bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic diversity, population structure, and genome-wide association reveal genetic differentiation and trait improvements in mango
Authors: Ma Xiaowei , Wu Hongxia , Liu Bin , Wang Songbiao , Zhang Yuehua , Su Muqing , Zheng Bin , Pan Hongbing , Du Bang , Wang Jun , He Ping , Chen Qianfu , An Hong , Xu Wentian , Luo Xiang
Published: July 2024

Mango (Mangifera indica L.) has been widely cultivated as a culturally and economically significant fruit tree for roughly 4000 years. Despite its rich history, little is known about the crop’s domestication, genomic variation, and the genetic loci underlying agronomic traits. This study employs the whole-genome re-sequencing of 224 mango accessions sourced from 22 countries, with an average sequencing depth of 16.37×, to explore their genomic variation and diversity. Through phylogenomic analysis, M. himalis J.Y. Liang, a species grown in China, was reclassified into the cultivated mango group known as M. indica. Moreover, our investigation of mango population structure and differentiation revealed that Chinese accessions could be divided into two distinct gene pools, indicating the presence of independent genetic diversity ecotypes. By coupling genome-wide association studies with analyses of genotype variation patterns and expression patterns, we identified several candidate loci and dominant genotypes associated with mango flowering capability, fruit weight, and volatile compound production. In conclusion, our study offers valuable insights into the genetic differentiation of mango populations, paving the way for future agronomic improvements through genomic-assisted breeding.
Muscle-Driven Predictive Physics Simulations of Quadrupedal Locomotion in the Horse
Authors: van Bijlert Pasha A , Geijtenbeek Thomas , Smit Ineke H , Schulp Anne S , Bates Karl T
Published: July 2024

Synopsis

Musculoskeletal simulations can provide insights into the underlying mechanisms that govern animal locomotion. In this study, we describe the development of a new musculoskeletal model of the horse, and to our knowledge present the first fully muscle-driven, predictive simulations of equine locomotion. Our goal was to simulate a model that captures only the gross musculoskeletal structure of a horse, without specialized morphological features. We mostly present simulations acquired using feedforward control, without state feedback (“top-down control”). Without using kinematics or motion capture data as an input, we have simulated a variety of gaits that are commonly used by horses (walk, pace, trot, tölt, and collected gallop). We also found a selection of gaits that are not normally seen in horses (half bound, extended gallop, ambling). Due to the clinical relevance of the trot, we performed a tracking simulation that included empirical joint angle deviations in the cost function. To further demonstrate the flexibility of our model, we also present a simulation acquired using spinal feedback control, where muscle control signals are wholly determined by gait kinematics. Despite simplifications to the musculature, simulated footfalls and ground reaction forces followed empirical patterns. In the tracking simulation, kinematics improved with respect to the fully predictive simulations, and muscle activations showed a reasonable correspondence to electromyographic signals, although we did not predict any anticipatory firing of muscles. When sequentially increasing the target speed, our simulations spontaneously predicted walk-to-run transitions at the empirically determined speed. However, predicted stride lengths were too short over nearly the entire speed range unless explicitly prescribed in the controller, and we also did not recover spontaneous transitions to asymmetric gaits such as galloping. Taken together, our model performed adequately when simulating individual gaits, but our simulation workflow was not able to capture all aspects of gait selection. We point out certain aspects of our workflow that may have caused this, including anatomical simplifications and the use of massless Hill-type actuators. Our model is an extensible, generalized horse model, with considerable scope for adding anatomical complexity. This project is intended as a starting point for continual development of the model and code that we make available in extensible open-source formats.
Recovering sedimentary ancient DNA of harmful dinoflagellates accumulated over the last 9000 years off Eastern Tasmania, Australia
Authors: Armbrecht Linda , Bolch Christopher J S , Paine Bradley , Cooper Alan , McMinn Andrew , Woodward Craig , Hallegraeff Gustaaf
Published: July 2024

Harmful algal blooms (HABs) have had significant adverse impacts on the seafood industry along the Tasmanian east coast over the past 4 decades. To investigate the history of regional HABs, we performed analyses of sedimentary ancient DNA (sedaDNA) in coastal sediments up to ~9000 years old collected inshore and offshore of Maria Island, Tasmania. We used metagenomic shotgun sequencing and a hybridisation capture array (“HABbaits1”) to target three harmful dinoflagellate genera, Alexandrium, Gymnodinium, and Noctiluca. Bioinformatic and DNA damage analyses verified the authenticity of the sedaDNA sequences. Our results show that dinoflagellates of Alexandrium genera have been present off eastern Tasmania during the last ~8300 years, and we sporadically detected and unambiguously verified sequences of Gymnodinium catenatum that were present offshore up to ~7600 years ago. We also recovered sedaDNA of the fragile, soft-bodied Noctiluca scintillans with increased relative abundance since 2010, consistent with plankton surveys. This study enabled us to identify challenges of sedaDNA sequence validation (in particular for G. catenatum, a microreticulate gymnodinoid species) and provided guidance for the development of tools to monitor past and present HAB species and improvement of future HAB event predictions.
Model-based estimation of individual-level social determinants of health and its applications in All of Us
Authors: Kim Bo Young , Anthopolos Rebecca , Do Hyungrok , Zhong Judy
Published: July 2024

Objectives

We introduce a widely applicable model-based approach for estimating individual-level Social Determinants of Health (SDoH) and evaluate its effectiveness using the All of Us Research Program.

