bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Predictive and Prognostic Biomarkers in Lower Female Genital Tract Pathology: PD-L1, MMR, HER2, p16, p53, and Beyond
Authors: Mills Anne M. , Pinto Andre
Published: September 2024

Biomarkers play a crucial role in the diagnosis, treatment planning, and prognosis of premalignant and malignant lesions and are increasingly used in neoplasia of the lower female genital tract (LFGT) including the cervix, vagina, and vulva. This review will discuss key biomarkers routinely used in LFGT pathology, including programmed cell death ligand 1 (PD-L1), mismatch repair (MMR), and tumor mutational burden (TMB) testing, which are FDA-approved companion diagnostics for anti-PD-1 checkpoint inhibitors. Recent developments in HER2 testing as a marker for anti-HER2 therapies, and prognostic biomarkers such as p53 in HPV-independent vulvar intraepithelial lesions and carcinomas, are also reviewed.
Markers of extracellular matrix degradation and inflammasome activation are associated with carotid plaques in virally suppressed people with HIV in Botswana
Authors: Ueland Thor , Nkele Isaac , Hoel Hedda , Lockman Shahin , Michelsen Annika E. , Moshomo Thato , Aukrust Pål , Mohammed Terence , Trøseid Marius , Mosepele Mosepele
Published: September 2024

Background:

HIV is associated with increased risk of cardiovascular disease. We investigated soluble markers of extracellular matrix (ECM) remodeling and inflammation in relation to presence of carotid plaques in a well characterized adult cross-sectional study of people with HIV (PWH) and matched people without HIV in Botswana.

Methods:

Using enzyme immunoassays we analyzed plasma ECM remodeling mediators including galectin-3 (GAL-3), cystatin B (CysB), and growth/differentiation factor 15 (GDF-15) and the inflammatory marker interleukin (IL)-18 in 196 without HIV and 197 PWH of which 36 were ART-naïve.

Results:

We found (i) PWH had higher plasma levels of the ECM markers GAL-3 and CysB and the NLRP3 inflammasome activation marker IL-18, mainly in ART naïve participants, (ii) PWH on ART had markedly higher GDF-15, associated with use of first generation nucleoside analogs; iii) high levels of CysB and IL-18 correlated with presence of carotid plaques

Conclusion:

In PWH, high levels of CysB and IL-18 were associated with the presence of carotid plaques. For IL-18, this was observed in the study population as a whole, whereas the association for CysB was restricted to PWH.
Evaluating the Efficacy of Wrist-Ankle Acupuncture Combined With Patient-Controlled Intravenous Analgesia for Managing Post Uvulopalatopharyngoplasty
Authors: Chen Hai-Jing , Zheng Ying-Song , Chen Ling-Qin , Xiong Guo-Feng , Xu Jia-Ni
Published: September 2024

Objective:

The aim of this study is to investigate the impact of combining wrist-ankle acupuncture with patient-controlled intravenous analgesia (PCIA) on active pain and food intake in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) after undergoing uvulopalatopharyngoplasty (UPPP).

Methods:

Sixty patients with OSAHS who underwent UPPP at our hospital’s Department of Otorhinolaryngology from January 2020 to October 2023 were selected and randomly divided into 2 groups of 30 each: an observation group and a control group. The control group received general anesthesia administered by an anesthesiologist and used a PCIA pump. In addition to this treatment, the observation group received the combined intervention of wrist-ankle acupuncture. Active pain levels were monitored at 0, 6, 12, 24, 36, and 48 hours after UPPP, and food intake was observed at 24, 36, and 48 hours postoperation. The results were compared and recorded for both groups.

Results:

The analgesic effect on active pain in the observation group was significantly greater than in the control group at 6, 12, 24, 36, and 48 hours postoperation, and the differences were statistically significant (P<0.05). In addition, when comparing food intake scores at 24, 36, and 48 hours postoperation, the observation group had significantly higher food intake than the control group, and the differences were statistically significant (P<0.05).

Conclusions:

The combined intervention of wrist-ankle acupuncture and PCIA provides effective pain relief for OSAHS patients after UPPP, enhances their food intake, improves their quality of life, and supports early recovery.
Advances in breathlessness support services for people with serious illness
Authors: Takemura Naomi , Maddocks Matthew , Brighton Lisa Jane
Published: September 2024

Purpose of review

Breathlessness remains a common and distressing symptom among people with serious illness, particularly in advanced disease. This review synthesises recent advances in the development, characteristics, and outcomes of breathlessness support services.

