bluuebunny/crossref_metadata_2025 huggingface dataset:
Voice patches in the marmoset auditory cortex revealed by wide-field calcium imaging
Authors: Zhang Yang , Song Xindong , Guo Yueqi , Chen Chenggang , Osmanski Michael S , Wang Xiaoqin
Published: February 2024

Species-specific vocalizations are behaviorally critical sounds. Similar to faces, species-specific vocalizations are important for the survival and social interactions of both humans and vocal animals. Face patches have been found in the brains of both human and non-human primates. In humans, a voice patch system has been identified on the lateral superior temporal gurus (STG) that is selective to human voices over other sounds. In non-human primates, while vocalization-selective regions were found on the rostral portion of the temporal lobe outside of the auditory cortex in both macaques and marmosets using functional magnetic resonance imaging (fMRI), it is yet clear whether vocalization-selective regions are present in the auditory cortex. Using wide-field calcium imaging, a technique with both high temporal and high spatial resolution, we discovered two voice patches in the marmoset auditory cortex that preferentially respond to marmoset vocalizations over other sounds and carry call types and identity information. One patch is located on the posterior primary auditory cortex (A1), and the other one is located on the anterior non-core region of the auditory cortex. These voice patches are functionally connected and hierarchically organized as shown by latency and selectivity analyses. Our findings reveal the existence of voice patches in the auditory cortex of marmosets and support the notion that similar cortical architectures are adapted for recognizing communication signals for both vocalizations and faces in different primate species.
Maternal Immune Activation Alters Temporal Precision of Spike Generation of CA1 Pyramidal Neurons by Unbalancing GABAergic Inhibition in the Offspring
Authors: Griego Ernesto , Cerna Camila , Sollozo-Dupont Isabel , Fuenzalida Marco , Galván Emilio J.
Published: February 2024

Maternal immune activation (MIA) represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that MIA induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced MIA model. Our data provide evidence that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. Collectively, these findings contribute to the understanding of the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.

Highlights

LPS injection during pregnancy (MIA) increases cytokine production and decreases litter size.

MIA increases the temporal summation of EPSPs in hippocampal neurons.

MIA alters spatial summation and increases the probability of action potential discharge.

MIA alters the inhibitory/excitatory balance of CA1 pyramidal cells.

MIA alters the expression of GAD-positive interneurons.

MIA alters the performance of several behavioral tests in offspring.
Characterization of the SARS-CoV-2 BA.5 Variants in H11-K18-hACE2 Hamsters
Authors: Dong Mei , Lin Haofeng , Pan Margaret , Huang Minghong , Liu Meiqin , Jiang Rendi , Lai Yana , Shi Aimin , Yao Bing , Hu Ben , Shi Zhengli , Zhang Aihua , Gao Yun , Zeng Wentao , Jianmin Li
Published: February 2024

This study aims to comprehensively characterize the SARS-CoV-2 BA.5 variants using K18 hACE2 transgenic mice and golden hamsters as model organisms. Previous research on SARS-CoV-2 has utilized both mouse and hamster models, leading to conflicting results concerning the virus’s lethality. In our study, the finding suggests that H11-K18 hACE2 golden hamsters closely mimic the disease progression observed in human COVID-19 cases caused by BA.5 variants, demonstrating consistent severity and symptoms comparable to severe infections.

Additionally, hamsters exhibit heightened respiratory viral replication, accurately reflecting the clinical viral kinetics observed in humans. The study emphasizes the critical importance of selecting an appropriate animal model for SARS-CoV-2 research, while also providing robust support for the hypothesis that BA.5 variants contribute to fatal outcomes in COVID-19 cases. These findings highlight the pivotal role of the golden hamster model in advancing our understanding of the pathogenic mechanisms underlying SARS-CoV-2 variants, as well as in the development of targeted therapeutic strategies.

Significance Statement

Our research work explores groundbreaking insights that could reshape our understanding of COVID-19 and pave the way for targeted therapies. We use golden hamster models to express the possibility of different animal models could contribute to human diseases. We hope this finding could clarify some conflicts existed, and help further development of medication for COVID.
Partitioning the Genomic Components of Behavioral Disinhibition and Substance Use (Disorder) Using Genomic Structural Equation Modeling
Authors: Horwitz Tanya B. , Zorina-Lichtenwalter Katerina , Gustavson Daniel E. , Grotzinger Andrew D. , Stallings Michael C.
Published: February 2024

