNA, is unable to form condensates. The Y61E mutant solubilizes pre-formed H-NS condensates with DNA in a few minutes with nearly an order of magnitude speed-up in droplet dissolution at 310 K relative to 298 K, demonstrating rapid molecular transport between dilute and condensed phases. Our results establish that the oligomerization of H-NS is intrinsically tied not only to DNA binding but also its phase-separation tendencies, while showcasing the regulatable and programmable nature of heterotypic condensates formed by an archetypal NAP via multiple cues and their lifetimes.
Geospatial analysis of the presence of hypertension, diabetes, obesity, and lifestyles in the Peruvian population
Authors: Loayza-Castro Joan A. , Valladoli-Sansoval Lupita Ana Maria , Vásquez-Romero Luisa Erika Milagros - , Zuzunaga-Montoya Fiorella E. , Astucuri Hidalgo Jhonatan Roberto , Vera-Ponce Víctor Juan
Published: August 2024

Introduction: In Peru, the prevalence of diabetes mellitus (DM), hypertension (HTN), and obesity has increased significantly while healthy lifestyles have declined. However, the geographic distribution of these conditions at the provincial level has not been fully elucidated. Objective: To conduct a geospatial analysis to provide a comprehensive view of the distribution of DM, HTN, obesity, and lifestyles across Peruvian provinces. Materials and Methods: An analytical cross-sectional study was conducted using data from the 2023 Demographic and Family Health Survey (DHS). Descriptive analysis of the study variables was performed, and geospatial analysis techniques, including heat maps and the Local Moran's Index, were used to identify distribution patterns and clusters. Results: The national prevalence of DM, HTN, and obesity was 5.66%, 20.43%, and 27.67%, respectively. It was found that 8.35% were current smokers, 2.24% consumed alcohol excessively, and 90.69% consumed fewer than five servings of fruits and vegetables daily. Geospatial analysis revealed hotspots of high DM prevalence in the provinces of Oyon (Lima) and Daniel Alcides Carrion (Pasco), HTN in Putumayo (Loreto) and Corongo (Ancash), and obesity in Putumayo and Maynas (Loreto), and Pallasca (Ancash). Regarding lifestyles, clusters of high alcohol consumption were identified in the provinces of Piura and Cajamarca, high tobacco consumption in Loreto and San Martin, and low fruit and vegetable consumption in Lima and Huanuco. Conclusions: Marked geographical disparities were observed in the prevalence of chronic diseases and unhealthy lifestyles among Peruvian provinces, with a notable concentration in jungle regions and some coastal Andean areas.
Maternal obesogenic environment and its association with childhood obesity in Peru: A 9-year analysis of a national survey
Authors: Loayza-Castro Joan A. , Vera-Ponce Víctor Juan , Vásquez-Romero Luisa Erika Milagros - , Astucuri Hidalgo Jhonatan Roberto , Sanchez-Tamay Nataly Mayely , Zuzunaga-Montoya Fiorella E.
Published: August 2024

Introduction: Childhood obesity is a global public health concern with increasing prevalence in Peru. The obesogenic environment, including maternal and family environmental factors, plays a crucial role in the development of childhood obesity. Objective: To analyze the association between the maternal obesogenic environment and obesity in children under five years of age in Peru. Methods: An analytical cross-sectional study used data from the Demographic and Family Health Survey (DHS) from 2014 to 2022. To assess the obesogenic environment, variables such as maternal obesity, television use, smoking, and maternal anemia were analyzed. Childhood obesity was a body mass index Z-score > +3 standard deviations. A Poisson regression model was used to calculate crude and adjusted prevalence ratios. Results: The prevalence of childhood obesity was 1.99%. Obese mothers were found to be 1.52 times more likely to have obese children (aPR=1.52, 95% CI 1.40-1.65; p<0.001). No significant associations were found between frequent television use, maternal smoking, and anemia with childhood obesity after adjusting for multiple factors. Conclusion: This study highlights the importance of the maternal obesogenic environment, especially maternal obesity, in developing childhood obesity in Peru. Comprehensive interventions that address multiple aspects of the family obesogenic environment, including the prevention and management of maternal obesity, promotion of healthy lifestyles, and strengthening of public policies that foster healthy environments, are recommended.
Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling
Authors: Mcleod Jonathan C. , Lim Changhyun , Stokes Tanner , Sharif Jalil-Ahmad , Zeynalli Vagif , Wiens Lucas , D’Souza Alysha C , Colenso-Semple Lauren , McKendry James , Morton Robert W. , Mitchell Cameron J. , Oikawa Sara Y. , Wahlestedt Claes , Paul Chapple J , McGlory Chris , Timmons James A. , Phillips Stuart M.
Published: August 2024