Recent findings

The expanding body of evidence regarding breathlessness support services has broadened and strengthened our understanding of clinical and cost-effectiveness. The expansion of these services, into diverse settings and including digital delivery, has augmented their reach and accessibility to a wider population. Additionally, there is increasing attention to the psychological aspects of breathlessness and its management, including the challenges of optimising breathlessness support services for long-term benefit.

Recent studies have made substantial progress in enhancing our knowledge of breathlessness support services and their impact on people with serious illness. Innovations extending services into new countries and settings, including use of digital platforms for intervention delivery, plus increased recognition of psychological mechanisms, have the potential to support more people with serious illness to live as best as possible with breathlessness.
Proposal to add a Note to Rule 8 of the International Code of Nomenclature of Prokaryotes to clarify the meaning of the term ‘stem’
Authors: Oren Aharon , Kostovski Marko , Pallen Mark J.
Published: September 2024

According to the Rules of the International Code of Nomenclature of Prokaryotes (ICNP) and its appendices, names of higher taxa are formed by the addition of the appropriate suffix to the stem of the name of the type genus, and word stems derived from Latin and/or Greek are combined to compound names by means of an appropriate connecting vowel. The way the word ‘stem’ is used in the ICNP differs from the meaning of this term in textbooks of Latin and Greek grammar. We therefore propose to add a Note to Rule 8, clarifying that the term ‘stem’ when used in the ICNP corresponds with that part of the word that does not vary among the forms of the noun in the oblique cases, i.e., cases other than the nominative, and which can be obtained by deleting the ending of the genitive singular.
DRED: A Comprehensive Database of Genes Related to Repeat Expansion Diseases
Authors: Shi Qingqing , Dai Min , Ma Yingke , Liu Jun , Liu Xiuying , Wang Xiu-Jie
Published: September 2024

Expansion of tandem repeats in genes often causes severe neuromuscular diseases, such as fragile X syndrome, huntington’s disease, and spinocerebellar ataxia. However, information on genes associated with repeat expansion diseases is scattered throughout the literature, systematic prediction of potential genes that may cause diseases via repeat expansion is also lacking. Here, we develop DRED, a Database of genes related to Repeat Expansion Diseases, as a manually-curated database that covers all known 61 genes related to repeat expansion diseases reported in PubMed and OMIM, along with detailed repeat information for each gene. DRED also includes 516 genes with the potential to cause diseases via repeat expansion, which were predicted basing on their repeat composition, genetic variations, genomic features, and disease associations. Various types of information on repeat expansion diseases and their corresponding genes/repeats are presented in DRED, together with links to external resources, such as NCBI and ClinVar. DRED provides user-friendly interfaces with comprehensive functions, and can serve as a central data resource for basic research and repeat expansion disease-related medical diagnosis. DRED is freely accessible athttp://omicslab.genetics.ac.cn/dred, and is frequently updated to include newly reported genes related to repeat expansion diseases.
Doblin: Inferring dominant clonal lineages from DNA barcoding time-series
Authors: Serohijos Adrian , Gagne-Leroux David , Gencel Melis
Published: September 2024

The lineage dynamics and history of cells in a population reflect the interplay of evolutionary forces they experience, namely mutation, drift, and selection. When the population is polyclonal, lineage dynamics also manifest the extent of clonal competition among co-existing mutational variants. If the population exists in a community of other species, the lineage dynamics could also reflect the ecological interaction of the population with the rest of the community. Recent advances in high-resolution lineage tracking via DNA barcoding, coupled with next-generation sequencing of bacteria, yeast, and mammalian cells, allow for precise quantification of clonal dynamics in these organisms. In this work, we introduce Doblin, an R suite for identifying dominant barcode lineages based on high-resolution lineage tracking data. We first benchmarked the accuracy of Doblin using lineage data from evolutionary simulations, showing that it recovers the identity of clones and relative fitness in the simulation. Subsequently, we applied Doblin to analyze clonal dynamics in laboratory evolutions of E. coli populations undergoing antibiotic treatment and in colonization experiments of the gut microbial community. Doblin's versatility allows it to be applied to lineage time-series data across different experimental setups.
A brainstem circuit controls cough-like airway defensive behaviors in mice
Authors: Xu Xiaoshan , Nie Xiupeng , Zhang Weijia , Jiang He-Hai , Liu Bingyi , Ren Yanyan , Wang Tingting , Xu Xiang , Yang Jing , Luo Fujun
Published: September 2024