Materials and Methods

Our approach utilizes aggregated SDoH datasets to estimate individual-level SDoH, demonstrated with examples of no high school diploma (NOHSDP) and no health insurance (UNINSUR) variables. Models are estimated using American Community Survey data and applied to derive individual-level estimates for All of Us participants. We assess concordance between model-based SDoH estimates and self-reported SDoHs in All of Us and examine associations with undiagnosed hypertension and diabetes.

Results

Compared to self-reported SDoHs, the area under the curve for NOHSDP is 0.727 (95% CI, 0.724-0.730) and for UNINSUR is 0.730 (95% CI, 0.727-0.733) among the 329 074 All of Us participants, both significantly higher than aggregated SDoHs. The association between model-based NOHSDP and undiagnosed hypertension is concordant with those estimated using self-reported NOHSDP, with a correlation coefficient of 0.649. Similarly, the association between model-based NOHSDP and undiagnosed diabetes is concordant with those estimated using self-reported NOHSDP, with a correlation coefficient of 0.900.

Discussion and Conclusion

The model-based SDoH estimation method offers a scalable and easily standardized approach for estimating individual-level SDoHs. Using the All of Us dataset, we demonstrate reasonable concordance between model-based SDoH estimates and self-reported SDoHs, along with consistent associations with health outcomes. Our findings also underscore the critical role of geographic contexts in SDoH estimation and in evaluating the association between SDoHs and health outcomes.
Reconstruction and denoising of high-dimensional seismic data via Frobenius-nuclear mixed norm constraints
Authors: Luo Fei , Yan Lanlan , Cai Jiexiong , Guo Kai
Published: July 2024

The seismic data acquisition design with ‘two-wide and one-high’ geometry effectively improves the imaging quality of seismic records. However, when data are acquired in the field, complex near surface conditions and environmental factors can introduce a variety of noises and gaps in seismic data, impacting the accuracy of seismic imaging. Currently, the method of low-rank matrix/tensor completion is commonly employed for data reconstruction after normal moveout (NMO). In a complex subsurface medium, common midpoint data processed with NMO may not satisfy the linear or quasi-linear assumptions within local data windows. Therefore, this paper exploits the inherent low-rank structure of high-dimensional data to propose a high-dimensional tensor completion method under the Frobenius-nuclear mixed norm constraint (FN-TC). This method unfolds the 4D data tensor into the frequency-space domain along its modes (m, n) and subsequently imposes a non-convex Frobenius-nuclear mixed norm constraint on the unfolded approximate matrices. This approach closely approximates the rank function of the factor matrices, thereby enhancing the accuracy of data modeling. Theoretical and practical studies demonstrate that the novel FN-TC approach can effectively reconstruct high-dimensional seismic data and suppress noise, thereby providing data support for subsequent high-precision seismic imaging.
Probing outbursts of the transient neutron star low-mass X-ray binary Aql X-1 with NICER: a study of spectral evolution
Authors: Putha Karthik Gananath , Bhargava Yash , Bhattacharyya Sudip
Published: July 2024

X-ray observations of neutron star (NS) low-mass X-ray binaries (LMXBs) are useful for probing the physical processes close to the NS and for constraining source parameters. Aql X-1 is a transient NS LMXB that frequently undergoes outbursts and provides an excellent opportunity to study source properties and accretion mechanisms in a strong-gravity regime over a wide range of accretion rates. In this work, we systematically investigate the spectral evolution of Aql X-1 usingNICER observations during the source outbursts in 2019 and 2020. The NICER observations cover the complete transition of the source from its canonical hard state to a soft state and back. The spectra extracted from most observations can be explained by a partially Comptonized accretion disc. We find that the system can be described by an accretion disc with an inner temperature of $\sim 0.7$ keV and a Comptonizing medium of thermal electrons at $\sim 2$ keV, while the photon index is strongly degenerate with the covering fraction of the medium. We also find evidence of Fe K$\alpha$ fluorescence emission in the spectra, indicating reprocessing of the Comptonized photons. We observe an absorption column density higher than the Galactic column density for most of the observations, indicating a significant local absorption. For some of the observations in the 2020 outburst, however, the local absorption is negligible.
A phenomenological study of the evolution of shock-induced O i emission lines in the spectrum of nova V2891 Cygni
Authors: Pandey Ruchi , Srivastava Mudit K , Shaw Gargi
Published: July 2024