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growthin vivo,while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, includingCYTOR– which was leukocyte-associated (FDR = 4.9 x10-7). Novel hypertrophy-linked ncRNAs includedPPP1CB-DT(myofibril assembly genes, FDR = 8.15 x 10-8), andEEF1A1P24andTMSB4XP8(vascular remodelling and angiogenesis genes, FDR = 2.77 x 10-5). We also discovered that hypertrophy lncRNAMYREMshows a specific myonuclear expression patternin vivo. Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways.

One Sentence Summary

We used an optimised transcriptomic strategy to identify a set of ncRNA genes regulated during skeletal muscle hypertrophy in one hundred and forty-four people, with network modelling and spatial imaging providing biological context.
Functional Electrical Stimulation and Brain-Machine Interfaces for Simultaneous Control of Wrist and Finger Flexion
Authors: Mender Matthew J , Ward Ayobami L , Cubillos Luis H , Kelberman Madison M , Costello Joseph T , Temmar Hisham , Wallace Dylan M , Lin Edanjen T , Lam Jordan L W , Willsey Matthew S , Ganesh Kumar Nishant , Kung Theodore A , Patil Parag G , Chestek Cynthia A
Published: August 2024

Brain-machine interface (BMI) controlled functional electrical stimulation (FES) is a promising treatment to restore hand movements to people with cervical spinal cord injury. Recent intracortical BMIs have shown unprecedented successes in decoding user intentions, however the hand movements restored by FES have largely been limited to predetermined grasps. Restoring dexterous hand movements will require continuous control of many biomechanically linked degrees-of-freedom in the hand, such as wrist and finger flexion, that would form the basis of those movements. Here we investigate the ability to restore simultaneous wrist and finger flexion, which would enable grasping with a controlled hand posture and assist in manipulating objects once grasped. We demonstrate that intramuscular FES can enable monkeys with temporarily paralyzed hands to move their fingers and wrist across a functional range of motion, spanning an average 88.6 degrees at the metacarpophalangeal joint flexion and 71.3 degrees of wrist flexion, and intramuscular FES can control both joints simultaneously in a real-time task. Additionally, we demonstrate a monkey using an intracortical BMI to control the wrist and finger flexion in a virtual hand, both before and after the hand is temporarily paralyzed, even achieving success rates and acquisition times equivalent to able-bodied control with BMI control after temporary paralysis in two sessions. Together, this outlines a method using an artificial brain-to-body interface that could restore continuous wrist and finger movements after spinal cord injury.
Time Makes Space: Emergence of Place Fields in Networks Encoding Temporally Continuous Sensory Experiences
Authors: Wang Zhaoze , Di Tullio Ronald W. , Rooke Spencer , Balasubramanian Vijay
Published: August 2024

The vertebrate hippocampus is believed to use recurrent connectivity in area CA3 to support episodic memory recall from partial cues. This brain area also contains place cells, whose location-selective firing fields implement maps supporting spatial memory. Here we show that place cells emerge in networks trained to remember temporally continuous sensory episodes. We model CA3 as a recurrent autoencoder that recalls and reconstructs sensory experiences from noisy and partially occluded observations by agents traversing simulated arenas. The agents move in realistic trajectories modeled from rodents and environments are modeled as continuously varying, high-dimensional, sensory experience maps (spatially smoothed Gaussian random fields). Training our autoencoder to accurately pattern-complete and reconstruct sensory experiences with a constraint on total activity causes spatially localized firing fields, i.e., place cells, to emerge in the encoding layer. The emergent place fields reproduce key aspects of hippocampal phenomenology: a) remapping (maintenance of and reversion to distinct learned maps in different environments), implemented via repositioning of experience manifolds in the network’s hidden layer, b) orthogonality of spatial representations in different arenas, c) robust place field emergence in differently shaped rooms, with single units showing multiple place fields in large or complex spaces, and d) slow representational drift of place fields. We argue that these results arise because continuous traversal of space makes sensory experience temporally continuous. We make testable predictions: a) rapidly changing sensory context will disrupt place fields, b) place fields will form even if recurrent connections are blocked, but reversion to previously learned representations upon remapping will be abolished, c) the dimension of temporally smooth experience sets the dimensionality of place fields, including during virtual navigation of abstract spaces. Code for our experiments is available at1.
Molecular phylogenetics illuminates the evolutionary history and hidden diversity of Australian cave crickets (Orthoptera: Rhaphidophoridae)
Authors: Beasley-Hall Perry G , Trewick Steven A , Eberhard Stefan M , Zwick Andreas , Reed Elizabeth H , Cooper Steven J B , Austin Andrew D
Published: August 2024