Externalizing behaviors encompass manifestations of risk-taking, self-regulation, aggression, sensation-/reward-seeking, and impulsivity. Externalizing research often includes substance use (SU), substance use disorder (SUD), and other (non-SU/SUD) “behavioral disinhibition” (BD) traits. Genome-wide and twin research have pointed to overlapping genetic architecture within and across SUB, SUD, and BD. We created single-factor measurement models—each describing SUB, SUD, or BD traits--based on mutually exclusive sets of European ancestry genome-wide association study (GWAS) statistics exploring externalizing variables. We then applied trivariate Cholesky decomposition to these factors in order to identify BD-specific genomic variation and assess the partitioning of BD’s genetic covariance with each of the other facets. Even when the residuals for indicators relating to the same substance were correlated across the SUB and SUD factors, the two factors yielded a large zero-order correlation (rg=.803). BD correlated strongly with the SUD (rg=.774) and SUB factors (rg=.778). In our initial decompositions, 33% of total BD variance remained after removing variance associated with SUD and SUB. The majority of covariance between BD and SU and between BD and SUD was shared across all factors. When only nicotine/tobacco, cannabis, and alcohol were included for the SUB/SUD factors, their zero-order correlation increased to rg=.861; in corresponding decompositions, BD-specific variance decreased to 27%. In summary, BD, SU, and SUD were highly genetically correlated at the latent factor level, and a significant minority of genomic BD variation was not shared with SU and/or SUD. Further research can better elucidate the properties of BD-specific variation by exploring its genetic/molecular correlates.
Nanobody-targeted conditional antimicrobial therapeutics
Authors: Ngambenjawong Chayanon , Ko Henry , Pishesha Novalia , Ploegh Hidde L. , Bhatia Sangeeta N.
Published: February 2024

Conditional therapeutics that rely on disease microenvironment-specific triggers for activation are a promising strategy to improve therapeutic cargos. Among the investigated triggers, protease activity is used most often, because of its dysregulation in several diseases. How to optimally fine-tune protease activation for different therapeutic cargos remains a challenge. Here, we designed nanobody-targeted conditional antimicrobial therapeutics to deliver a model therapeutic peptide and protein to the site of bacterial infection. We explored several parameters that influence proteolytic activation. We report the use of targeting nanobodies to enhance the activation of therapeutics that are otherwise activated inefficiently, despite extensive optimization of the cleavable linker. Specifically, pairing of Ly6G/C or ADAM10-targeting nanobodies with ADAM10-cleavable linkers improved activation via proximity-enabled reactivity. More broadly, this optimization framework provides a guideline for the development of conditional therapeutics to treat various diseases where protease activity is dysregulated.
In-situ microscopy-assisted meniscus-guided coating for highly sensitive reduced graphene oxide-based nanocomposite biosensor
Authors: Kim Su Yeong , Kim Min , Lee Jeong-Chan , Jeon Byeongjoo , Kim Hanul , Choi Siyoung Q. , Oh Byungkook , Kang Heemin , Kim Hyung-Ryong , Park Steve
Published: February 2024

Meniscus-guided coating provides great potential for fabricating the nanomaterial-based thin film into high-performance biomedical devices due to the strong relationship between its experimental parameters and the resulting structural properties. However, the complex leverages of various fluid dynamics phenomena hamper optimization of structural properties and device performances. This is due to the absence of in-depth analytical techniques to observe, interpret, and control the solidification process. In this work, we propose an analytical strategy based on the rheological properties of a rGO-based solution using computational fluid dynamics modeling and in situ high-speed microscopy. Through this, we reveal the principles of the solidification mechanism that creates a rGO-based nanocomposite in the form of highly- and evenly-wrinkled thin film and the experimental condition at which this mechanism occurs. The optimized thin film presents high electroconductivity, low chip-to-chip signal variation, and multiplexed electrochemical biosensing performance for three classes of antibodies related to the excessive enrichment of endoplasmic reticulum stress, with detection limits of picomolar levels. This optimizing technique can be universally applied to understanding various solution-based coating systems, and can streamline the production of large-area and high-quality nanocomposite biosensors.
Modeling heterogeneity in single-cell perturbation states enhances detection of response eQTLs
Authors: Valencia Cristian , Nathan Aparna , Kang Joyce B. , Rumker Laurie , Lee Hyunsun , Raychaudhuri Soumya
Published: February 2024

Identifying response expression quantitative trait loci (reQTLs) can help to elucidate mechanisms of disease associations. Typically, such studies model the effect of perturbation as discrete conditions. However, perturbation experiments usually affect perturbed cells heterogeneously. We demonstrated that modeling of per-cell perturbation state enhances power to detect reQTLs. We use public single-cell peripheral blood mononuclear cell (PBMC) data, to study the effect of perturbations withInfluenza A virus(IAV),Candida albicans(CA),Pseudomonas aeruginosa(PA), andMycobacterium tuberculosis(MTB) on gene regulation. We found on average 36.9% more reQTLs by accounting for single cell heterogeneity compared to the standard discrete reQTL model. For example, we detected a decrease in the eQTL effect of rs11721168 forPXKin IAV. Furthermore, we found that on average of 25% reQTLs have cell-type-specific effects. For example, in IAV the increase of the eQTL effect of rs10774671 forOAS1was stronger in CD4+T and B cells. Similarly, in all four perturbation experiments, the reQTL effect forRPS26was stronger in B cells. Our work provides a general model for more accurate reQTL identification and underscores the value of modeling cell-level variation.
Pooled CRISPR interference screening identifies crucial transcription factors in gas-fermentingClostridium ljungdahlii
Authors: Zhang Huan , Feng Huibao , Xing Xin-Hui , Jiang Weihong , Zhang Chong , Gu Yang
Published: February 2024