The respiratory tract is subject to complex neural control for eupneic breathing and distinct airway defensive reflexes. Growing evidence has highlighted significant heterogeneity of airway-innervating vagal sensory neurons in mediating various respiratory functions, however, the central neuronal pathways and neural circuits involved in the airway regulation remain less understood. Combining whole-body plethysmography (WBP), audio, and video tracking to access breathing and airway defensive behaviors in conscious animals, we developed a quantitative paradigm implementing the mouse as a model to study cough-like defensive behaviors. Using TRAP2 transgenic mice and in vivo fiber photometry, we found that the neural activity in the caudal spinal trigeminal nucleus (SP5C) is strongly correlated with tussigen-evoked cough-like responses. Impairing synaptic outputs or chemogenetic inhibition of the SP5C effectively abolished these cough-like reflexes. Optogenetic stimulation of SP5C excitatory neurons or their projections to the ventral respiratory group (VRG) triggered robust cough-like behaviors without tussive stimuli. Notably, tonic elevation of SP5C excitability caused spontaneous cough-like activities chronically in mice. Together, our data provide strong evidence for a previously unrecognized brainstem circuit that controls cough-like defensive behaviors in mice.
Vaginal Tissue Engineering via Gelatin-Elastin Fiber-Reinforced Hydrogels
Authors: Zambuto Samantha G. , Kolluru Samyuktha S. , Hamdaoui Abir , Mascot Annabella M. , Sutcliffe Siobhan S. , Lowder Jerry L. , Oyen Michelle L.
Published: September 2024

The vagina is a fibromuscular tube-shaped organ spanning from the hymenal ring to the cervix that plays critical roles in menstruation, pregnancy, and female sexual health. Vaginal tissue constituents, including cells and extracellular matrix components, contribute to tissue structure, function, and prevention of injury. However, much microstructural function remains unknown, including how the fiber-cell and cell-cell interactions influence macromechanical properties. A deeper understanding of these interactions will provide critical information needed to reduce and prevent vaginal injuries. Our objectives for this work herein are to first engineer a suite of biomaterials for vaginal tissue engineering and second to characterize the performance of these biomaterials in the vaginal microenvironment. We successfully created fiber-reinforced hydrogels of gelatin-elastin electrospun fibers infiltrated with gelatin methacryloyl hydrogels. These composites recapitulate vaginal material properties, including stiffness, and are compatible with the vaginal microenvironment: biocompatible with primary vaginal epithelial cells and in acidic conditions. This work significantly advances progress in vaginal tissue engineering by developing novel materials and developing a state-of-the-art tissue engineered vagina.
Type III interferons suppress influenza A virus infection independently of STAT activation by triggering cell death
Authors: Prus Wiktor , Grabowski Frederic , Koza Paulina , Korwek Zbigniew , Czerkies Maciej , Kochańczyk Marek , Lipniacki Tomasz
Published: September 2024

Type III interferons (IFN-λ1–λ4) are known to limit influenza virus infectionsin vivoand are non-redundant to type I interferons (IFN-α and IFN-β). Here, we demonstratedin vitrothat type III interferons limit infection with influenza A virus (IAV) independently of STAT1 and STAT2 activation. Despite the fact that the knockout of the IFN-λ receptor (subunit IFNLR1), compared to the knockout of the IFN-β receptor (subunit IFNAR1), is associated with higher levels of STAT1/2 phosphorylation during infection, it results in a greater proportion of IAV-infected cells and higher viral RNA and protein levels. We showed that the ratio of dying to infected cells is lower in IFNLR1-deficient cells compared to wild-type cells suggesting that type III interferons limit the spread of IAV by promoting the death of IAV-infected cells. In contrast, type I interferons induce a stronger accumulation of proteins coded by interferon-stimulated genes, and correspondingly suppress IAV spread more effectively than type III interferons when provided prior to infection. Overall, our results suggest an additional non-transcriptional role of type III interferons in the control of viral infections.

Key points

IFNAR1 deficiency leads to a significant reduction of STAT1/2 activation in cell populations infected with IAV and a small decrease in IAV proliferation.

IFNLR1 deficiency leads to a small reduction of STAT1/2 activation in cell populations infected with IAV and a significant increase in IAV proliferation.

IFN-λ controls the proliferation of IAV (but not RSV) independently of STAT1/2 signaling.