The eruption of Nova V2891 Cygni in 2019 offers a rare opportunity to explore the shock-induced processes in novae ejecta. The spectral evolution shows noticeable differences in the evolution of various oxygen emission lines such as O i 7773 Å, O i 8446 Å, O i 1.1286 μm, O i 1.3164 μm, etc. Here, we use spectral synthesis code cloudy to study the temporal evolution of these oxygen emission lines. Our photoionization model requires the introduction of a component with a very high density ($n \sim 10^{11}$ cm$^{-3}$) and an enhanced oxygen abundance (O/H $\sim$ 28) to produce the O i 7773 Å emission line, suggesting a stratification of material with high oxygen abundance within the ejecta. An important outcome is the behaviour of the O i 1.3164 μm line, which could only be generated by invoking the collisional ionization models in cloudy. Our phenomenological analysis suggests that O i 1.3164 μm emission originates from a thin, dense shell characterized by a high density of about $10^{12.5}\!-\!10^{12.8}$ cm$^{-3}$, which is most likely formed due to the strong internal collisions. If such is the case, the O i 1.3164 μm emission presents itself as a tracer of shock-induced dust formation in V2891 Cyg. The collisional ionization models have also been successful in creating the high-temperature conditions ($\sim 7.07\!-\!7.49 \times 10^5$ K) required to reproduce the observed high ionization potential coronal lines, which coincide with the epoch of dust formation and evolution of the O i 1.3164 μm emission line.
Can teleparallel f(T) models play a bridge between early and late time Universe?
Authors: Kavya N S , Mishra Sai Swagat , Sahoo P K , Venkatesha V
Published: July 2024

The ability of Big Bang Nucleosynthesis theory to accurately predict the primordial abundances of helium and deuterium, as well as the baryon content of the Universe, is considered one of the most significant achievements in modern physics. In the present study, we consider two highly motivated hybrid $f(T)$ models and constrain them using the observations from the Big Bang Nucleosynthesis era. In addition, using late-time observations of Cosmic Chronometers and Gamma-Ray Bursts, the ranges of the model parameters are confined which are in good agreement with early time bounds. Subsequently, the common ranges obtained from the analysis for early and late time are summarized. Further, we verify the intermediating epochs by investigating the profiles of cosmographic parameters using the model parameter values from the common range. From this study, we find the considered teleparallel models are viable candidates to explain the primordial-intermediating-present epochs.
Interventional neurorehabilitation for glioma patients: A systematic review
Authors: Ekert Justyna O , Goyal Anshit , Young Jacob S , Hervey-Jumper Shawn L , Berger Mitchel S
Published: July 2024

Harnessing the neuroplastic potential of the human brain is being increasingly recognized as an important neuro-oncological paradigm to facilitate safe resection of brain tumors while preserving neurological function and quality of life. Interventional neurorehabilitation, employing both invasive and noninvasive neuromodulation techniques, represents an important emerging therapeutic strategy to induce or enhance neural plasticity to promote functional recovery in brain tumor patients. This study aimed to conduct a comprehensive review of interventional neurorehabilitation techniques for glioma patients.

Methods

In accordance with PRISMA guidelines, searches of Medline, Embase, Web of Science, APA PsycINFO, and Cochrane were undertaken from database inception to November 28, 2023. Studies reporting on neuromodulation applied to glioma patients were included.

Results

Seven studies reporting findings from 118 patients met the inclusion criteria. Three neuromodulation techniques were identified and included transcranial magnetic stimulation (TMS) reported in 5 out of 7 (71.4%) studies; transcranial direct current stimulation (tDCS); and continuous cortical electrical stimulation (cCES) using grid electrodes, reported in one study each. All studies applying noninvasive stimulation to ameliorate postoperative deficits demonstrated an improvement on at least one outcome measure. The 2 studies applying tDCS and cCES to induce plasticity reported evidence of functional reorganization.

Conclusions

There is emerging evidence of benefits of neuromodulation to improve postoperative outcome in glioma patients. In the current literature, noninvasive stimulation has shown to have a favorable safety profile. Large-scale, double-blind, sham-controlled trials are warranted to further investigate the effectiveness of these interventions for modulating different cognitive networks in patients undergoing glioma surgery.
‘From highs to lows: a cautionary tale of nitrous oxide recreational use leading to sub-acute combined degeneration of the cord’
Authors: Osman Ayman , Yousif Dalia , Hickman Simon , Branagh William
Published: July 2024

Background: Several causes lead to subacute combined degeneration (SACD) of the spinal cord, with nitrous oxide (N2O) inhalation rapidly emerging as the leading cause of functional Vitamin B12 deficiency [1]. Case Presentation: A 28-year-old man presented with numbness in the extremities and an unstable gait despite having a normal serum Vitamin B12 level. He also disclosed the recreational abuse of N2O. Magnetic Resonance Imaging (MRI) of the cervical spine revealed abnormal signals consistent with SACD. The patient’s condition gradually improved after treatment with high dose Vitamin B12. Given the increasing number of N2O-induced SACD cases, the potential for drug abuse requires vigilance from clinicians. Conclusion: Healthcare providers are urged to inquire about a patient’s history of N2O inhalation to prevent the missed diagnosis of SACD.
Diabetic ketoacidosis masked by both Euglycemia and a primary metabolic alkalosis
Authors: Hillock Matthew F , Jarmon Cierra , Metropulos Anastasia E , King Rachael , Tchernodrinski Stefan , Principe Daniel R
Published: July 2024