Gas-fermentingClostridiumspecies hold tremendous promise for one-carbon biomanufacturing. To unlock their full potential, it is crucial to unravel and optimize the intricate regulatory networks that govern these organisms; however, this aspect is currently underexplored. In this study, we employed pooled CRISPR interference (CRISPRi) screening to uncover a wide range of functional transcription factors (TFs) inClostridium ljungdahlii, a representative species of gas-fermentingClostridium, with a special focus on the TFs associated with the utilization of carbon resources. Among the 425 TF candidates, we identified 75 and 68 TF genes affecting the heterotrophic and autotrophic growth ofC. ljungdahlii, respectively. We directed our attention on two of the screened TFs, NrdR and DeoR, and revealed their pivotal roles in the regulation of deoxyribonucleotides (dNTPs) supply, carbon fixation, and product synthesis inC. ljungdahlii, thereby influencing the strain performance in gas fermentation. Based on this, we proceeded to optimize the expression ofdeoRinC. ljungdahliiby adjusting its promoter strength, leading to improved growth rate and ethanol synthesis ofC. ljungdahliiwhen utilizing syngas. This study highlights the effectiveness of pooled CRISPRi screening in gas-fermentingClostridiumspecies, expanding the horizons for functional genomic research in these industrially important bacteria.
Neural decoding of the speech envelope: Effects of intelligibility and spectral degradation
Authors: MacIntyre Alexis Deighton , Carlyon Robert P , Goehring Tobias
Published: February 2024

During continuous speech perception, endogenous neural activity becomes time-locked to acoustic stimulus features, such as the speech amplitude envelope. This speech-brain coupling can be decoded using non-invasive brain imaging techniques, including electroencephalography (EEG). Neural decoding may provide clinical use as an objective measure of stimulus encoding by the brain - for example during cochlear implant (CI) listening, wherein the speech signal is severely spectrally degraded. Yet, interplay between acoustic and linguistic factors may lead to top-down modulation of perception, thereby complicating audiological applications. To address this ambiguity, we assess neural decoding of the speech envelope under spectral degradation with EEG in acoustically hearing listeners (n = 38; 18-35 years old) using vocoded speech. We dissociate sensory encoding from higher-order processing by employing intelligible (English) and non-intelligible (Dutch) stimuli, with auditory attention sustained using a repeated-phrase detection task. Subject-specific and group decoders were trained to reconstruct the speech envelope from held-out EEG data, with decoder significance determined via random permutation testing. Whereas speech envelope reconstruction did not vary by spectral resolution, intelligible speech was associated with better decoding accuracy in general. Results were similar across subject-specific and group analyses, with less consistent effects of spectral degradation in group decoding. Permutation tests revealed possible differences in decoder statistical significance by experimental condition. In general, while robust neural decoding was observed at the individual and group level, variability within participants would most likely prevent the clinical use of such a measure to differentiate levels of spectral degradation and intelligibility on an individual basis.
Nasal commensals reduceStaphylococcus aureusproliferation by restricting siderophore availability
Authors: Zhao Y , Bitzer A , Power JJ , Belikova D , Torres-Salazar B , Adolf LA , Gerlach DL , Krismer B , Heilbronner S
Published: February 2024

Background

The human microbiome is critically associated with human health and disease. One aspect of this is that antibiotic-resistant opportunistic bacterial pathogens such as methicillin-resistantStaphylococcus aureuscan reside within the nasal microbiota which increases the risk of infections. Epidemiological studies of the nasal microbiome have revealed positive and negative correlations between non-pathogenic species andS. aureus, but the underlying molecular mechanisms remain poorly understood. The nasal cavity is iron-limited and bacteria are known to produce iron-scavenging siderophores to proliferate in such environments. Siderophores are public goods that can be consumed by all members of a bacterial community. Accordingly, siderophores are known to mediate bacterial competition and collaboration but their role in the nasal microbiome is unknown.

Results

Here we show that siderophore acquisition is crucial forS. aureusnasal colonizationin vivo. We screened 94 nasal bacterial strains from seven genera for their capacity to produce siderophores as well as to consume the siderophores produced byS. aureus.We found that 80% of the strains engaged in siderophoremediated interactions withS. aureus.Non-pathogenic corynebacterial species were found to be prominent consumers ofS. aureussiderophores. In co-culture experiments, consumption of siderophores by competitors reducedS. aureusgrowth in an iron-dependent fashion.