IFN-λ signaling increases the ratio of the dead to the infected cells, likely by promoting death in IAV-infected cells.
Chronobiological rhythms control of site- and cell-specific miRNA and mRNA genes and networks across the central nervous system
Authors: Zacharias Amanda M , O'Connor Ciara D , Topouza Danai G , Fang Zhi Yi , Ghazinejad Helia , Chen Hanlin , Duan Qingling , Ghasemlou Nader
Published: September 2024

Biological rhythms control gene expression, but effects on central nervous system (CNS) cells and structures remain undefined. While circadian (24-hour) rhythms are most studied, many genes have periods of greater and less than 24-hours; these fluctuations can be both site- and cell-specific. Identifying patterns of gene rhythmicity across the CNS is necessary for both the study of chronobiology and to make sense of data obtained in the laboratory. We now identify cycling mRNAs, miRNAs, gene networks and novel mRNA-miRNA co-expression pairs in the cortex, hypothalamus, and corpus striatum using high-dimensional datasets. A searchable catalogue (https://www.ghasemloulab.ca/chronoCNS) was created to help refine the analysis of cellular/molecular rhythmicity across the CNS. Immunofluorescence was also used to confirm the rhythmicity of key targets across cells in these structures, with strong cycling signatures in resting oligodendrocytes. Our study sheds light on the contribution of circadian, ultradian, and infradian rhythms and mRNA-miRNA interactions to CNS function.
Acute sildenafil administration reduces susceptibility to induced atrial fibrillation in sheep
Authors: Denham Nathan C , Madders George W P , Hutchings D C , Smith C E R , Whitley A S , Obeidat M , Trafford A W , Pearman C M , Dibb K M
Published: September 2024

Background

Sildenafil is a PDE5 inhibitor with a very good safety profile and animal models suggest it may be beneficial in the treatment of heart failure and ventricular fibrillation. Sildenafil has also been associated with a reduced incidence of atrial fibrillation (AF) in a retrospective observational study. We have therefore sought to determine whether sildenafil has a direct effect on atrial electrophysiology and resultant AF burden.

Methods

Invasive electrophysiological studies were performed in 12 anaesthetised healthy adult female Welsh mountain sheep. Pacing protocols were performed in the right atrium before and after administration of an acute 10 mg intravenous bolus of sildenafil and the burden of AF assessed.

Results

Sildenafil profoundly reduced the vulnerability to AF, decreasing AF duration (112.2 ± 73.5 s vs. 3.3 ± 1.4 s), the number of burst pacing inductions causing AF (90 % vs 70 %) and the complexity of AF. The antiarrhythmic effects of sildenafil were determined to be resultant of prolongation of both the atrial effective refractory period (146.9 ± 7.2 ms vs 166.2 ± 32.5 ms) and the atrial excitation wavelength (12.9 ± 0.07 cm vs 15.0 ± 0.07 cm) and resulted in a shallower restitution curve, reflected in a decreased magnitude of monophasic action potential alternans (0.09 ± 0.001 mV vs 0.05 ± 0.10 mV).

Conclusions

In the subjectively healthy atria of a highly translational model a strong antiarrhythmic effect upon acute sildenafil application was observed suggestive of a potential clinical benefit in AF.
Wakefulness Induced by TAAR1 Partial Agonism is Mediated Through Dopaminergic Neurotransmission
Authors: Park Sunmee , Heu Jasmine , Hoener Marius C. , Kilduff Thomas S.
Published: September 2024

Trace amine-associated receptor 1 (TAAR1) is known to negatively regulate dopamine (DA) release. The partial TAAR1 agonist RO5263397 promotes wakefulness and suppresses NREM and REM sleep in mice, rats, and non-human primates. We tested the hypothesis that the TAAR1-mediated effects on sleep/wake were due, at least in part, to DA release. Male C57BL6/J mice (n=8) were intraperitoneally administered the D1R antagonist SCH23390, the D2R antagonist eticlopride, a combination of D1R+D2R antagonists or saline at ZT5.5, followed 30 min later by RO5263397 or vehicle (10% DMSO in DI water) at ZT6per os. EEG, EMG, subcutaneous temperature, and activity were recorded in each mouse across the 8 treatment conditions and sleep architecture was analyzed for 6 hours post-dosing. Consistent with our previous reports, RO5263397 increased wakefulness as well as the latency to NREM and REM sleep. D1, D2, and D1+D2 pretreatment reduced RO5263397-induced wakefulness during the first 1-2 hours after dosing, but only the D1+D2 combination attenuated the wake-promoting effect of RO5263397 from ZT6-8, mostly by increasing NREM sleep. Although D1+D2 antagonism blocked the wake-promoting effect of RO5263397, only the D1 antagonist significantly reduced the TAAR1-mediated increase in NREM latency. Neither the D1 nor the D2 antagonist affected TAAR1-mediated suppression of REM sleep. These results suggest that, whereas TAAR1 effects on wakefulness are mediated in part through the D2R, D1R activation plays a role in reversing the TAAR1-mediated increase in NREM sleep latency. By contrast, TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms.
Single-cell analysis of human airway epithelium identifies cell type-specific responses toAspergillusandCoccidioides
Authors: Harding Alfred T. , Crossen Arianne J. , Reedy Jennifer L. , Basham Kyle J. , Hepworth Olivia W. , Zhang Yanting , Shah Viral S. , Harding Hannah Brown , Surve Manalee V. , Simaku Patricia , Kwaku Geneva N. , Jensen Kristine Nolling , Otto Yohana , Ward Rebecca A. , Thompson George R. , Klein Bruce S. , Rajagopal Jayaraj , Sen Pritha , Haber Adam L. , Vyas Jatin M.
Published: September 2024