Diabetic ketoacidosis (DKA) is an acute, life-threatening metabolic complication of diabetes classically associated with hyperglycemia, metabolic acidosis, and ketosis. Though relatively uncommon, patients can also develop DKA with relative euglycemia, further complicating diagnosis. Here, we describe the case of a patient who presented with intractable vomiting secondary to diabetic gastroparesis. He was euglycemic, non-acidemic, and serum bicarbonate was within normal limits. However, labs were significant for ketonuria, an elevated anion gap, and an elevated beta-hydroxybutyrate. Given the high concern for euglycemic DKA in the setting of a competing primary metabolic alkalosis, he was transferred to the intensive care unit for intravenous insulin infusion and fluid resuscitation with significant clinical improvement and normalization of laboratory results. This serves as an important reminder that DKA can be masked by euglycemia as well as additional metabolic derangements, and should be suspected in any diabetic patient with an anion gap and/or ketosis.
Advancements in ectopic reservoir placement for inflatable penile prostheses
Authors: Wright Nicole M , Applewhite James P , Reddy Amit G , Khera Mohit
Published: July 2024

Introduction

Traditional reservoir placement (RP) into the space of Retzius during three-piece inflatable penile prosthesis implantation has been associated with serious bladder, iliac vessel, and bowel complications, encouraging the development of “ectopic” RP methods.

Objectives

In this study we sought to document an up-to-date, comprehensive analysis of ectopic RP techniques regarding both patient satisfaction and clinical complications.

Methods

A PubMed, Ovid MEDLINE, and Cochrane Library literature search of English language articles from 1966 to 2023 with keywords “inflatable,” “penile prosthesis,” “reservoir,” and “placement” gave 179 publications, 70 of which were included in a comprehensive chronology and investigation after review. Overall, 12 retrospective studies detailing 9 ectopic RP techniques were compared for discussion.

Results

Sufficient data for comparison were found for 9 ectopic RP methods: posterior/anterior to transversalis fascia (PTF/ATF); high submuscular (HSM); HSM “Five-Step” technique (HSM-FST); lateral retroperitoneal (LR); sub-external oblique (SEO); direct vision, transfascial (DVT); low submuscular with transfascial fixation (LSM w/ TFF); and midline submuscular reservoir (MSMR). Although rare, serious complications have occurred with the use of ectopic RP techniques: 2 bladder perforations on implantation with PTF RP, a delayed bowel obstruction with HSM RP, and a colonic injury in a patient with a history of colon surgery with LR RP. Generally, herniation is the most relevant clinical complication in ectopic RP. At the time of this review there was no reported herniation with LR, SEO, LSM w/ TFF, or MSMR, likely due to fixation steps and/or reinforced spaces. Regarding patient satisfaction, HSM, HSM-FST, and LSM w/ TFF had similarly high rates of patient satisfaction while other techniques had no patient satisfaction data available. Importantly, reservoir palpability/visibility relates directly to patient satisfaction. Levels of palpability and/or visibility were reported in patients who underwent PTF/ATF, HSM, HSM-FST, SEO, and LSM w/ TFF, whereas no palpability was reported in patients who underwent LR, DVT, and MSMR.

Conclusion

Proper comparison of ectopic methods is not possible without standardized patient surveys, consistent complication reporting, and larger sample sizes, indicating the need for a large, prospective, multisurgeon trial.
Fat body‐derived juvenile hormone acid methyltransferase functions to maintain iron homeostasis in Drosophila melanogaster
Authors: Ye Yun‐Yan , Liu Zhi‐Hua , Wang Hui‐Li
Published: July 2024

Iron homeostasis is of critical importance to living organisms. Drosophila melanogaster has emerged as an excellent model to study iron homeostasis, while the regulatory mechanism of iron metabolism remains poorly understood. Herein, we accidently found that knockdown of juvenile hormone (JH) acid methyltransferase (Jhamt) specifically in the fat body, a key rate‐limiting enzyme for JH synthesis, led to iron accumulation locally, resulting in serious loss and dysfunction of fat body. Jhamt knockdown‐induced phenotypes were mitigated by iron deprivation, antioxidant and Ferrostatin‐1, a well‐known inhibitor of ferroptosis, suggesting ferroptosis was involved in Jhamt knockdown‐induced defects in the fat body. Further study demonstrated that upregulation of Tsf1 and Malvolio (Mvl, homolog of mammalian DMT1), two iron importers, accounted for Jhamt knockdown‐induced iron accumulation and dysfunction of the fat body. Mechanistically, Kr‐h1, a key transcription factor of JH, acts downstream of Jhamt inhibiting Tsf1 and Mvl transcriptionally. In summary, the findings indicated that fat body‐derived Jhamt is required for the development of Drosophila by maintaining iron homeostasis in the fat body, providing unique insight into the regulatory mechanisms of iron metabolism in Drosophila.
Strength of enemy release from parasitoids is context-dependent in the invasive African Fig Fly,Zaprionus indianus
Authors: Walsh-Antzak Camille R. , Erickson Priscilla A.
Published: July 2024