Conclusions

Our data show a wide network of siderophore mediated interactions between the species of the human nasal microbiome and provide mechanistic evidence for inter-species competition and collaboration impacting pathogen proliferation. This opens avenues for designing nasal probiotics to displaceS. aureusfrom the nasal cavity of humans.
Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction
Authors: Müller Marion , Schubert Torben , Welke Cornelius , Schulz Tina Johanna , Patschkowski Thomas , Maske Tibor , Lengenfelder Luisa Andrea , Landwehrjohann Lucia , Donhauser Elfi , Vogt Elisa Theres , Stratmann Bernd , Hense Jurek , Lüdtke Simon , Düfer Martina , Tolstik Elen , Dierks Johann , Hormann Felix-Levin , Heiles Sven , Lorenz Kristina , Reil Jan-Christian , Schopfer Francisco Jose , Freeman Bruce A. , Rudolph Volker , Schlomann Uwe , Klinke Anna
Published: February 2024

Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunctions contribute to HFpEF progression. Nitro-oleic acid (NO2-OA) impacts metabolic processes by improving glucose tolerance and adipocyte function. In this study, 4 week treatment with NO2-OA ameliorated diastolic dysfunction in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. A proteomic analysis of left ventricular tissue revealed, that one third of the identified proteins, mostly mitochondrial proteins, were upregulated in hearts of NO2-OA-treated HFpEF mice compared to controls and vehicle-treated HFpEF mice, which was confirmed by immunoblot. Activation of the 5’-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediated an enhancement of mitochondrial biogenesis in hearts of NO2-OA-treated HFpEF mice. In cardiomyocytes under metabolic stress, NO2-OA increased mitochondrial protein level accompanied by enhanced oxidative phosphorylation. In conclusion, targeting mitochondrial integrity in HFpEF leads to improved diastolic function.
Negative Life Events and Epigenetic Ageing: a Study in the Netherlands Twin Register
Authors: Gonggrijp B.M.A. , van de Weijer S.G.A. , Bijleveld C.C.J.H. , Boomsma D.I. , van Dongen J.
Published: February 2024

We aimed to understand the long-term impact of negative life events (NLE) on epigenetic aging in 1,808 adults from the Netherlands Twin Register, analyzing five epigenetic biomarkers (Hannum, Horvath, PhenoAge, GrimAge, DunedinPACE) and a series of NLE, including victimization and economic hardship. In population-level analyses, associations between a higher number of NLE (particularly financial adversities, sexual crimes, and job loss) were seen for GrimAge and DunedinPACE biomarkers. The association between the number of NLE and financial problems and epigenetic age acceleration measured by the GrimAge biomarker persisted after adjusting for BMI, smoking, and white blood cell counts. In monozygotic twin pairs discordant for NLE (274 pairs) the associations were diminished, indicating that the population associations may be confounded by shared familial (genetic and environmental) factors. These findings underscore the intricate link between environmental stressors and biological aging, stressing the need for comprehensive studies considering both genetic and environmental influences.
Dissociable roles of neural pattern reactivation and transformation during recognition of words read aloud and silently: An MVPA study of the production effect
Authors: Bailey Lyam M. , Matheson Heath E. , Fawcett Jonathon M. , Bodner Glen E. , Newman Aaron J.
Published: February 2024

Recent work surrounding the neural correlates of episodic memory retrieval has focussed on the decodability of neural activation patterns elicited by unique stimuli. Research in this area has revealed two distinct phenomena: (i) neural pattern reactivation, which describes the fidelity of activation patterns between encoding and retrieval; (ii) neural pattern transformation, which describes systematic changes to these patterns. This study used fMRI to investigate the roles of these two processes in the context of the production effect, which is a robust episodic memory advantage for words read aloud compared to words read silently. Twenty-five participants read words either aloud or silently, and later performed old-new recognition judgements on all previously seen words. We applied multivariate analysis to compare measures of reactivation and transformation between the two conditions. We found that, compared with silent words, successful recognition of aloud words was associated with reactivation in the left insula and transformation in the left precuneus. By contrast, recognising silent words (compared to aloud) was associated with relatively more extensive reactivation, predominantly in left ventral temporal and prefrontal areas. We suggest that recognition of aloud words might depend on retrieval and metacognitive evaluation of speech-related information that was elicited during the initial encoding experience, while recognition of silent words is more dependent on reinstatement of visual-orthographic information. Overall, our results demonstrate that different encoding conditions may give rise to dissociable neural mechanisms supporting single word recognition.
Unraveling the Role of Urea Hydrolysis in Salt Stress Response during Seed Germination and Seedling Growth inArabidopsis thaliana
Authors: Bu Yuanyuan , Dong Xingye , Zhang Rongrong , Shen Xianglian , Liu Yan , Wang Shu , Takano Tetsuo , Liu Shenkui
Published: February 2024

Urea is intensively utilized as a nitrogen fertilizer in agriculture, originating either from root uptake or from catabolism of arginine by arginase. Despite its extensive use, the underlying physiological mechanisms of urea, particularly its adverse effects on seed germination and seedling growth under salt stress remains unclear. In this study, we demonstrate that salt stress induces excessive hydrolysis of arginine-derived urea, leading to an increase in cytoplasmic pH within seed radical cells, which, in turn, triggers salt-induced inhibition of seed germination (SISG) and hampers seedling growth. Our findings challenge the long-held belief that ammonium accumulation and toxicity are the primary causes of SISG, offering a novel perspective on the mechanism underlying these processes. This study provides significant insights into the physiological impact of urea hydrolysis under salt stress, contributing to a better understanding of SISG.
Multi-gradient Permutation Survival Analysis Identifies Mitosis and Immune Signatures Steadily Associated with Cancer Patient Prognosis
Authors: Cai Xinlei , Ye Yi , Liu Xiaoping , Fang Zhaoyuan , Chen Luonan , Li Fei , Ji Hongbin
Published: February 2024