Cave crickets (Orthoptera: Rhaphidophoridae) are a globally distributed group of insects found in dark, humid microhabitats including natural caves, alpine scree, and forest litter. Ten extant subfamilies are currently recognised and Macropathinae, which comprises the entirety of the fauna in South America, South Africa, Australia, and New Zealand, is thought to be the most ancient of these. The New Zealand rhaphidophorid fauna comprises high phylogenetic diversity throughout its mesic zone, with most species occurring above-ground. In contrast, the Australian fauna is poorly known, with an apparently greater relative proportion of species utilising caves as refugia. A robust phylogenetic framework is needed to underpin future taxonomic work on the group and potentially contrasting patterns of taxonomic diversity within Macropathinae. Here, we performed fossil-calibrated phylogenetic analysis using whole mitochondrial genomes and nuclear markers to reconstruct the evolutionary history of Macropathinae, with a focus on the Australian fauna. By dramatically increasing taxon sampling relative to past studies, we recovered the Australian fauna as rampantly polyphyletic, with the remaining Macropathinae nested amongst six distinct Australian lineages. Deep divergences between major clades imply additional Australian lineages remain undetected, either due to extinction or sampling bias, and have likely confounded past biogeographic signal. We inferred the radiation of Macropathinae began during the Lower Cretaceous prior to the fragmentation of Gondwana with a potential Pangaean origin for Rhaphidophoridae. Finally, we found evidence for several undescribed taxa of Australian Rhaphidophoridae, all of which qualify as short-range endemics, and discuss the conservation implications of these restricted distributions.
Serpina1e mediates the exercise-induced enhancement of hippocampal memory
Authors: Kim Hyunyoung , Shin Sanghee , Han Jeongho , Kim Jong-Seo , Park Hyungju
Published: August 2024

The exercise-induced enhancement of learning and memory is thought to be regulated by body□brain interactions via secretory proteins in the blood plasma1,2. Given the prominent role that skeletal muscle plays during exercise, the beneficial effects of exercise on cognitive functions appear to be mediated by muscle-derived secretory factors including myokines3,4. However, the specific myokines that exert beneficial effects on cognitive functions remain to be elucidated. Here, we reveal that a novel myokine, Serpina1e, acts a molecular mediator that directly supports long-term memory formation in the hippocampus. Using anin vivomyokine-labeling mouse model, proteomic analysis revealed that the Serpina1 family of proteins are the myokines whose levels increased the most in plasma after chronic aerobic exercise for 4 weeks. Systemic delivery of recombinant Serpina1e into sedentary mice was sufficient for reproducing the beneficial effect of exercise on hippocampus-associated cognitive functions. Moreover, plasma Serpina1e can cross the blood–cerebral spinal fluid (CSF) barrier and blood–brain barrier to reach the brain, thereby influencing hippocampal function. Indeed, an increase in the plasma level of Serpina1e promoted hippocampal neurogenesis, increased the levels of brain-derived neurotrophic factor (BDNF) and induced neurite growth. Our findings reveal that Serpina1e is a myokine that migrates to the brain and mediates exercise-induced memory enhancement by triggering neurotrophic growth signaling in the hippocampus. This discovery elucidates the molecular mechanisms underlying the beneficial effects of exercise on cognitive function and may have implications for the development of novel therapeutic interventions for alleviating cognitive disorders.
Targeted inference to identify drug repositioning candidates in the Danish health registries
Authors: Jung Alexander Wolfgang , Louloudis Ioannis , Brunak Soren , Mortensen Laust Hvas
Published: August 2024