Understanding the mechanisms underlying the success of biological invasions is essential to employ effective prediction and management strategies. Escape from natural enemies in invaded regions (enemy release hypothesis, ERH) and increased competitive ability are hallmarks of invasive species; however, these two processes are rarely studied within the same context. Here, we examined the effect of enemy release on the competition outcomes of a successful invasive insect pest in North America, the African fig fly (Zaprionus indianus). Parasitoid wasps such asLeptopilina heterotomathat parasitize drosophilid larvae may seek out established species with known host suitability over a novel species, so we hypothesizedZ. indianusmay have low susceptibility to parasitoids, giving them a competitive advantage over co-occurring drosophilids. We tested this hypothesis by comparing the adult emergence rates fromZ. indianuslarvae reared alone or in competition withDrosophila hydeiorD. simulanslarvae in the presence and absence of parasitoid wasps under low and high larval densities. At low larval densities,Z. indianusemerged at equal rates toD. hydeibut outcompetedD. simulans, and these outcomes were not affected by parasitoids. However, at high densities, the addition of parasitoids shifted competition outcomes in favor ofZ. indianus, suggesting enemy release provides a competitive advantage under some circumstances. These results indicate that the strength of enemy release inZ. indianusis widely dependent on contextual factors such as density and competitor species. This study emphasizes how a community approach to testing the ERH is vital as the overall interpretation of the presence and strength of enemy release differed between intraspecific and interspecific experiments. Further investigation of how these results apply to field environments could offer insight into howZ. indianusalters ecosystems and how productive biological control may limit the spread ofZ. indianus.

Short Abstract

Invasive species may succeed in new environments in part because they are less susceptible to diseases and parasites that have co-evolved with local hosts, giving invaders a competitive advantage. We tested this hypothesis by competing an invasive fruit fly against established species in the presence of parasitoid wasps that lay their eggs in fruit fly larvae. We found that the invasive species generally outcompeted other species in the presence of parasitoids, but the extent of its advantage depended on the species it was competing against and the number of larvae present.
Sex-related differences in vascular remodeling of sodium overloaded normotensive mice
Authors: Viegas Katia A. S. , Silva Juliane C. S. , Lima Rariane S. , Lima Cintia T. , Peron Natalia N. , Silva Maikon B. , Irigoyen Maria Claudia , Lacchini Silvia
Published: July 2024

Background and Aims:Primary hypertension affect about 20% of adults in developed societies and, associated with high salt intake, leads to vascular remodeling, an adaptive physiological response of blood vessels that driven by repair, inflammation, or cell growth, is but may contribute to vascular diseases over time. This study examined vascular remodeling in the aorta and cardiac arteries, focused on gender-specific responses to sodium overload.Methods and Results:Adult male and female C57Bl/6 mice were divided into six groups: control with filtered water (Cont M; Cont F), 1% NaCl for two weeks (Salt-2 M; Salt-2 F), and 1% NaCl for twelve weeks (Salt-12 M; Salt-12 F). Blood pressure (BP) and heart rate (HR) were measured using tail plethysmography, and metabolic cages recorded 24-hour water intake and urine output. Morphometric analysis of the aorta and cardiac arteries included assessments of elastic laminae and collagen fibers, using Weigert van Gieson and Picrosirius staining. No changes in BP and HR were observed. Sodium intake increased water consumption in both genders after two weeks, but only males showed increased urine output. Vascular responses differed: males exhibited delayed increases in aortic elastic lamellae, while females showed earlier changes. Elastic lamellae in cardiac arteries remained unchanged. Collagen deposition increased in aortic walls for both genders but decreased by 50% in male cardiac arteries. Males showed thick collagen fibers, while females had thin and thick fibers.Conclusion:High sodium intake caused arterial stiffness through distinct mechanisms in males and females, even in normotensive animals.
Resolving the chromatin impact of mosaic variants with targeted Fiber-seq
Authors: Bohaczuk Stephanie C. , Amador Zachary J. , Li Chang , Mallory Benjamin J. , Swanson Elliott G , Ranchalis Jane , Vollger Mitchell R. , Munson Katherine M. , Walsh Tom , Hamm Morgan O. , Mao Yizi , Lieber Andre , Stergachis Andrew B.
Published: July 2024

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules—a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with ~10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of theDMPKCTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated γ-globin (HBG1/HBG2) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of theHBG1promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.
Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis
Authors: Pessenda Gabriela , Ferreira Tiago R. , Paun Andrea , Kabat Juraj , Amaral Eduardo P. , Kamenyeva Olena , Gazzinelli-Guimaraes Pedro Henrique , Perera Shehan R. , Ganesan Sundar , Lee Sang Hun , Sacks David L.
Published: July 2024

In murine models of visceral leishmaniasis (VL), parasitization of resident Kupffer cells (resKCs) is responsible for early growth ofLeishmania infantumin the liver, which leads to granuloma formation and eventual parasite control. We employed the chronic VL model, and revealed an open niche established by KCs death and their migration outside of the sinusoids, resulting in their gradual replacement by monocyte-derived KCs (moKCs). While early granulomas were composed of resKCs, late granulomas were found outside of the sinusoids and contained resKC-derived macrophages, and monocyte-derived macrophages (momacs). ResKCs and moKCs within the sinusoids were identified as homeostatic/regulatory cells, while resKC-derived macrophages and momacs within late granulomas were pro-inflammatory. Despite the infection being largely confined to the resKC-derived macrophages, in the absence of monocyte recruitment, parasite control was strongly compromised. Macrophage heterogeneity, involving migration and reprogramming of resKCs, along with recruitment of monocyte-derived cells, is a hallmark of granuloma maturation and hepatic immunity in VL.
Real-time Plasmid Transmission Detection Pipeline
Authors: Scherff Natalie , Rothgänger Jörg , Weniger Thomas , Mellmann Alexander , Harmsen Dag
Published: July 2024

The spread of antimicrobial resistance among bacteria by horizontal plasmid transmissions poses a major challenge for clinical microbiology. Here, we evaluate a new real-time plasmid transmission detection pipeline implemented in the SeqSphere+(Ridom GmbH, Münster, Germany) software.