The inconsistency of the association between genes and cancer prognosis is often attributed to many variables that contribute to patient survival. Whether there exist the Genes Steadily Associated with Prognosis (GEARs) and what their functions are remain largely elusive. We have developed a novel method called “Multi-gradient Permutation Survival Analysis” (MEMORY) to screen the GEARs using RNA-seq data from the TCGA database. Then we employed a network construction approach to identify hub genes from GEARs, and utilized them for cancer classification. In the case of LUAD, the GEARs were found to be related to mitosis. Our analysis suggested that LUAD cell lines carryingPIK3CAmutations exhibit increased drug resistance. For BRCA, the GEARs were related to immunity. The analysis revealed thatCDH1mutation might influence immune infiltration through the EMT process in BRCA. We further explored the prognostic relevance of mitosis and immunity through their respective scores. This study offers significant biological insights into GEARs and highlights their potential as robust prognostic indicators across diverse cancer types.
Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities
Authors: Loukogeorgakis Stavros P. , Michielin Federica , Al-Juffali Noura , Jimenez Julio , Shibuya Soichi , Allen-Hyttinen Jessica , Eastwood Patrice , Alhendi Ahmed S.N. , Davidson Joseph , Naldi Eleonora , Maghsoudlou Panagiotis , Tedeschi Alfonso , Khalaf Sahira , Khabbush Aziza , Plate Manuela , Fachin Camila , Dias Andre Dos Santos , Sindhwani Nikhil , Scaglioni Dominic , Xenakis Theodoros , Sebire Neil , Giomo Monica , Eaton Simon , Toelen Jaan , Luni Camilla , Pavan Piero , Carmeliet Peter , Russo Francesca , Janes Samuel , Nikolic Marko Z. , Elvassore Nicola , Deprest Jan , Coppi Paolo De
Published: February 2024

Rationale

Congenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known.

Objectives

To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology.

Methods

Fetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel humanex vivomodel of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation (Figure 1A). A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDHin vivo.

Measurements and Main Results

VEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls.

Conclusions

This innovative approach could have a significant impact on the treatment of CDH.
DO ORGANIC, CONVENTIONAL, AND INTENSIVE APPROACHES IN LIVESTOCK FARMING HAVE AN IMPACT ON THE CIRCULATION OF INFECTIOUS AGENTS? A SYSTEMATIC REVIEW, FOCUSED ON DAIRY CATTLE
Authors: Pajoro Massimo , Brilli Matteo , Pezzali Giulia , Kramer Laura , Moroni Paolo , Bandi Claudio
Published: February 2024

A common thought is that extensive and organic breeding systems are associated with lower prevalence of infections in livestock animals, compared to intensive ones. In addition, organic systems limit the use of antimicrobial drugs, which may lead to lower emergence of antimicrobial resistances (AMR). To examine these issues, avoiding any a priori bias, we carried out a systematic literature search on dairy cattle breeding. Search was targeted to publications that compared different types of livestock farming (intensive, extensive, conventional, organic) in terms of the circulation of infectious diseases and AMR. A total of 101 papers were finally selected. These papers did not show any trend in the circulation of the infections in the four types of breeding systems. However, AMR was more prevalent on conventional dairy farms compared to organic ones. The prevalence of specific pathogens and types of resistances were frequently associated with specific risk factors that were not strictly related to the type of farming system. In conclusion, we did not find any evidence suggesting that extensive and organic dairy farming bears any advantage over the intensive and conventional ones, in terms of the circulation of infectious agents.
RNA dicing regulates the expression of an oncogenic JAK1 isoform
Authors: Malka Yuval , van der Kammen Rob , Ju Shinyeong , Alkan Ferhat , Lee Cheolju , Faller William James
Published: February 2024