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environmentin vitroand investigate cellular responses to two diverse, clinically significant fungal pathogens,Aspergillus fumigatusandCoccidioides posadasii. To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cell subtypes affected and specific pathways differed between fungi, withA. fumigatusandC. posadasiitriggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with eitherA. fumigatusorC. posadasii, providing a vital dataset to dissect the mechanism of disease and potentially identify targetable pathways.

Importance

Fungal infections in the lungs are dreaded complications for those with compromised immune systems and have limited treatment strategies available. These options are restricted further by the increased prevalence of treatment-resistant fungi. Many studies focus on how our immune systems respond to these pathogens, yet airway epithelial cells remain an understudied component of fungal infections in the lungs. Here, the authors provide a transcriptional analysis of primary human airway epithelial cells stimulated by two distinct fungal pathogens,Aspergillus fumigatusandCoccidioides posadasii. These data will enable further mechanistic studies of the contribution of the airway epithelium to initial host responses and represent a powerful new resource for investigators.
Modulation of cortico-muscular coupling associated with split-belt locomotor adaptation
Authors: Oshima Atsushi , Yokoyama Hikaru , Kaneko Naotsugu , Takahashi Ryogo , Takiyama Ken , Nakazawa Kimitaka
Published: September 2024

Humans can adjust their walking patterns according to the demands of their internal and external environments, referred to as locomotor adaptation. Although significant functional coupling (i.e. cortico-muscular coherence [CMC]) has been shown between cortical and lower-limb muscle activity during steady-state walking, little is known about CMC in locomotor adaptation. Therefore, we investigated the adaptation-dependent modulation of the CMC between the sensorimotor region and the tibialis anterior muscle using a split-belt locomotor adaptation paradigm that can impose an asymmetric perturbation. We hypothesized that the CMC would temporarily decrease after exposure to the asymmetric perturbation and removal of the perturbation because of a mismatch between the predicted and actual sensory feedback. We also hypothesized that the CMC would increase as adaptation and de-adaptation to perturbation progressed because the motor system could become able to predict sensory feedback. Our findings revealed that the CMC temporarily decreased after exposure to and removal of the perturbation. Moreover, the CMC increased with adaptation and de-adaptation to perturbation. Although these results depend on the leg, frequency bands, and gait phases, they partially support our hypothesis. These findings suggest that flexible updating of cortico-muscular coupling in the motor system is a key mechanism underlying locomotor adaptation in humans. The results from our study on healthy young individuals contribute to the understanding of neuromuscular control of gait and provide valuable insight for optimising gait rehabilitation.

Key points

Locomotor adaptation plays a crucial role in our daily activities and gait rehabilitation.

Although knowledge regarding the brain and muscle activities associated with locomotor adaptation has been accumulated, little is known about the functional coupling of the brain and muscle activities.

Using high-density EEG and lower limb EMG, we demonstrated the modulation of cortico-muscular coherence between the sensorimotor region and the tibialis anterior muscle with adaptation and de-adaptation during a split-belt treadmill walking paradigm.

Our findings suggest that flexible updating of cortico-muscular coupling in the motor system underlies locomotor adaptation in humans.

Understanding the human brain’s control of muscles during split-belt locomotor adaptation will deepen our knowledge of neuromuscular control of gait and provide valuable insights for gait rehabilitation.
Unlocking expanded flagellin perception through rational receptor engineering
Authors: Li Tianrun , Bolanos Esteban Jarquin , Stevens Danielle , Sha Hanxu , Prigozhin Daniil M , Coaker Gitta
Published: September 2024

