bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial neglect after subcortical stroke: sometimes a cortico-cortical disconnection syndrome
Authors: Sperber Christoph , Rosenzopf Hannah , Wawrzyniak Max , Klingbeil Julian , Saur Dorothee , Karnath Hans-Otto
Published: April 2024

Background and Objectives

Spatial neglect is commonly attributed to lesions of a predominantly right-hemispheric cortical network. Although spatial neglect was also repeatedly observed after lesions to the basal ganglia and the thalamus, many anatomical network models omit these structures. We investigated if disruption of functional or structural connectivity can explain spatial neglect in subcortical stroke.

Methods

We retrospectively investigated data of first-ever, acute stroke patients with right-sided lesions of the basal ganglia (n = 27) or the thalamus (n = 16). Based on lesion location, we estimated i) functional connectivity via lesion-network mapping with normative resting state fMRI data, ii) structural white matter disconnection and iii) tract-wise disconnection of association fibres based on normative tractography data to investigate the association of spatial neglect and disconnection measures.

Results

Apart from very small clusters of functional disconnection observed in inferior/middle frontal regions in lesion-network symptom mapping for basal ganglia lesions, our analyses found no evidence of functional or structural subcortico-cortical disconnection. Instead, the multivariate consideration of lesion load to several association fibres predicted the occurrence of spatial neglect (p = 0.0048; AUC = 0.76), which were the superior longitudinal fasciculus, inferior occipitofrontal fasciculus, superior occipitofrontal fasciculus, and the uncinate fasciculus.

Conclusion

Disconnection of long (cortico-cortical) association fibres can explain spatial neglect in subcortical stroke. Like the competing theory of remote cortical hypoperfusion, this mechanism does not require the assumption of a genuine role for subcortical grey matter structures in spatial neglect.
Correlating Protein Aggregate Structure with Cellular Function in Differentiated Muscle Cells: Discriminating Pathogenic from Non-Pathogenic Forms
Authors: Mallon Sander D. , Bos Erik , Sheikhhassani Vahid , Shademan Milad , Rocca Dino , Voortman Lenard M. , Mashaghi Alireza , Sharp Thomas H. , Raz Vered
Published: April 2024

Ageing has a major adverse impact on maintaining cellular proteostasis and age-related dysregulation leads to an increase in protein aggregation. Equivalently, the accumulation of aggregated proteins accelerates proteostasis impairment. Accumulation of protein aggregates and impaired proteostasis are hallmarks of ageing-associated neuromuscular disorders and tissue degeneration is predominantly in post-mitotic muscle and neuronal cells. A short alanine expansion mutation in the Poly(A) binding protein nuclear 1 (PABPN1) causes Oculopharyngeal muscular dystrophy (OPMD), a rare age-associated protein aggregation myopathy. PABPN1 is a vital RNA-binding protein but OPMD pathology is limited to skeletal muscles connected to nuclear aggregates. In contrast to the mutant PABPN1, the wild-type PABPN1 forms age-associated non-pathogenic aggregates.

We generated an inducible muscle cell models for mutant and wild-type PABPN1 protein aggregation. By combining four different, but complementary, imaging modalities, covering micro- to nanoscale resolutions, we were able to characterise differences in structure and dynamics between pathogenic and non-pathogenic PABPN1 aggregates in differentiated muscle cells. These data allowed us to correlate the structure of aggregates to cellular function, providing important insights into how aggregates lead to cell dysfunction in post-mitotic cells.

Graphical summary
Group social dynamics in a semi-natural setup reveal an adaptive value for aggression in male mice
Authors: Anpilov Sergey , Shemesh Yair , Benjamin Asaf , Biagini Tommaso , Sztainberg Yehezkel , Richter-Levin Alon , Forkosh Oren , Chen Alon
Published: April 2024

Background

Maladaptive aggression in humans is associated with several psychiatric conditions and lacks effective treatment. Nevertheless, aggression constitutes an essential behavior throughout the animal kingdom as long as it is tightly regulated. Studying how social dominance hierarchies (SDH) regulate aggression and access to resources in an enriched environment (EE) can narrow the translational gap between aggression in animal models and humans normal and pathological behavior.

Methods

The ‘social box’ (SB) is a semi-natural setup for automatic and prolonged monitoring of mouse group dynamics. We utilized the SB to decipher complex tradeoffs between aggression, social avoidance, resource allocation, and dominance in two mouse models of increased aggression: (i) a model of early exposure to EE and (ii) a model of oxytocin receptor deficiency (OxtR-/-). While EE increases aggression as an adaptive response to external stimuli, hyper-aggression in OxtR-/-mice is accompanied by marked abnormalities in social behavior.

Results

EE groups exhibited significant social avoidance, and an increased proportion of their encounters developed into aggressive interactions, resulting in lower levels of exploratory activity and overall aggression. The hierarchy in EE was more stable than in control groups, and dominance was correlated with access to resources. In OxtR-/-groups, mice engaged in excessive social encounters and aggressive chasing, accompanied by increased overall activity. In OxtR-/-groups, dominance hierarchies existed but were not correlated with access to resources.