Within the pipeline, a local Mash plasmid database is created and Mash searches with a distance threshold of 0.001 are used to trigger plasmid transmission early warning alerts (EWA). Clonal transmissions are detected using cgMLST allelic differences. The integrated tools MOB-suite, NCBI AMRFinderPlus, CGE MobileElementFinder, pyGenomeViz, and MUMmer are used to characterize plasmids and for visual pairwise plasmid comparisons, respectively. We evaluated the pipeline using published hybrid assemblies (Oxford Nanopore Technology/Illumina) of a surveillance and outbreak dataset with plasmid transmissions. To emulate prospective usage, samples were imported in chronological order of sampling date. Different combinations of the user-adjustable parameters sketch size (1,000 vs 10,000) and plasmid size correction were tested and discrepancies between resulting clusters were analyzed with Quast.

When using a sketch size of 1,000 with size correction turned on, the SeqSphere+pipeline agreed with the published data and produced the same clonal and carbapenemase-carrying plasmid clusters. EWAs were in the correct chronological order.

In summary, the developed pipeline presented here is suitable for integration into clinical microbiology settings with limited bioinformatics knowledge due to its automated analyses and alert system, which are combined with the GUI-based SeqSphere+platform. Thus, with its integrated sample database, (near) real-time plasmid transmission detection is within reach in bacterial routine-diagnostic settings when long-read sequencing is employed.

Importance

Plasmid-mediated spread of antimicrobial resistance (AMR) is a major challenge for clinical microbiology and monitoring of potential plasmid transmissions is essential to combat further dissemination. Whole-genome sequencing (WGS) is often used to surveil nosocomial transmissions but usually limited to the detection of clonal transmissions (based on chromosomal markers). Recent advances in long-read sequencing technologies enable full reconstruction of plasmids and the detection of very similar plasmids but so far easy-to-use bioinformatic tools for this purpose were missing. Here we present an evaluation of an innovative real-time plasmid transmission detection pipeline. It is integrated into the GUI-based SeqSphere+software, which already offers cgMLST based pathogen outbreak detection. It requires very limited bioinformatics knowledge, and its database, automated analyses, and alert system make it well suited for prospective clinical application.
Where the patterns are: repetition-aware compression for colored de Bruijn graphs⋆
Authors: Campanelli Alessio , Pibiri Giulio Ermanno , Fan Jason , Patro Rob
Published: July 2024

We describe lossless compressed data structures for thecoloredde Bruijn graph (or, c-dBG). Given a collection of reference sequences, a c-dBG can be essentially regarded as a map fromk-mers to theircolor sets. The color set of ak-mer is the set of all identifiers, orcolors, of the references that contain thek-mer. While these maps find countless applications in computational biology (e.g., basic query, reading mapping, abundance estimation, etc.), their memory usage represents a serious challenge for large-scale sequence indexing. Our solutions leverage on the intrinsic repetitiveness of the color sets when indexing large collections of related genomes. Hence, the described algorithms factorize the color sets into patterns that repeat across the entire collection and represent these patterns once, instead of redundantly replicating their representation as would happen if the sets were encoded as atomic lists of integers. Experimental results across a range of datasets and query workloads show that these representations substantially improve over the space effectiveness of the best previous solutions (sometimes, even dramatically, yielding indexes that are smaller by an order of magnitude). Despite the space reduction, these indexes only moderately impact the efficiency of the queries compared to the fastest indexes.

Software

The implementation of the indexes used for all experiments in this work is written inC++17and is available athttps://github.com/jermp/fulgor.
A Powered Simple Walking Model Modifies the Rate of Recovery Definition: Human Walking Deviates Drastically from Pendular Motion During the Double Support Phase
Authors: Hosseini-Yazdi Seyed-Saleh
Published: July 2024

This study proposes a modified definition of the original rate of recovery (ROR) in human walking, derived from a powered simple walking model and center of mass work. The metric captures the proportion of energy transferred from one step to the next by incorporating total step mechanical dissipation. Our simulation results show that the modified ROR decreases nearly linearly with increasing walking speed on even terrain due to collision impulses scaling with velocity (𝑐𝑜∼𝑣ave) and energy dissipation scaling quadratically. For nominal even walking at 1.25 m. s-1, the analytical ROR was 85%, depicting higher rates than previously proposed. Empirical data, however, reveal lower ROR values due to additional energy dissipation factors, such as elevated collision dissipation or negative net single support work, which are not captured by the analytical model. In contrast to the analytical model, the experimental results also show a maximum rate of recovery occurring at 1.21 m. s-1(59.4%). This peak appeared when total step dissipation was considered. We also demonstrated that the ROR trajectory was not symmetrical as previously presented but depended on the total step dissipation. For uneven terrains with step height variations of ±0.036 m, the average analytical model ROR was 82%, suggesting that a completely random uneven terrain may be analytically approximated by even walking. However, the elevated energetic demands of uneven walking, primarily due to suboptimal pre-emptive push-offs (timing or magnitude), must further decrease the ROR. Similarly, other walking conditions associated with increased metabolic costs, such as aging or when vision about the coming terrain is denied (restricted lookahead: max rate 58.5%), are also expected to result in reduced RORs.
Neuronal GPCR NMUR-1 regulates energy homeostasis in response to pathogen infection
Authors: Wibisono Phillip , Liu Yiyong , Roberts Kenneth P , Baluya Dodge , Sun Jingru
Published: July 2024