The surface-localized receptor kinase FLS2 detects the flg22 epitope from bacterial flagella. FLS2 is conserved across land plants, but bacterial pathogens exhibit polymorphic flg22 epitopes. Most FLS2 homologs possess narrow perception ranges, but four with expanded perception ranges have been identified. Using diversity analyses, AlphaFold modeling, and amino acid properties, key residues enabling expanded recognition were mapped to FLS2's concave surface, interacting with the co-receptor and polymorphic flg22 residues. Synthetic biology enabled engineering of expanded recognition from QvFLS2 (Quercus variabilis) and FLS2XL (Vitis riparia) into homologs with canonical perception. Evolutionary analyses across three plant orders showed residues under positive selection aligning with those binding the co-receptor and flg22's C-terminus, suggesting more alleles with expanded perception exist. Our experimental data enabled the identification of specific receptor amino acid properties and AlphaFold3 metrics that facilitate predicting FLS2-flg22 recognition. This study provides a framework for rational receptor engineering to enhance pathogen restriction.
Bone adhered soil as a source of target and environmental DNA and proteins
Authors: de-Dios Toni , Bonucci Biancamaria , Barbieri Rémi , Kushniarevich Alena , D’Atanasio Eugenia , Dittmar Jenna M , Cessford Craig , Solnik Anu , Robb John E. , Warinner Christina , Oras Ester , Scheib Christiana L.
Published: September 2024

In recent years, sediments from cave environments have provided invaluable insights into ancient hominids, as well as past fauna and flora. Unfortunately, locations with favourable conditions for ancient DNA (aDNA) preservation in sediments are scarce. In this study we analysed a set of samples obtained from soil adhered to different human skeletal elements, originating from Neolithic to Medieval sites in England, and performed metagenomics and metaproteomics analysis. From them, we were able to recover aDNA sequences matching the genomes of endogenous gut and oral microbiome bacteria. We also found the presence of genetic data corresponding to animals and plants. In particular we managed to retrieve the partial genome and proteome of a Black Rat (Rattus rattus), sharing close genetic affinities to other medievalRattus rattus. Furthermore, we have also been able to reconstruct a partial human genome. The genetic profile of those human sequences matches the one recovered from the original skeletal element. Our results demonstrate that material usually discarded, as it is soil adhering to human remains, can be used to get a glimpse of the environmental conditions at the time of the death of an individual, even in contexts where due to harsh environmental conditions, the skeletal remains themselves are not preserved.
Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids
Authors: Capendale Pamela E. , Ambikan Anoop T. , García-Rodríguez Inés , Vieira de Sá Renata , Pajkrt Dasja , Wolthers Katja C. , Neogi Ujjwal , Sridhar Adithya
Published: September 2024

Parechovirus ahumpari 3 (HPeV-3), is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.
Nanomedicines targeting signaling of protease-activated receptor 2 in organelles provide sustained analgesia
Authors: Teng Shavonne L. , Latorre Rocco , Bhansali Divya , Lewis Parker K. , Pollard Rachel E. , Peach Chloe J. , Sokrat Badr , Thanigai Gokul S.A. , Chiu Tracy , Jensen Dane D. , Jimenez-Vargas Nestor N. , Mocherniak Abby , Parreiras-E-Silva Lucas T. , Bouvier Michel , Bogyo Matthew , Gaspari Michael M. , Vanner Stephen J. , Pinkerton Nathalie M. , Leong Kam W. , Schmidt Brian L. , Bunnett Nigel W.
Published: September 2024

Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of GPCR signaling in organelles are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically-encoded biosensors targeted to subcellular compartments were used to analyze organelle-specific signaling of protease-activated receptor 2 (PAR2); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to selectively antagonize intracellular PAR2signaling of pain. PAR2agonists evoked sustained activation of PAR2, Gαq and β-arrestin-1 in early, late and recycling endosomes and thecis- andtrans. Golgi apparatus, and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with organelle-targeted biosensors. Dendrimer and core-shell polymeric NPs accumulated in early and late endosomes of HEK293 cells, colonic epithelial cells and nociceptors, detected by confocal imaging of fluorescent NPs. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR2 antagonist. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR2, Gαq and β-arrestin-1 activation in endosomes and the Golgi apparatus and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs targeted neurons, sites of PAR2expression. Both NP-AZ3451 formulations, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. Thus, organelle-specific PAR2signals in colonocytes and nociceptors mediate pain. Antagonism of PAR2in organelles, rather than at the plasma membrane, provides effective pain relief.
ProtRNA: A Protein-derived RNA Language Model by Cross-Modality Transfer Learning
Authors: Zhang Ruoxi , Ma Ben , Xu Gang , Ma Jianpeng
Published: September 2024

Protein language models (PLM), such as the highly successful ESM-2, have proven to be particularly effective. However, language models designed for RNA continue to face challenges. A key question is: can the information derived from PLMs be harnessed and transferred to RNA? To investigate this, a model termed ProtRNA has been developed by cross-modality transfer learning strategy for addressing the challenges posed by RNA’s limited and less conserved sequences. By leveraging the evolutionary and physicochemical information encoded in protein sequences, the ESM-2 model is adapted to processing "low-resource" RNA sequence data. The results show comparable or even superior performance in various RNA downstream tasks, with only 1/8 the trainable parameters and 1/6 the training data employed by other baseline RNA language models. This approach highlights the potential of cross-modality transfer learning in biological language models.
IFN-I signaling in type 2 conventional dendritic cells supports TH2 and T follicular helper differentiation after allergen immunization
Authors: Webb Greta R , Hilligan Kerry L , Old Sam I , Tang Shiau-Choot , Lamiable Olivier , Ronchese Franca
Published: September 2024