Conclusion

Measuring aggression and social dominance hierarchies in a semi-natural setup reveals the adaptive value of aggression in EE and OxtR-/-mice, respectively. This approach can enhance translational research of pathological aggression.
One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients
Authors: Bénit Paule , Rak Malgorzata , Rustin Pierre
Published: April 2024

With the hope of better understanding and characterizing the dramatic differences in antioxidant response of human cells carrying mutations in the frataxin gene responsible for Friedreich ataxia (FRDA), we studied primary cultures of skin fibroblasts derived from five FRDA patients harboring different large expansion sizes in the frataxin gene. Because oxidative stress was previously established to be instrumental in FRDA, among the many enzymes likely to modulate sensitivity to oxidative stress, we selected some previously shown to play a critical role in this stress. However, we failed to identify a consistent clue to order individual cultures based on these measurements. We therefore focused our study on cell death of FRDA fibroblasts and its modulation by different antioxidants under culture conditions exacerbating sensitivity to oxidative stress. Under conditions that force the cells to rely on mitochondrial activity, we observed significant yet variable FRDA cell proliferation. These conditions were thereafter used to screen the effectiveness of a set of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA,i.e.Uridine, Pyruvate, and Pioglitazone, to prevent or slow down cell mortality. We observed a surprising variability of response to antioxidant molecules even under the similar, controlled conditions used to culture patient’s fibroblasts. We conclude that the specific response of each individual already discernable at cellular level may well play an important role in the frequent difficulties encounter to reach firm conclusions when testing the capacity of antioxidants to counteract the consequences of frataxin depletion, including in clinical trials.
Measuring single-cell density with high throughput enables dynamic profiling of immune cell and drug response from patient samples
Authors: Wu Weida , Ishamuddin Sarah H. , Quinn Thomas W. , Yerrum Smitha , Zhang Ye , Debaize Lydie L. , Kao Pei-Lun , Duquette Sarah Marie , Murakami Mark A. , Mohseni Morvarid , Chow Kin-Hoe , Miettinen Teemu P. , Ligon Keith L. , Manalis Scott R.
Published: April 2024

Cell density, the ratio of cell mass to volume, is an indicator of molecular crowding and therefore a fundamental determinant of cell state and function. However, existing density measurements lack the precision or throughput to quantify subtle differences in cell states, particularly in primary samples. Here we present an approach for measuring the density of 30,000 single cells per hour with a precision of 0.03% (0.0003 g/mL) by integrating fluorescence exclusion microscopy with a suspended microchannel resonator. Applying this approach to human lymphocytes, we discovered that cell density and its variation decrease as cells transition from quiescence to a proliferative state, suggesting that the level of molecular crowding decreases and becomes more regulated upon entry into the cell cycle. Using a pancreatic cancer patient-derived xenograft model, we found that theex vivodensity response of primary tumor cells to drug treatment can predictin vivotumor growth response. Our method reveals unexpected behavior in molecular crowding during cell state transitions and suggests density as a new biomarker for functional precision medicine.
Screening great ape museum specimens for DNA viruses
Authors: Hämmerle Michelle , Guellil Meriam , Trgovec-Greif Lovro , Cheronet Olivia , Sawyer Susanna , Ruiz-Gartzia Irune , Lizano Esther , Rymbekova Aigerim , Gelabert Pere , Bernardi Paolo , Han Sojung , Rattei Thomas , Schuenemann Verena J. , Marques-Bonet Tomas , Guschanski Katerina , Calvignac-Spencer Sebastien , Pinhasi Ron , Kuhlwilm Martin
Published: April 2024

Natural history museum collections harbour a record of wild species from the past centuries, providing a unique opportunity to study animals as well as their infectious agents. Thousands of great ape specimens are kept in these collections, and could become an important resource for studying the evolution of DNA viruses. Their genetic material is likely to be preserved in dry museum specimens, as reported previously for monkeypox virus genomes from historical orangutan specimens. Here, we screened 209 great ape museum specimens for 99 different DNA viruses, using hybridization capture coupled with short-read high-throughput sequencing. We determined the presence of multiple viruses within this dataset from historical specimens and obtained several near-complete viral genomes. In particular, we report high-coverage (>18-fold) hepatitis B virus genomes from one gorilla and two chimpanzee individuals, which are phylogenetically placed within clades infecting the respective host species.
Urbanization Affects Nest Material Composition and Use of Anthropogenic Materials in Blue Tit Nests (Cyanistes caeruleus)
Authors: Roy Joseph , Dominoni Davide M.
Published: April 2024