Electronic health records can be used to track diagnoses and drug prescriptions in large heterogeneous populations over time. Coupled with recent advances in causal inference from observational data, these records offer new opportunities to emulate clinical trials and identify potential targets for drug repositioning. Here, we run a hypothesis generating cohort study of Danes aged 50 to 80 years from 2001 to 2015 (n = 2,512,380), covering a total of 23,371,354 years of observations. We examine prescription drugs at ATC level-4 and their effect on 9 major disease outcomes. Using Bayesian time-varying Cox regression and longitudinal minimum loss estimation, our analysis successfully reproduces known drug-disease associations from clinical trials, such as the reduction in the 3-year absolute risk of death associated with Statins (ATC:C10AA) -0.8% (95% CI =[-1.2%, -0.5%]) and -0.8% (95% CI =[-1.3%, -0.2%]) for females and males, respectively. Additionally, we discovered novel associations that suggest potential repositioning opportunities. For instance, Statins were associated with a reduction in the 3-year absolute risk of dementia by -0.3% (95% CI =[-0.5%, -0.1%]) for females and -0.2% (95% CI =[-0.4%, 0.1%]) for males. Furthermore, Biguanides (ATC:P01BB) stands out as a particularly interesting candidate with absolute risk reductions across various outcomes. In total, we identified 76 potential drug-disease pairs for further investigation. However, it should be stressed that the emulation of clinical trials here is solely of hypothesis generating nature and identified effects need to be corroborated with additional evidence, preferably from RTCs, as the risk of confounding by indication in this study is substantial. In summary, this study provides a large-scale screen of prescribed drugs and their effect on major debilitating disease in the Danish health registries. This provides an additional source of information that can be used in the search for possible repositioning candidates.
CaMutQC: An R Package for Integrative Quality Control of Cancer Somatic Mutations
Authors: Wang Xin , Jiang Tengjia , Shen Ao , Chen Yaru , Zhou Yanqing , Liu Jie , Zhao Shuhan , Chen Shifu , Ren Jian , Zhao Qi
Published: August 2024

The quality control and filtration of cancer somatic mutations (CAMs), including the elimination of false positives resulting from technical bias and the selection of key mutation candidates, is crucial for downstream analysis in cancer genomics. Due to diverse needs and the absence of standardized filtering criteria, the filtering strategies employed vary from study to study, often leading to reduced efficiency, accuracy, and comparability across similar analyses. Here we present CaMutQC, a heuristic quality control and soft-filtering R/Bioconductor package for CAMs. With CaMutQC, the removal of false positives, selection of potential mutation candidates, and Tumor Mutation Burden estimation can be executed in a single line of code, using default or customized parameters. A filter report and a code log generated after the filtration process assist with recording and comparison. The application of CaMutQC on a Whole-exome Sequencing (WES) benchmark dataset demonstrated its impressive capability by eliminating 85.55% of false positive mutations while retaining 90.72% of true positive mutations. Additionally, an extra 11.56% of true positive mutations were recused by the union strategy embedded in CaMutQC. CaMutQC is now available through Bioconductor athttps://bioconductor.org/packages/CaMutQC/under the GPL v3 license, and it will be updated regularly to incorporate top filtration strategy and parameter sets shared within the community.
Subsets of extraocular motoneurons produce kinematically distinct saccades during hunting and exploration
Authors: Dowell Charles K. , Hawkins Thomas , Bianco Isaac H.
Published: August 2024

Animals construct diverse behavioural repertoires by moving a limited number of body parts with varied kinematics and patterns of coordination. There is evidence that distinct movements can be generated by changes in activity dynamics within a common pool of motoneurons, or by selectively engaging specific subsets of motoneurons in a task-dependent manner. However, in most cases we have an incomplete understanding of the patterns of motoneuron activity that generate distinct actions and how upstream premotor circuits select and assemble such motor programmes. In this study, we used two closely related but kinematically distinct types of saccadic eye movement in larval zebrafish as a model to examine circuit control of movement diversity. In contrast to the prevailing view of a final common pathway, we found that in oculomotor nucleus, distinct subsets of motoneurons were engaged for each saccade type. This type-specific recruitment was topographically organised and aligned with ultrastructural differ-ences in motoneuron morphology and afferent synaptic innervation. Medially located motoneu-rons were active for both saccade types and circuit tracing revealed a type-agnostic premotor pathway that appears to control their recruitment. By contrast, a laterally located subset of motoneurons was specifically active for hunting-associated saccades and received premotor in-put from pretectal hunting command neurons. Our data support a model in which generalist and action-specific premotor pathways engage distinct subsets of motoneurons to elicit varied movements of the same body part that subserve distinct behavioural functions.
The BDNF/TrkB pathway in Somatostatin-expressing neurons suppresses cocaine-seeking behaviour
Authors: Didio Giuliano , Aitta-aho Teemu , Umemori Juzoh , Castrén Eero
Published: August 2024