A key question in current immunology is how the innate immune system generates high levels of specificity. Our previous study inCaenorhabditis elegansrevealed that NMUR-1, a neuronal G protein-coupled receptor homologous to mammalian receptors for the neuropeptide neuromedin U (NMU), regulates distinct innate immune responses to different bacterial pathogens. Here, by using quantitative proteomics and functional assays, we discovered that NMUR-1 regulates F1FOATP synthase and ATP production in response to pathogen infection, and that such regulation contributes to NMUR-1-mediated specificity of innate immunity. We further demonstrated that ATP biosynthesis and its contribution to defense is neurally controlled by the NMUR-1 ligand CAPA-1 and its expressing neurons ASG. These findings indicate that NMUR-1 neural signaling regulates the specificity of innate immunity by controlling energy homeostasis as part of defense against pathogens. Our study provides mechanistic insights into the emerging roles of NMU signaling in immunity across animal phyla.
From histology to macroscale function in the human amygdala
Authors: Auer Hans , Cabalo Donna Gift , Rodriguez-Cruces Raul , Benkarim Oualid , Paquola Casey , DeKraker Jordan , Wang Yezhou , Valk Sofie , Bernhardt Boris C. , Royer Jessica
Published: July 2024

The amygdala is a subcortical region in the mesiotemporal lobe that plays a key role in emotional and sensory functions. Conventional neuroimaging experiments treat this structure as a single, uniform entity, but there is ample histological evidence for subregional heterogeneity in microstructure and function. The current study characterized subregional structure-function coupling in the human amygdala, integratingpost mortemhistology andin vivoMRI at ultrahigh fields. Core to our work was a novel neuroinformatics approach that leveraged multiscale texture analysis as well as non-linear dimensionality reduction techniques to identify salient dimensions of microstructural variation in a 3Dpost mortemhistological reconstruction of the human amygdala. We observed two axes of subregional variation in this region, describing inferior-superior as well as medio-lateral trends in microstructural differentiation that in part recapitulated established atlases of amygdala subnuclei. Translating our approach toin vivoMRI data acquired at 7 Tesla, we could demonstrate generalizability of these spatial trends across 10 healthy adults. We then cross-referenced microstructural axes with functional blood-oxygen-level dependent (BOLD) signal analysis obtained during task-free conditions, and revealed a close association of structural axes with macroscale functional network embedding, notably the temporo-limbic, default mode, and sensory-motor networks. Our novel multiscale approach consolidates descriptions of amygdala anatomy and function obtained from histological andin vivoimaging techniques.
Pseudo-perplexity in One Fell Swoop for Protein Fitness Estimation
Authors: Kantroo Pranav , Wagner Günter P. , Machta Benjamin B.
Published: July 2024

Protein language models trained on the masked language modeling objective learn to predict the identity of hidden amino acid residues within a sequence using the remaining observable sequence as context. They do so by embedding the residues into a high dimensional space that encapsulates the relevant contextual cues. These embedding vectors serve as an informative context-sensitive representation that not only aids with the defined training objective, but can also be used for other tasks by downstream models. We propose a scheme to use the embeddings of an unmasked sequence to estimate the corresponding masked probability vectors for all the positions in a single forward pass through the language model. This One Fell Swoop (OFS) approach allows us to efficiently estimate the pseudo-perplexity of the sequence, a measure of the model’s uncertainty in its predictions, that can also serve as a fitness estimate. We find that ESM2 OFS pseudo-perplexity performs nearly as well as the true pseudo-perplexity at fitness estimation, and more notably it defines a new state of the art on the ProteinGym Indels benchmark. The strong performance of the fitness measure prompted us to investigate if it could be used to detect the elevated stability reported in reconstructed ancestral sequences. We find that this measure ranks ancestral reconstructions as more fit than extant sequences. Finally, we show that the computational efficiency of the technique allows for the use of Monte Carlo methods that can rapidly explore functional sequence space.
Antiviral immunity within neural stem cells distinguishes viral strain differences in forebrain organoids
Authors: Vazquez Christine , Negatu Seble G. , Bannerman Carl D. , Sriram Sowmya , Ming Guo-Li , Jurado Kellie A.
Published: July 2024

Neural stem cells have intact innate immune responses that protect them from virus infection and cell death. Yet, viruses can antagonize such responses to establish neuropathogenesis. Using a forebrain organoid model system at two developmental time points, we identified that neural stem cells, in particular radial glia, are basally primed to respond to virus infection by upregulating several antiviral interferon-stimulated genes. Infection of these organoids with a neuropathogenic Enterovirus-D68 strain, demonstrated the ability of this virus to impede immune activation by blocking interferon responses. Together, our data highlight immune gene signatures present in different types of neural stem cells and differential viral capacity to block neural-specific immune induction.
LRRK2 kinase activity restricts NRF2-dependent mitochondrial protection in microglia
Authors: Weindel Chi G. , Ellzey Lily M. , Coleman Aja K. , Patrick Kristin L. , Watson Robert O.
Published: July 2024