Avian nests are complex structures that protect eggs and nestlings. Nest-building behaviour varies between species and habitats, and recent work has highlighted that in areas with high human activity and low availability of natural nest material, birds may use anthropogenic material to construct nests. However, we still know relatively little about how nest composition is affected by human presence, including along urban gradients. Here we present the results of a study where we examined how nest composition differed between an urban and a forest population of blue tits, and the impact that variation in nest composition had on reproductive success. We found a significant decrease in the amount of natural materials and an increase in anthropogenic materials in urban compared to forest nests. Earlier urban nests showed a higher amount of anthropogenic materials compared to late urban nests. The amount of moss incorporated in a nest was the strongest predictor of fledgling success, suggesting that the use of anthropogenic material by urban birds might be a maladaptation, and/or that urban birds are constrained in the amount of moss they can use to build their nests. Future studies should aim at quantifying the availability of natural materials to distinguish between these two hypotheses.
LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics
Authors: Shinozuka Kenneth , Tewarie Prejaas K.B. , Luppi Andrea , Lynn Christopher , Roseman Leor , Muthukumaraswamy Suresh , Nutt David J. , Carhart-Harris Robin , Deco Gustavo , Kringelbach Morten L.
Published: April 2024

Psychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiving brain signals, as determined by directed functional connectivity. We measure directed functional hierarchy in a magnetoencephalography (MEG) dataset of 16 healthy human participants who were administered a psychedelic dose (75 micrograms, intravenous) of lysergic acid diethylamide (LSD) under four different conditions. LSD diminishes the asymmetry of directed connectivity when averaged across time. Additionally, we demonstrate that machine learning classifiers distinguish between LSD and placebo more accurately when trained on one of our hierarchy metrics than when trained on traditional measures of functional connectivity. Taken together, these results indicate that LSD weakens the hierarchy of directed connectivity in the brain by increasing the balance between senders and receivers of neural signals.
Self-Assembled Origami Neural Probes for Scalable, Multifunctional, Three-Dimensional Neural Interface
Authors: Yan Dongxiao , Ruiz Jose Roberto Lopez , Hsieh Meng-Lin , Jeong Daeho , Vöröslakos Mihály , Lanzio Vittorino , Warner Elisa V. , Ko Eunah , Tian Yi , Patel Paras R. , ElBidweihy Hatem , Smith Connor S. , Lee Jae-Hyun , Cheon Jinwoo , Buzsáki György , Yoon Euisik
Published: April 2024

Flexible intracortical neural probes have drawn attention for their enhanced longevity in high-resolution neural recordings due to reduced tissue reaction. However, the conventional monolithic fabrication approach has met significant challenges in: (i) scaling the number of recording sites for electrophysiology; (ii) integrating of other physiological sensing and modulation; and (iii) configuring into three-dimensional (3D) shapes for multi-sided electrode arrays. We report an innovative self-assembly technology that allows for implementing flexible origami neural probes as an effective alternative to overcome these challenges. By using magnetic-field-assisted hybrid self-assembly, multiple probes with various modalities can be stacked on top of each other with precise alignment. Using this approach, we demonstrated a multifunctional device with scalable high-density recording sites, dopamine sensors and a temperature sensor integrated on a single flexible probe. Simultaneous large-scale, high-spatial-resolution electrophysiology was demonstrated along with local temperature sensing and dopamine concentration monitoring. A high-density 3D origami probe was assembled by wrapping planar probes around a thin fiber in a diameter of 80∼105 μm using optimal foldable design and capillary force. Directional optogenetic modulation could be achieved with illumination from the neuron-sized micro-LEDs (μLEDs) integrated on the surface of 3D origami probes. We could identify angular heterogeneous single-unit signals and neural connectivity 360° surrounding the probe. The probe longevity was validated by chronic recordings of 64-channel stacked probes in behaving mice for up to 140 days. With the modular, customizable assembly technologies presented, we demonstrated a novel and highly flexible solution to accommodate multifunctional integration, channel scaling, and 3D array configuration.
Identification of genetic bases of male fertility inPyricularia oryzaeby Genome Wide Association Study (GWAS)
Authors: Lassagne Alexandre , Adreit Henri , Malagnac Fabienne , Charriat Florian , Dumartinet Thomas , Parinello Hugues , Gonzalez Anne-Alicia , Tharreau Didier , Fournier Elisabeth
Published: April 2024

The reproductive system of an organism impacts the emergence and evolution of adaptive variants in response to selective constraints. The understanding of the sexual mode of reproduction in pathogens helps to understand their life history. In filamentous Ascomycete fungi, mating type system and the production of gametes are required to reproduce sexually. In the phytopathogenic AscomycetePyricularia oryzae, studies of the genetic determinants of sexual reproduction are still limited to the mating type system. This study focuses on identifying the genes involved in male fertility through the production of male gametes known as microconidia. We performed a GWAS analysis coupled with a local score approach on a wild recombinant population ofPyricularia oryzaephenotyped for microconidia production. We identified one genomic region significantly associated with the quantity of microconidia produced. This region contained nine candidate genes, some of them annotated with functions associated to sexual reproduction in model fungi such asNeurospora crassa,Podospora anserinaandSordaria macrospora. The most promising candidate gene contains a Jumonji domain. Proteins belonging to the Jumonji family are conserved among Eukaryotes and are known to be involved in chromatin regulation.
BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function
Authors: Wright Nathaniel E. , Kennedy Domenick E. , Ai Junting , Veselits Margaret L. , Attaway Mary , Yoon Young me , Durkee Madeleine S. , Veselits Jacob , Maienschein-Cline Mark , Mandal Malay , Clark Marcus R.
Published: April 2024

Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation andIgkrecombination. We hypothesized BRWD1 might play similar insulative roles in the periphery. InBrwd1-/-follicular B cells, GC initiation and class switch recombination following immunization were inhibited. In contrast, inBrwd1-/-GC B cells there was admixing of chromatin accessibility across GC subsets and transcriptional dysregulation including induction of inflammatory pathways. This global molecular GC dysregulation was associated with specific defects in proliferation, affinity maturation, and tolerance. These data suggest that GC subset identity is required for some but not all GC-attributed functions. Furthermore, these data demonstrate a central role for BRWD1 in orchestrating epigenetic transitions at multiple steps along B cell developmental and activation pathways.
Intrinsic diving reflex enhances cognitive performance by alleviating microvascular dysfunction in vascular cognitive impairment
Authors: Tambo Willians , Powell Keren , Wadolowski Steven , Sciubba Daniel , Brines Michael , Li Chunyan
Published: April 2024

Vascular cognitive impairment (VCI) stands as the second-most prominent contributor to cognitive decline, lacking efficacious interventions. Chronic cerebral hypoperfusion (CCH) triggers microvascular dysfunction, which plays a critical role in VCI pathophysiology, emerging as a pivotal therapeutic target. While interventions addressing facets of microvascular dysfunction like angiogenesis and blood-brain barrier functionality show promise, the evaluation of microvascular constriction, another key component, remains unexplored. The diving reflex (DR) represents an oxygen-conserving response, characterized by robust vasodilation and potentially also inducing angiogenesis. In this investigation, we studied DR’s functionality and underlying mechanisms within a rat bilateral common carotid artery occlusion induced CCH model. Remarkably, progressive hippocampal microvascular constriction exhibited strong correlations with short-term memory impairment during both early (R2=0.641) and late phases (R2=0.721) of CCH. Implementation of DR led to a significant reduction in microvascular constriction within the hippocampus (∼2.8-fold) and striatum (∼1.5-fold), accompanied by enhanced vasodilatory capacity and heightened expression of vasoactive neuropeptides. Furthermore, DR attenuated microvascular degeneration across various brain subregions affected by CCH, concomitant with increased levels of multiple angiogenic factors. The reinforced microvascular integrity facilitated by DR corresponded with significantly improved short-term recognition memory and long-term spatial memory functions observed during the late phase of CCH. The comprehensive and synergistic effects of DR on various aspects of microvascular function and cognitive preservation highlight its potential as a disease-modifying therapeutic strategy in VCI.
Exploring the PET in vivo generator134Ce as a theranostic match for225Ac
Authors: Bauer David , De Gregorio Roberto , Pratt Edwin C. , Bell Abram , Michel Alexa , Lewis Jason S.
Published: April 2024

Purpose

The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of134Ce offer perspectives for developing innovative in vivo investigations not possible with225Ac. In this work,225Ac- and134Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match,134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging.

Methods

The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with225Ac or134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The225Ac and134Ce-labeled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.

Results

In vitro and in vivo studies with both225Ac and134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of134Ce’s PET-compatible daughter134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing225Ac-labelled tracers are not quantitatively represented by134Ce PET imaging.

Conclusion

When employing slow-internalizing vectors,134Ce might not be an ideal match for225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of134La. However, this same characteristic makes it possible to estimate the redistribution of225Ac’s progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.

TOC Graphic

Redistribution of progeny. Investigating the225Ac and134Ce decay chain. This figure was created with BioRender.
Divergent Subregional Information Processing in Mouse Prefrontal Cortex During Working Memory
Authors: Sonneborn Alex , Bartlett Lowell , Olson Randall J , Milton Russell , Abbas Atheir I
Published: April 2024

Working memory (WM) is a critical cognitive function allowing recent information to be temporarily held in mind to inform future action. This process depends on coordination between key subregions in prefrontal cortex (PFC) and other connected brain areas. However, few studies have examined the degree of functional specialization between these subregions throughout the phases of WM using electrophysiological recordings in freely-moving animals, particularly mice. To this end, we recorded single-units in three neighboring medial PFC (mPFC) subregions in mouse — supplementary motor area (MOs), dorsomedial PFC (dmPFC), and ventromedial (vmPFC) — during a freely-behaving non-match-to-position WM task. We found divergent patterns of task-related activity across the phases of WM. The MOs is most active around task phase transitions and encodes the starting sample location most selectively. Dorsomedial PFC contains a more stable population code, including persistent sample-location-specific firing during a five second delay period. Finally, the vmPFC responds most strongly to reward-related information during the choice phase. Our results reveal anatomically and temporally segregated computation of WM task information in mPFC and motivate more precise consideration of the dynamic neural activity required for WM.
Genome-Wide Transcriptome Dynamics in Auxin Homeostasis During Fruit Development in Strawberry (F. xananassa)
Authors: Jang Yoon Jeong , Kim Taehoon , Lin Makou , Kim Jeongim , Begcy Kevin , Liu Zhongchi , Lee Seonghee
Published: April 2024