mRNA transcripts have limited potential for protein synthesis, defined by their open reading frames1. However, recent advances have revealed a far more complex reality, in which the proteome exceeds the perceived limits of the transcriptome2–6exposing a significant gap in our understanding. Our prior studies have demonstrated that mRNA can undergo further processing, yielding truncated, uncapped mRNAs with translation potential2,7. Yet, the biological importance of this process remains mostly unclear. Here, we demonstrate that cleavage within the coding sequence of JAK1 mRNA produces an uncapped variant downstream to the cleavage site, at the expense of the full-length transcript. This results in the independent translation of the JH1 kinase domain, a process we term ‘RNA dicing’. Notably, canonical and diced JAK1 variants have distinct impacts on cell proliferation and tumorigenesis, operating independently, localizing to distinct cellular compartments. In addition, the activation of JAK1 signaling through IFNγ induction promotes the dicing of JAK1, thereby altering the balance of isoforms present. Base editor screens reveal that stop-codon nonsense mutations, which are typically considered loss-of-function, have differing impacts depending on their position relative to the dicing site. In agreement with this, JAK1 nonsense frameshift (JAK1fs) mutations in endometrial tumors inhibit the tumor-suppressive functions of canonical JAK1, while amplifying the oncogenic potential of the diced JH1 kinase domain. Lastly, we demonstrate that Momelotinib8, a JAK1-specific inhibitor, is more effective in cancer cells carrying a “loss-of-function” JAK1fs mutation, highlighting the significant impact of RNA dicing biology as a potent tool for patient stratification. Our findings characterize RNA dicing as a fundamental regulatory machinery that diversifies the potential products of a single mRNA molecule, and allows for significant variation in biological function.
Using runs of homozygosity and machine learning to disentangle sources of inbreeding and infer self-fertilization rates
Authors: Zeitler Leo , Gilbert Kimberly J.
Published: February 2024

Runs of homozygosity (ROHs) are indicative of elevated homozygosity and inbreeding due to mating of closely related individuals. Self-fertilization can be a major source of inbreeding which elevates genomewide homozygosity and thus should also create long ROHs. While ROHs are frequently used to understand inbreeding in the context of conservation and selective breeding, as well as for consanguinity of populations and their demographic history, it remains unclear how ROH characteristics are altered by selfing and if this confounds expected signatures of inbreeding due to demographic change. Using simulations, we study the impact of the mode of reproduction and demographic history on ROHs. We apply random forests to identify unique characteristics of ROHs, indicative of different sources of inbreeding. We pinpoint distinct features of ROHs that can be used to better characterize the type of inbreeding the population was subjected to and to predict outcrossing rates and complex demographic histories. Using additional simulations and four empirical datasets, two from highly selfing species and two from mixedmaters, we predict the selfing rate and validate our estimations. We find that self-fertilization rates are successfully identified even with complex demography. Population genetic summary statistics improve algorithm accuracy particularly in the presence of additional inbreeding, e.g., from population bottlenecks. Our findings highlight the importance of ROHs in disentangling confounding factors related to various sources of inbreeding and demonstrate situations where such sources cannot be differentiated. Additionally, our random forest models provide a novel tool to the community for inferring selfing rates using genomic data.
Exposure assessment suggests some cytotoxicBacillus cereusgroup genotypes can grow over 3 logs in HTST milk throughout the shelf life at temperature abuse conditions
Authors: Su Jun , Chandross-Cohen Tyler , Qian Chenhao , Carroll Laura , Kimble Kayla , Yount Mackenna , Wiedmann Martin , Kovac Jasna
Published: February 2024

CytotoxicBacillus cereusgroup strains are common causes of foodborne illness including diarrhea. However, our ability to assess food safety risks associated with the exposure to cytotoxicB. cereusgroup strainsviacontaminated food is limited due to the lack of predictive tools. In this study, we experimentally quantified the growth of 17 cytotoxicB. cereusgroup strains, representing six phylogenetic groups, in skim milk broth and used the growth data to develop an exposure assessment model. While none of the tested strains showed detectable growth in HTST milk at 4 or 6°C, 15 of the 17 strains showed growth at 10°C, 1 of the 17 strains showed growth at 8°C, and all strains grew at ≥14°C. Growth data for 16 strains allowed us to generate linear secondary growth models, which were then used to develop the exposure assessment model. We simulated a five-stage supply chain with up to 35 consumer storage days, as that was the timing when distinguishable variations in percent milk containers over 105CFU/m with differentB. cereusgenotypes were observed. When the initial contamination level of the HTST milk is set at an average of 100 CFU/mL, the model predicts that, on consumer home storage day 21 and 35, 2.81±0.66 and 4.13±2.53 % (mean ± standard deviation) of the milk containers would exceedB. cereusgroup concentrations of 105CFU/mL; these data represent the average across all strains. Sensitivity analysis showed that variation in the input parameter Q0, the initial physiological state of cells, has the largest effect on model’s prediction for 1 of 4 group II isolates, 1 of 6 group IV isolates and both group V isolates, suggesting the need to better characterize the growth parameters of these isolates. What-if scenario analysis showed that increased mean and variability in storage temperature at the consumer’s home both have substantial influence on final predictedB. cereusgroup concentration in milk containers. This model introduces an initial tool designed to facilitate risk-based food safety decision making for products that are contaminated with lowB. cereusgroup levels.
p300 KAT regulates SOX10 stability and function in human melanoma
Authors: Waddell Aaron , Grbic Nicole , Leibowitz Kassidy , Wyant W. Austin , Choudhury Sabah , Park Kihyun , Collard Marianne , Cole Philip A. , Alani Rhoda M.
Published: February 2024

SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in melanoma proliferation, while preventing a concomitant increase in tumor cell invasion. Here, we report that the lysine acetyltransferase (KAT)EP300andSOX10gene loci on Chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor, A-485, downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlowmelanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion, and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.
Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice
Authors: Hwang Jiyeon , Lee Sangbhin , Okada Junichi , Liu Li , Pessin Jeffrey E. , Chua Streamson C. , Schwartz Gary J. , Jo Young-Hwan
Published: February 2024

The visceral organ-brain axis, mediated by vagal sensory neurons, is essential for maintaining various physiological functions. Here, we investigate the impact of liver-projecting vagal sensory neurons on energy balance, hepatic steatosis, and anxiety-like behavior in mice under obesogenic conditions. A small subset of vagal sensory neurons in both the left and right ganglia innervate the liver and project centrally to the nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, and peripherally to the periportal areas in the liver. Surprisingly, the loss of liver-projecting vagal sensory neurons via caspase-induced selective destruction of advillin-positive neurons prevents diet-induced obesity, and these outcomes are associated with increased energy expenditure. Although males and females exhibit improved glucose homeostasis following disruption of liver-projecting vagal sensory neurons, only male mice display increased insulin sensitivity. Furthermore, the loss of liver-projecting vagal sensory neurons limits the progression of hepatic steatosis in mice fed a steatogenic diet. Intriguingly, mice lacking liver-innervating vagal sensory neurons also exhibit less anxiety-like behavior compared to control mice. Therefore, modulation of the liver-brain axis may aid in designing effective treatments for both psychiatric and metabolic disorders associated with obesity and MAFLD.
Development of a 3Din vitrohuman-sized model of cervical dysplasia to evaluate the delivery of ethyl cellulose-ethanol injection for the treatment of cervical dysplasia ablation
Authors: Cadena Ines A , Adhikari Gatha , Almer Alyssa , Jenne Molly , Obasi Ndubuisi , Zurita Nicolas F. Soria , Rochefort Willie E , Mueller Jenna L. , Fogg Kaitlin C.
Published: February 2024

Cervical cancer, the second leading cause of cancer-related death for women worldwide, remains a preventable yet persistent disease that disproportionately affects women in low and middle-income countries (LMICs). While existing therapies for treating cervical dysplasia are effective, they are often inaccessible in LMICs. Ethanol ablation is an alternative low-cost, accessible therapy that we previously enhanced into an ethyl cellulose (EC)-ethanol gel formulation to improve efficacy. When seeking to evaluate EC-ethanol for cervical dysplasia, we found a paucity of relevant animal models. Thus, in this study, we developed a 3Din vitromodel of cervical dysplasia featuring a central lesion of cervical cancer cells surrounded by fibroblasts and keratinocytes to enable the evaluation of EC-ethanol and other novel therapeutics. Our GelMA-based 3D model successfully captured the architectural complexity of cervical dysplasia, showcasing cell response and high viability. The GelMA hydrogel formulation (8.7% w/v) exhibited viscoelastic properties akin to human cervical tissue. Using micro-CT imaging, we assessed EC-ethanol injection deposition in the hydrogel, revealing retention of virtually the entire injected volume near the injection site. Finally, we evaluated the EC-ethanol injection’s efficacy in eliminating cervical cancer cells. The EC-ethanol injection led to a significant decrease in cancer cell viability while preserving healthy cells in the 3Din vitromodel. Taken together, ourin vitromodel mirrored the architecture of cervical dysplasia and demonstrated the potential of EC-ethanol for localized treatment of cervical dysplasia.
MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative
Authors: Yang Zikun , Cieza Basilio , Reyes-Dumeyer Dolly , Lee Annie , Ma Yiyi , Yilmaz Elanur , Lantigua Rafael , Miller Gary W , Brown Lewis M , Honig Lawrence , Ciener Benjamin , Leskinen Sandra , Sivakumar Sharanya , Vardarajan Badri , Dugger Brittany N , Jin Lee-Way , Murray Melissa E , Dickson Dennis W , Rissman Robert A , Hiniker Annie , Pericak-Vance Margaret , Vance Jeff , Foroud Tatiana M , Kizil Caghan , Teich Andrew F , Mayeux Richard , Tosto Giuseppe
Published: February 2024

Alzheimer’s Disease (AD) exhibits a complex molecular and phenotypic profile. Investigating gene expression plays a crucial role in unraveling the disease’s etiology and progression. Transcriptome data across ethnic groups lack, negatively impacting equity in intervention and research.

We employed 565 brains across six U.S. brain banks (n=399 non-Hispanic Whites,n=113 Hispanics,n=12 African Americans) to generated bulk RNA sequencing from prefrontal cortex. We sought to identify cross-ancestry and ancestry-specific differentially expressed genes (DEG) across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We further validated our findings using the Religious Orders Study/Memory Aging Project brains (ROS/MAP;n=1,095) and performed metanalysis (n=1,660). We conducted Gene Set and Variation and Enrichment analysis (GSVA; GSEA). We employed a machine-learning approach for phenotype prediction and gene prioritization to construct a polytranscriptomics risk score (PTRS) splitting our sample into training and testing sub-samples, either randomly or by ethnicity (“ancestry-agnostic” and “ancestry-aware”, respectively). Lastly, we validated top DEG using single-nucleus RNA sequencing (snRNAseq) data.