Type 2 dendritic cells (DC2s) are essential for TH2 differentiation, but the signaling pathways involved in allergen sensing, DC activation and instruction of CD4+ T cell priming remain unclear. Previous transcriptomic analyses demonstrated a type-I interferon (IFN-I) signature in skin cDC2s following immunization with non-viable larvae ofNippostrongylus brasiliensis(Nb), house dust mite (HDM), andSchistosomaegg antigen (SEA). Blocking IFN-I signaling with anti-IFNAR1 (aIFNAR1) led to reduced TH2 cytokine responses to these antigens, however, the phenotype of cytokine-producing CD4+ T cells was not further defined. Here we show that conditional loss of IFNAR1 signaling in CD11c+ DCs significantly impaired effector TH2 and TFH CD4+ T cell responses toNb.In vivoproliferation experiments demonstrated reduced numbers of highly divided CD4+ T cells in IFNAR1ΔCD11cmice compared to IFNAR1WT, with the highly divided population comprising both TH2 and TFH. Characterization of the cDC2 compartment by flow cytometry and bulk RNAseq demonstrated lower numbers ofNb+ cDC2s in the skin-draining LN and a reduced expression ofIl15andIl15Rain IFNAR1ΔCD11cmice compared to IFNAR1WT, while expression of costimulatory molecules including CD80, CD86,Cd40andPdcd1lg2(PD-L2) was not impaired. Therefore, IFN-I conditioning of skin cDC2s is necessary for their effective priming of CD4+ T cell responses to allergens, providing evidence for a role of tissue cytokines in driving cDC2 activation in a TH2 context.
Enantiomeric histidine-rich peptide coacervates enhance antigen delivery to T cells
Authors: Pramanik Ushasi , Das Anirban , Brown Elise M. , Struckman Heather L. , Wang Huihao , Stealey Samuel , Sprunger Macy L. , Wasim Abdul , Fascetti Jonathan , Mondal Jagannath , Silva Jonathan R. , Zustiak Silviya P. , Jackrel Meredith E. , Rudra Jai S.
Published: September 2024

Peptides and peptidomimetics that self-assemble via LLPS have recently emerged as building blocks for fabricating functional biomaterials due to their unique physicochemical properties and dynamic nature. One of life’s most distinctive signatures is its selectivity for chiral molecules and, to date, coacervates comprised of D-amino acids have not been reported. Here, we demonstrate that histidine-rich repeats of (GHGXY)4(X=L/V/P) and their enantiomers undergo LLPS opening new avenues for enhancing coacervate stability. Through a series of biophysical studies, we find that LLPS kinetics, droplet size, fusion, and encapsulation efficiency are dictated by the primary sequence. Further, these coacervates can encapsulate therapeutic cargo which are then internalized via endocytic mechanisms. Finally, we show that the coacervates enhance antigen presentation to CD4+and CD8+T cells resulting in robust proliferation and production of functional cytokines. Collectively, our study describes the development and characterization of enantiomeric peptide coacervates as attractive vaccine delivery vehicles with tunable physicochemical properties.

HIGHLIGHTS

D amino acid-peptides were used for the first time to construct phase separating coacervates

Chirality does not restrict LLPS or modulate other coacervate properties

Antigen delivery using chiral coacervates enhances and prolongs presentation to T cells

PROGRESS AND POTENTIAL

Peptides can undergo self-assembly via liquid-liquid phase separation (LLPS) to result in solute-rich coacervates that can serve as biomaterials. Using histidine-rich peptide repeats, this work demonstrates that peptides composed of entirely D-amino acids can form functional coaceravtes. The kinetics of LLPS and bulk properties of the droplets can be controlled through simple amino acid substitutions. The coacervates, while immunologically inert, exert an adjuvanting effect and enhance antigen presentation to T cells leading to proliferation and functional cytokine production. The materials showcased here possess high translational potential for combined delivery of immunomodulators and antigens for vaccine delivery against infectious diseases or cancer. The deliverables from this study will also inspire the development of chiral systems that will contribute to the knowledge of cellular processes associated with phase changes integral to both physiology and pathology.
Foot placement control underlies stable locomotion across species
Authors: De Comite Antoine , Seethapathi Nidhi
Published: September 2024