The plant hormone auxin plays a crucial role in regulating important functions in strawberry fruit development. Although a few studies have described the complex auxin biosynthetic and signaling pathway in wild diploid strawberry (Fragaria vesca), the molecular mechanisms underlying auxin biosynthesis and crosstalk in octoploid strawberry fruit development are not fully characterized. To address this knowledge gap, comprehensive transcriptomic analyses were conducted at different stages of fruit development and compared between the achene and receptacle to identify developmentally regulated auxin biosynthetic genes and transcription factors during the fruit ripening process. Similar to wild diploid strawberry, octoploid strawberry accumulates high levels of auxin in achene compared to receptacle. Consistently, genes functionating in auxin biosynthesis and conjugation, such as TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAAs), YUCCA (YUCs), and GRETCHEN HAGEN 3 (GH3s) were found to be primarily expressed in the achene, with low expression in the receptacle. Interestingly, several genes involved in auxin transport and signaling like PIN-FORMED (PINs), AUXIN/INDOLE-3-ACETIC ACID proteins (Aux/IAAs), TRANSPORT INHIBITOR RESPONSE 1 / AUXIN-SIGNALING F-BOX (TIR/AFBs) and AUXIN RESPONSE FACTOR (ARFs) were more abundantly expressed in the receptacle. Moreover, by examining DEGs and their transcriptional profiles across all six developmental stages, we identified key auxin-related genes co-clustered with transcription factors from the NAM-ATAF1,2-CUC2/ WRKYGQK motif (NAC/WYKY), BASIC REGION/ LEUCINE ZIPPER motif (bZIP), and APETALA2/Ethylene Responsive Factor (AP2/ERF) groups. These results elucidate the complex regulatory network of auxin biosynthesis and its intricate crosstalk within the achene and receptacle, enriching our understanding of fruit development in octoploid strawberries.
Microstructural Mapping of Neural Pathways in Alzheimer's Disease using Macrostructure-Informed Normative Tractometry
Authors: Feng Yixue , Chandio Bramsh Q , Villalon-Reina Julio E , Thomopoulos Sophia I , Nir Talia M , Benavidez Sebastian , Laltoo Emily , Chattopadhyay Tamoghna , Joshi Himanshu , Venkatasubramanian Ganesan , John John P , Jahanshad Neda , Reid Robert I , Jack Clifford R , Weiner Michael M , Thompson Paul M ,   the Alzheimer's Disease Neuroimaging Initiative
Published: April 2024

Introduction: Diffusion MRI is sensitive to the microstructural properties of brain tissues and shows great promise in detecting the effects of degenerative diseases. However, many approaches analyze single measures averaged over regions of interest, without considering the underlying fiber geometry. Methods: Here, we propose a novel Macrostructure-Informed Normative Tractometry (MINT) framework, to investigate how white matter microstructure and macrostructure are jointly altered in mild cognitive impairment (MCI) and dementia. We compare MINT-derived metrics with univariate metrics from diffusion tensor imaging (DTI), to examine how fiber geometry may impact interpretation of microstructure. Results: In two multi-site cohorts from North America and India, we find consistent patterns of microstructural and macrostructural anomalies implicated in MCI and dementia; we also rank diffusion metrics' sensitivity to dementia. Discussion: We show that MINT, by jointly modeling tract shape and microstructure, has potential to disentangle and better interpret the effects of degenerative disease on the brain's neural pathways.
Role of miRNA 383 in regulating the mitochondrial machinery and carcinogenesis
Authors: Maurya Ashutosh Kumar , Raji Grace R. , Kumar V.B. Sameer
Published: April 2024

MicroRNAs are a class of small non-coding RNAs, which regulate the expression pattern of various genes in a mechanism similar to RNAi. Along with their importance in normal physiology, microRNAs play crucial role in cancer initiation and progression. Various microRNAs have been reported to be associated with the important hallmarks of the cancer including altered mitochondrial machinery. With our in-silico analysis we found that miR 383 has targets on crucial mitochondrial genes involved in electron transport chain. So, next we checked the role of miR 383 in modulation of the mitochondrial machinery and effect of this alteration in the process of carcinogenesis. The results suggested that miR 383 contribute to carcinogenesis, possibly by modulating the mitochondrial machinery via targeting ND4L and ATP6 genes involved in the complex 1 & 5 of electron transport chain.
MicroRNA 106b: Role in the reprograming of mitochondrial machinery and carcinogenesis in hepatic cells
Authors: Maurya Ashutosh Kumar , Edatt Lincy , Kumar V.B. Sameer
Published: April 2024