We identified several DEG associated with Braak staging: AD-known genesVGF(Padj=3.78E- 07) andADAMTS2(Padj=1.21E-04) were consistently differentially expressed across statistical models, ethnicities, and replicated in ROS/MAP. Genes from the heat shock protein (HSP) family, e.g.HSPB7(Padj=3.78E-07), were the top differentially expressed genes and replicated in ROS/MAP. Ethnic-stratified analyses prioritizedTNFSF14andSPOCD1as top Hispanics DEG. GSEA highlighted “Alzheimer disease” (Padj=4.24E-06) and “TYROBP causal network in microglia” (Padj=1.68E-08) pathways. Up- and down-regulated genes were enriched in several pathways (e.g. “Immune response activation signal pathways”, “Vesicle-mediated transport in synapse”, “cognition”). Ancestry-agnostic and ancestry-aware PTRS effectively classified brains (AUC=0.77 and 0.73 respectively) and replicated in ROS/MAP. snRNAseq validated prioritized genes, includingVGF (downregulated in neurons;Padj=1.1 E-07).

This is the largest diverse AD transcriptome in post-mortem brain tissue, to our knowledge. We identified perturbated genes, pathways and network expressions in AD brains resulting in cross- ethnic and ethnic-specific findings, ultimately highlighting the diversity within AD pathogenesis. The latter underscores the need for an integrative and personalized approach in AD studies.
nERdy: network analysis of endoplasmic reticulum dynamics
Authors: Samudre Ashwin , Gao Guang , Cardoen Ben , Nabi Ivan Robert , Hamarneh Ghassan
Published: February 2024

The endoplasmic reticulum (ER) comprises smooth tubules, ribosome-studded sheets, and peripheral sheets that can present as tubular matrices. ER shaping proteins determine ER morphology, however, their role in tubular matrix formation requires reconstructing the dynamic, convoluted ER network. Existing reconstruction methods are sensitive to parameters or require extensive annotation and training for deep learning. We introduce nERdy, an image processing based approach, and nERdy+, a D4-equivariant neural network, for accurate extraction and representation of ER networks and junction dynamics, outperforming previous methods. Comparison of stable and dynamic representations of the extracted ER structure reports on tripartite junction movement and distinguishes tubular matrices from peripheral ER networks. Analysis of live cell confocal and STED time series data shows that Atlastin and Reticulon 4 promote dynamic tubular matrix formation and enhance junction dynamics, identifying novel roles for these ER shaping proteins in regulating ER structure and dynamics.
Neuronal-class specific molecular cues drive differential myelination in the neocortex
Authors: Jokhi Vahbiz , Domínguez-Iturza Nuria , Kim Kwanho , Shetty Ashwin S. , Yuan Wen , Di Bella Daniela , Abbate Catherine , Oyler-Castrillo Paul , Jin Xin , Simmons Sean , Levin Joshua Z. , Brown Juliana R. , Arlotta Paola
Published: February 2024

In the neocortex, oligodendrocytes produce distinct amounts of myelin in each cortical layer and along the axons of individual neuron types. Here we present a comprehensive single-cell molecular map of mouse cortical oligodendrocytes across different cortical layers and stages of myelination, spanning the initiation of cortical myelination into adulthood. We apply this dataset to show that neuron-class specific signals drive oligodendrocyte maturation and differential myelination across cortical layers. We find that each layer contains a similar compendium of oligodendrocyte classes, indicating that oligodendrocyte heterogeneity cannot explain layer-specific myelination. To evaluate whether neuronal diversity drives differential myelination across cortical layers, we generated a predicted ligand-receptor interactome between projection neuron types and oligodendrocyte states, across cortical layers and time.In vivofunctional testing identifiedFgf18,Ncam1, andRspo3as novel, neuron-derived pro-myelinating signals. Our results highlight neuron-class-dependent control of myelin distribution in the neocortex.
Local desensitization to dopamine devalues recurring behavior
Authors: Miner Lauren E. , Gautham Aditya K. , Crickmore Michael A.
Published: February 2024

Goal achievement adjusts the relative importance of future behaviors. We use Drosophila to study this form of motivational control, finding that prior matings make males increasingly likely to abandon future copulations when challenged. Repetition-induced devaluation results from a reduction in dopamine reception by the Copulation Decision Neurons (CDNs), which mediate the decision to end matings. Dopamine signaling to the CDNs sustains matings in real time, but also triggers a lasting, β-arrestin-dependent desensitization of the D2R on the CDNs, leaving subsequent matings susceptible to disruption. When D2R desensitization is experimentally prevented, the male treats each mating as if it were his first. These findings provide a generalizable mechanism of motivational control and reveal a natural function for the long-studied susceptibility of the D2R to drug-induced inactivation.