Cocaine addiction is a highly debilitating condition consisting of compulsive self-administration and seek for the substance of abuse, and its most challenging feature is the high rate of relapse. Addiction and relapse share similarities with neural plasticity which acts through the Brain-Derived Neurotrophic Factor and its receptor TrkB. Somatostatin (SST) expressing interneurons are involved in neuronal plasticity and are important in modulating cocaine-seeking behaviour in mice. We tested the role of TrkB in Somatostatin (SST)-expressing neurons in the extinction of cocaine-seeking behaviour, using mice in which TrkB has been knocked out specifically in SST neurons. We have observed that in these mice, once a cocaine-conditioned place preference is acquired, its extinction through seven days of extinction training is impaired, showing how this process relies on neural plasticity in SST neurons. When we promoted plasticity during extinction training using a light-activable TrkB in SST neurons in the prefrontal cortex of cocaine-conditioned mice, relapse of cocaine-seeking was prevented. Our data identify the critical role of TrkB-mediated plasticity within SST neurons in the extinction of and relapse to cocaine addiction.
Perceived multisensory common cause relations shape the ventriloquism effect but only marginally the trial-wise aftereffect
Authors: Kayser Christoph , Heuer Herbert
Published: August 2024

Combining multisensory cues is fundamental for perception and action, and reflected by two frequently-studied phenomena: multisensory integration and sensory recalibration. In the context of audio-visual spatial signals, these are exemplified by the ventriloquism effect and its aftereffect. The ventriloquism effect occurs when the perceived location of a sound is biased by a concurrent visual stimulus, while the aftereffect manifests as a recalibration of sound localization after exposure to spatially discrepant stimuli. The relationship between these processes—whether recalibration is a direct consequence of integration or operates independently—remains debated. This study investigates the role of causal inference in these processes by examining whether trial-wise judgments of audio-visual stimuli as originating from a common cause influence both the ventriloquism effect and the immediate aftereffect. Using a spatial paradigm, participants made explicit judgments about the common cause of stimulus pairs, and their influence on both perceptual biases was assessed. Our results indicate that while multisensory integration is contingent on common cause judgments, the immediate recalibration effect is not. This suggests that recalibration can occur independently of the perceived commonality of the multisensory stimuli, challenging the notion that recalibration is solely a byproduct of integration.
Allocating Limited Surveillance Effort for Outbreak Detection of Endemic Foot and Mouth Disease
Authors: Greiner Ariel , Herrera-Diestra José Luis , Tildesley Michael , Shea Katriona , Ferrari Matthew
Published: August 2024

Foot and Mouth Disease (FMD) affects cloven-hoofed animals globally and has become a major economic burden for many countries around the world. Countries that have had recent FMD outbreaks are prohibited from exporting most meat products; this has major economic consequences for farmers in those countries, particularly farmers that experience outbreaks or are near outbreaks. Reducing the number of FMD outbreaks in countries where the disease is endemic is an important challenge that could drastically improve the livelihoods of millions of people. As a result, significant effort is expended on surveillance; but there is a concern that uninformative surveillance strategies may waste resources that could be better used on control management. Rapid detection through sentinel surveillance may be a useful tool to reduce the scale and burden of outbreaks. In this study, we use an extensive outbreak and cattle shipment network dataset from the Republic of Türkiye to test three possible strategies for sentinel surveillance allocation that differ in their data requirements: ranging from low to high data needs, we allocate limited surveillance to [1] farms that frequently send and receive shipments of animals (Network Connectivity), [2] farms near other farms with past outbreaks (Spatial Proximity) and [3] farms that receive many animals from other farms with past outbreaks (Network Proximity). We determine that all of these surveillance methods find a similar number of outbreaks – 2-4.5 times more outbreaks than were detected by surveying farms at random. On average across surveillance efforts, the Network Proximity and Network Connectivity methods each find a similar number of outbreaks and the Spatial Proximity method always finds the fewest outbreaks. Since the Network Proximity method does not outperform the other methods, these results indicate that incorporating both cattle shipment data and outbreak data provides only marginal benefit over the less data-intensive surveillance allocation methods for this objective. We also find that these methods all find more outbreaks when outbreaks are rare. This is encouraging, as early detection is critical for outbreak management. Overall, since the Spatial Proximity and Network Connectivity methods find a similar proportion of outbreaks, and are less data-intensive than the Network Proximity method, countries with endemic FMD whose resources are constrained could prioritize allocating sentinels based on whichever of those two methods requires less additional data collection.