Cancer is a disease of unregulated cell growth. The process of initiation and progression of cancer is called carcinogenesis and the factors possessing ability to induce carcinogenesis are called carcinogens. Along with the coding sequence, the non-coding sequence also play very crucial role in the process of carcinogenesis. MicroRNAs are small non-coding RNAs having targets on both the classes of genes important in cancer i.e., oncogenes and tumour suppressor genes, thus act as key play in carcinogenesis. Dysfunctional mitochondrial metabolism has been widely reported in cancer and this malfunctioning could be brought in by suppression of the expression pattern of important mitochondrial genes by microRNAs. Our in-silico analysis revealed that miR 106b possess targets on several important mitochondrial genes involved in various complexes of electron transport chain. Further, we checked the role of miR 106b in reprogramming of the mitochondrial mechanism and carcinogenesis. The results suggested that miR 106b contributes to carcinogenesis in hepatic cells by modulating the mitochondrial metabolism.
The mechanical and sensory signature of plant-based and animal meat
Authors: St. Pierre Skyler R. , Darwin Ethan C. , Adil Divya , Aviles Magaly C. , Date Archer , Dunne Reese A. , Lall Yanav , Vallecillo María Parra , Medina Valerie A. Perez , Linka Kevin , Levenston Marc E. , Kuhl Ellen
Published: April 2024

Eating less meat is associated with a healthier body and planet. Yet, we remain reluctant to switch to a plant-based diet, largely due to the sensory experience of plant-based meat. Food scientists characterize meat using a double compression test, which only probes one-dimensional behavior. Here we use tension, compression, and shear tests–combined with constitutive neural networks–to automatically discover the behavior of eight plant-based and animal meats across the entire three-dimensional spectrum. We find that plant-based sausage and hotdog, with stiffnesses of 95.9±14.1kPa and 38.7±3.0kPa, successfully mimic their animal counterparts, with 63.5±45.7kPa and 44.3±13.2 kPa, while tofurky is twice as stiff, and tofu is twice as soft. Strikingly, a complementary food tasting survey produces in nearly identical stiffness rankings for all eight products (ρ=0.833, p=0.015). Probing the fully three-dimensional signature of meats is critical to understand subtle differences in texture that may result in a different perception of taste.

Our data and code are freely available athttps://github.com/LivingMatterLab/CANN
Deep learning-driven imaging of cell division and cell growth across an entire eukaryotic life cycle
Authors: Ramakanth Shreya , Kennedy Taylor , Yalcinkaya Berk , Neupane Sandhya , Tadic Nika , Buchler Nicolas E. , Argüello-Miranda Orlando
Published: April 2024

The life cycle of biomedical and agriculturally relevant eukaryotic microorganisms involves complex transitions between proliferative and non-proliferative states such as dormancy, mating, meiosis, and cell division. New drugs, pesticides, and vaccines can be created by targeting specific life cycle stages of parasites and pathogens. However, defining the structure of a microbial life cycle often relies on partial observations that are theoretically assembled in an ideal life cycle path. To create a more quantitative approach to studying complete eukaryotic life cycles, we generated a deep learning-driven imaging framework to track microorganisms across sexually reproducing generations. Our approach combines microfluidic culturing, life cycle stage-specific segmentation of microscopy images using convolutional neural networks, and a novel cell tracking algorithm, FIEST, based on enhancing the overlap of single cell masks in consecutive images through deep learning video frame interpolation. As proof of principle, we used this approach to quantitatively image and compare cell growth and cell cycle regulation across the sexual life cycle ofSaccharomyces cerevisiae. We developed a fluorescent reporter system based on a fluorescently labeled Whi5 protein, the yeast analog of mammalian Rb, and a new High-Cdk1 activity sensor, LiCHI, designed to report during DNA replication, mitosis, meiotic homologous recombination, meiosis I, and meiosis II. We found that cell growth preceded the exit from non-proliferative states such as mitotic G1, pre-meiotic G1, and the G0 spore state during germination. A decrease in the total cell concentration of Whi5 characterized the exit from non-proliferative states, which is consistent with a Whi5 dilution model. The nuclear accumulation of Whi5 was developmentally regulated, being at its highest during meiotic exit and spore formation. The temporal coordination of cell division and growth was not significantly different across three sexually reproducing generations. Our framework could be used to quantitatively characterize other single-cell eukaryotic life cycles that remain incompletely described. An off-the-shelf user interfaceYeastvisionprovides free access to our image processing and single-cell tracking algorithms.
bayesTPC: Bayesian inference for Thermal Performance Curves in R
Authors: Sorek Sean , Smith John W. , Huxley Paul J. , Johnson Leah R.
Published: April 2024

1

Reliable predictions of arthropod responses to climatic warming are important because many of these species perform important roles that can directly impact human society.

Thermal performance curves (TPCs) provide useful information on the physiological constraints that limit the capacity of temperature-sensitive organisms (like arthropods) to exist and grow.

NLS pipelines for fitting TPCs are widely available, but these approaches rely on assumptions that can yield unreliable parameter estimates.