Mounting evidence supports a critical role for central nervous system (CNS) glial cells in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s Disease (PD), Multiple Sclerosis (MS), as well as neurovascular ischemic stroke. Previously, we found that loss of the PD-associated gene leucine-rich repeat kinase 2 (Lrrk2) in macrophages, peripheral innate immune cells, induced mitochondrial stress and elevated basal expression of type I interferon (IFN) stimulated genes (ISGs) due to chronic mitochondrial DNA engagement with the cGAS/STING DNA sensing pathway. Here, we report that loss of LRRK2 results in a paradoxical response in microglial cells, a CNS-specific macrophage population. In primary murine microglia and microglial cell lines, loss ofLrrk2reduces tonic IFN signaling leading to a reduction in ISG expression. Consistent with reduced type I IFN, mitochondria fromLrrk2KO microglia are protected from stress and have elevated metabolism. These protective phenotypes involve upregulation of NRF2, an important transcription factor in the response to oxidative stress and are restricted by LRRK2 kinase activity. Collectively, these findings illustrate a dichotomous role for LRRK2 within different immune cell populations and give insight into the fundamental differences between immune regulation in the CNS and the periphery.
Silicon Nitride Induces Osteoconduction Via Activated Mitochondrial Oxidative Phosphorylation and Neovascularization
Authors: Gonzales Wayne , Khade Ronit , Kondo Takeru , Arimoto Satomi , Inagaki Taro , Hokugo Akishige , Kaczor-Urbanowicz Karolina Elżbieta , McEntire Bryan , Bock Ryan , Ogawa Takahiro , Pezzotti Giuseppe , Nishimura Ichiro
Published: July 2024

Silicon nitride (Si3N4: SiN) is a thermodynamically stable ceramic material with excellent mechanical properties, and wear and corrosion resistance for industrial applications. SiN has been proposed for orthopedic and dental implant applications owing to its enhanced osteoconduction. However, the biological mechanisms underlying SiN-induced bone formation have not been fully elucidated. In this study, SiN significantly increasedin vitromineralization of human bone marrow mesenchymal stromal cells (BM-MSC) andin vivoperi-implant bone volume in mouse femurs compared to conventionally used titanium (Ti) implants. RNA sequencing of BM-MSC cultured on SiN disks revealed that functional gene clusters associated with mitochondrial oxidative phosphorylation were significantly elevated. SiN in an aqueous solution has been shown to release ammonium/ammonia, which may provide a source for glutamine-dependent energy production, and BM-MSC upregulated the expression of a key enzyme, glutamate-ammonia ligase under osteogenic conditions. Additionally, SiN increased the expression of functional gene clusters involved in vascular formation. The upregulation ofHIF1a in vitroand increased VEGFR3-positive blanching vascular structuresin vivoimplied that SiN induced neovascularization. This study revealed an important mechanism through which SiN stimulated osteoconduction by unique glutamine-driven mitochondrial oxidative phosphorylation and established oxygen and nutrient supply by neovascularization, leading to stable osseointegration.
Engineering Microglial Cells to Promote Spinal Cord Injury Recovery
Authors: Zhou Qingsheng , Liu Jianchao , Fang Qiongxuan , Zhang Chunming , Liu Wei , Sun Yifeng
Published: July 2024

Spinal cord injury (SCI) can result in irreversible damage, leading to lifelong paralysis for affected individuals. Microglia’s dual impact on neuronal regeneration after SCI, driven by their distinct roles at different stages, merits further study. We conducted a bioinformatic analysis of single-cell transcriptomes (scRNA), spatial transcriptomic (ST) data, and bulk RNA-seq data from Gene Expression Omnibus (GEO) datasets. The data were processed using R packages such as “Seurat”, “DESeq2”,“limma” and “GSVA.” Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and the Enrichr web servers. Analysis of single-cell data and spatial transcriptomics has revealed notable changes in the microglial cell landscape in SCI. These changes encompass the inhibition of innate microglial cells, while reactive microglial cells exhibit pronounced reactive hyperplasia. Moreover, the TGFβ signaling pathway plays a crucial role in regulating the migration of innate microglial cells to enhance SCI recovery. However, reactive microglial cells exhibiting high Trem2 expression contribute to the neuroinflammatory response and can effectively modulate neural cell death in SCI. In particular, inhibiting Trem2 in reactive microglial cells not only reduces inflammation but also mitigates spinal cord injury, and enhancing the TGFβ signaling pathway. What’s more, the use of iPSC-derived microglial cells, which have demonstrated their capacity to augment the potential for replacing the functions of naive microglial cells, iPSC-derived microglia have the potential to replace the functions of naive microglial cells, holds significant promise in addressing SCI. Therefore, we posit that the engineering of microglial cells to promote the SCI recovery. The approach ofinhibiting Trem2-mediated neuroinflammatory responses and transplanting iPSC-derived microglia with long-term TGFβ stimulation may offer potential improvements in SCI recovery.