We presentbayesTPC, anRpackage for fitting TPCs to trait responses using the nimble language and machinery as the underlying engine for Markov Chain Monte Carlo.bayesTPCaims to support the adoption of Bayesian approaches in thermal physiology, and promote TPC fitting that adequately quantifies uncertainty.
Ancestral reconstruction of polyethylene terephthalate degrading cutinases reveals a rugged and unexplored sequence-fitness landscape
Authors: Vongsouthi Vanessa , Georgelin Rosemary , Matthews Dana , Saunders Jake , Lee Brendon M. , Ton Jennifer , Damry Adam M. , Frkic Rebecca L. , Spence Matthew A. , Jackson Colin J.
Published: April 2024

The enzymatic degradation of polyethylene terephthalate (PET) is a promising method of advanced plastic recycling. Traditional protein engineering methods often fall short in exploring protein sequence space for optimal enzymes due to structural and rational design limitations. Our study addresses this by using multiplexed ancestral sequence reconstruction (mASR) to explore the evolutionary sequence space of PET-degrading cutinases. With a dataset of 397 cutinase sequences, we created a diverse library of ancestral sequences. Experimental characterization of 48 ancestral sequences revealed a wide range of PETase activities, highlighting the value of mASR in uncovering functional variants when compared to traditional ASR. Our results showed that PETase activity in cutinases evolved through diverse pathways involving distal mutations to the active site, and is readily accessible within this family. Additionally, our analysis of the PETase fitness landscape using one-hot encoding (OHE) and local ancestral sequence embedding (LASE) highlighted the effectiveness of LASE in capturing sequence features relevant to activity. This work emphasizes the utility of mASR as a protein engineering tool for identifying enhanced PET-degrading enzymes, and the advantages of the LASE embedding scheme in mapping the PETase fitness landscape.
Dispersed Transcription Start Sites Modulate uORF-Mediated Regulation in Arabidopsis
Authors: Wu Hsin-Yen Larry , Hsu Polly Yingshan
Published: April 2024

In eukaryotic mRNAs, upstream open reading frames (uORFs) in the 5′ untranslated regions (5′ UTRs) often attenuate the translation of downstream main ORFs (mORFs). While some uORFs are beneficial by playing important regulatory roles, uORFs are generally disfavored in evolution. Here we studied how uORF repression is suppressed in Arabidopsis. We found that the heterogeneous distribution of transcription start sites (TSSs) results in heterogeneous 5′ UTRs that selectively exclude uORFs from mRNAs. Thus, only a subset of the transcripts from “uORF-containing” genes truly contain uORFs. Importantly, the fraction of uORFs remaining within transcripts determines uORF overall repressiveness. Interestingly, uORFs that encode conserved peptides are almost exclusively preserved within mRNAs, implying coevolution between TSSs and functional uORFs. Consistent with TSSs determining uORF presence, a sharp transition of AUG frequency between promoters and 5′ UTRs was observed, and this pattern differentiates between genes lacking and carrying translated uORFs. Remarkably, while 55% of the genes are predicted to contain uORFs, upon accounting for the heterogeneous TSSs, only 9% of the transcripts within the mRNA pool genuinely contain uORFs. Our results highlight a profound effect of TSS distribution in determining uORF repressiveness, a factor that was previously overlooked. As a warning note, the TSS heterogeneity should be taken into consideration when studying various 5′ UTR features, such as RNA structures and protein binding motifs, in post-transcriptional gene regulation. The uORFs and other features preferentially preserved in 5′ UTRs (i.e., downstream of TSSs) are more likely to be functional as the result of natural selection.
Taking advantage of reference-guided assembly in a slowly-evolving lineage: application to Testudo graeca
Authors: Mira-Jover Andrea , Graciá Eva , Giménez Andrés , Fritz Uwe , Rodríguez-Caro Roberto Carlos , Bourgeois Yann
Published: April 2024

Background

Obtainingde novochromosome-level genome assemblies greatly enhances conservation and evolutionary biology studies. For many research teams, long-read sequencing technologies (that produce highly contiguous assemblies) remain unaffordable or unpractical. For the groups that display high synteny conservation, these limitations can be overcome by a reference-guided assembly using a close relative genome. Of chelonians, terrestrial tortoises are considered one of the most endangered taxa, which calls for more genomic resources. Here we make the most of high synteny conservation in chelonians to produce the first chromosome-level genome assembly of genusTestudowith one of the most iconic tortoise species in the Mediterranean basin:T. graeca.

Results

We used high quality, paired-end Illumina sequences to build a reference-guided assembly with the chromosome level assembly ofGopherus evgoodei.We reconstructed a 2.29 Gb haploid genome with a scaffold N50 of 107.598 Mb and 5.37% gaps. We sequenced 25998 protein-coding genes, and a 41.2% fraction was determined as repetitive in our assembled genome. Demographic history reconstruction based on the genome revealed two events (population decline and recovery) consistent with previously suggested phylogeographic patterns for the species. This outlines the value of genomes like this for phylogeographic studies.

Conclusions

Our results highlight the value of using close relatives to producede novodraft assemblies in species where such resources are unavailable. OurTestudo graecaannotated genome paves the way to delve deeper into the species’ evolutionary history and provides a valuable resource to increase making direct conservation efforts on their threatened populations.
A roadmap for implanting microelectrode arrays to evoke tactile sensations through intracortical microstimulation
Authors: Downey John E , Schone Hunter R , Foldes Stephen T , Greenspon Charles , Liu Fang , Verbaarschot Ceci , Biro Daniel , Satzer David , Moon Chan Hong , Coffman Brian A , Youssofzadeh Vahab , Fields Daryl , Hobbs Taylor G , Okorokova Elizaveta , Tyler-Kabara Elizabeth C , Warnke Peter C , Gonzalez-Martinez Jorge , Hatsopoulos Nicholas G , Bensmaia Sliman J , Boninger Michael L , Gaunt Robert A , Collinger Jennifer L
Published: April 2024

Intracortical microstimulation (ICMS) is a method for restoring sensation to people with paralysis as part of a bidirectional brain-computer interface to restore upper limb function. Evoking tactile sensations of the hand through ICMS requires precise targeting of implanted electrodes. Here we describe the presurgical imaging procedures used to generate functional maps of the hand area of the somatosensory cortex and subsequent planning that guided the implantation of intracortical microelectrode arrays. In five participants with cervical spinal cord injury, across two study locations, this procedure successfully enabled ICMS-evoked sensations localized to at least the first four digits of the hand. The imaging and planning procedures developed through this clinical trial provide a roadmap for other brain-computer interface studies to ensure successful placement of stimulation electrodes.
Exploring the role of Large Language Models (LLMs) in hematology: a systematic review of applications, benefits, and limitations
Authors: Mudrik Aya , Nadkarni Girish N , Efros Orly , Glicksberg Benjamin S , Klang Eyal , Soffer Shelly
Published: April 2024

Rationale and Objectives

Large Language Models (LLMs) have the potential to enhance medical training, education, and diagnosis. However, since these models were not originally designed for medical purposes, there are concerns regarding their reliability and safety in clinical settings. This review systematically assesses the utility, advantages, and potential risks of employing LLMs in the field of hematology.

Materials and Methods

We searched PubMed, Web of Science, and Scopus databases for original publications on LLMs application in hematology. We limited the search to articles published in English from December 01 2022 to March 25, 2024, coinciding with the introduction of ChatGPT. To evaluate the risk of bias, we used the adapted version of the Quality Assessment of Diagnostic Accuracy Studies criteria (QUADAS-2).

Results

Eleven studies fulfilled the eligibility criteria. The studies varied in their goals and methods, covering medical education, diagnosis, and clinical practice. GPT-3.5 and GPT-4’s demonstrated superior performance in diagnostic tasks and medical information propagation compared to other models like Google’s Bard (currently called Gemini). GPT-4 demonstrated particularly high accuracy in tasks such as interpreting hematology cases and diagnosing hemoglobinopathy, with performance metrics of 76% diagnostic accuracy and 88% accuracy in identifying normal blood cells. However, the study also revealed discrepancies in model consistency and the accuracy of provided references, indicating variability in their reliability.

Conclusion

While LLMs present significant opportunities for advancing clinical hematology, their incorporation into medical practice requires careful evaluation of their benefits and limitations.
Programmes evaluated after teaching infection prevention and control training in health or social care settings: A mapping review
Authors: Brainard Julii , Swindells Isabel Catalina , Hammer Charlotte Christiane , Hornsey Emilio
Published: April 2024

Objective

To provide an overview of country settings, study designs, pathogens, response stage, outcomes and monitoring periods that were described in studies that may provide evidence about effectiveness of training in infection prevention and control programmes, for health or social care workers.

Methods

A systematic review was undertaken to find and summarise aspects of relevant studies published from 2000-2023. Eligible studies had to have pre and post evaluation or post-intervention evaluation in case of trials only. Eligible outcomes were knowledge; adherence/compliance; skills or practice; incidence; case-related mortality. Eligible infectious diseases were those caused by any single cell biological entity (eg virus or protozoa) where vectors were not the primary transmission pathway. Infection prevention settings had to be health/social care (not community or environmental), and participants had to be health or social care staff or trainee staff. Articles from three bibliographic databases were dual-screened independently and key data were extracted and verified. Findings are summarised quantitatively and narratively.

Findings

Included studies numbered 210, of which 187 were pre-post study design and 23 had concurrent comparator arms. Most studies (n=128) were undertaken in high income country settings, especially in the USA (n=31), and 47 were in European Union member countries. There were 20 studies based in China, and 5 in India. Frequency of phases were preparedness (n=47), readiness (n=29), response (n=146), and recovery (n=4). The most commonly mentioned pathogens were SARS-CoV-2 (n=73) and anti-microbial-resistant organisms (AMROs, n=54). Most settings were health care centres but long-term care facilities (n=13) and healthcare delivered by emergency responders (3) were also mentioned. Dental professionals or students were in just 3 studies and 10 studies had trainee health professionals as participants.

Conclusion

The research questions for which the most evidence is likely to exist about effectiveness of IPC training of health care workers would be in response phase in high income countries, especially if the relevant pathogens were AMROs or SARS-CoV-2. In contrast, the prospects are not good for finding evidence that could deliver confident conclusions about optimal IPC training programmes in low income countries, for most specific diseases (eg. cholera or tuberculosis) or in non-response phases.