Abstract

Animals navigate their environment stably without inefficient course corrections despite unavoidable errors. In humans and some robots, this stability is achieved by controlling the placement of the foot on the ground such that recent movement errors are corrected. However, it is unknown whether and how animals with diverse nervous systems and body mechanics use such foot placement control: foot trajectories of many-legged animals are considered as stereotypical velocity-driven patterns, as opposed to error-driven. Here, we posit a control structure for stabilizing foot placement in any legged embodiment by unifying velocity-driven and body state-driven contributions, and develop a framework to discover control strategies used across species from natural locomotor variability. Using this framework, we find evidence for body state-dependent foot placement control in flies and mice, previously only shown to exist in humans. We discover that the urgency and centralization of the foot placement control strategy is shaped by the animal’s neuromechanical embodiment. More inherently stable many-legged embodiment is associated with a lower control magnitude and timescale. Further, many-legged embodiment is accompanied by decentralized control with modular control functions, timescales, and gains, whereas analogous functions are centralized across both legs in humans. Our approach discovers signatures of stabilizing control across species and reveals how different neuromechanical embodiments achieve a shared functional goal: foot placement control.
Causality Analysis of Protein Corona Composition: Phosphatidylcholine-Enhances Plasma Proteome Profiling by Proteomics
Authors: Rafieioskouei Arshia , Rogale Kenneth , Saei Amir Ata , Mahmoudi Morteza , Bonakdarpour Borzoo
Published: September 2024

The study of the protein corona, the immediate and evolving biomolecular coating that forms on the surface of nanoparticles when exposed to a biological environment, is a crucial area in nanomedicine. This phenomenon significantly influences the behavior, functionality, and biological interactions of nanoparticles with biosystems. Until now, conclusions regarding the role of the protein corona in specific biological applications have been based on establishingcorrelationrather thancausation. By understanding causality, researchers can predict how changes in nanoparticle properties or biological conditions will affect protein corona composition, in turn affecting the nanoparticle interactions with the biosystems and their applications. This predictive capability is essential for designing nanoparticles with specific characteristics tailored for therapeutic and diagnostic nanomedicine applications. Here, we explore the concept of “actual causality” (by Halpern and Pearl) to mathematically prove how various small molecules, including metabolites, lipids, vitamins, and nutrients, spiked into plasma can induce diverse protein corona patterns on identical nanoparticles. This approach significantly enhances the depth of plasma proteome profiling. Our findings reveal that among the various spiked small molecules, phosphatidylcholine was the actual cause of the observed increase in the proteomic depth of the plasma sample. By considering the concept of causality in the field of protein corona, the nanomedicine community can substantially improve their ability to design safer and more efficient nanoparticles for both diagnostic and therapeutic purposes.
ScReNI: single-cell regulatory network inference through integrating scRNA-seq and scATAC-seq data
Authors: Xu Xueli , Liang Yanran , Tang Miaoxiu , Wang Jiongliang , Wang Xi , Li Yixue , Wang Jie
Published: September 2024

Single cells exhibit heterogeneous gene expression profiles and chromatin accessibility, measurable separately via single-cell RNA sequencing (scRNA-seq) and single-cell transposase chromatin accessibility sequencing (scATAC-seq). Consequently, each cell possesses a unique gene regulatory network. However, limited methods exist for inferring cell-specific regulatory networks, particularly through the integration of scRNA-seq and scATAC-seq data. Here, we develop a novel algorithm named single-cell regulatory network inference (ScReNI), which leveragesk-nearest neighbors and random forest algorithms to integrate scRNA-seq and scATAC-seq data for inferring gene regulatory networks at the single-cell level. ScReNI is built to analyze both paired and unpaired datasets for scRNA-seq and scATAC-seq. Using these two types of single-cell sequencing datasets, we validate that a higher fraction of regulatory relationships inferred by ScReNI are detected by chromatin immunoprecipitation sequencing (ChIP-seq) data. ScReNI shows superior performance in network-based cell clustering when compared to existing single-cell network inference methods. Importantly, ScReNI offers the unique function of identifying cell-enriched regulators based on each cell-specific network. In summary, ScReNI facilitates the inferences of cell-specific regulatory networks and cell-enriched regulators.
eDNA sampling systems for salmon ecosystem monitoring
Authors: Deeg Christoph M , Saunders Robert G , Tam Christopher , Kaukinen Karia , Li Shaorong , Bass Arthur L ,   Uu-a-thluk Fisheries, Miller Kristi M
Published: September 2024

Environmental DNA (eDNA) is transforming the way aquatic ecosystems are monitored and managed by scientists, resource managers, ENGOs, First Nations communities, and citizen scientists alike. However, the lack of sampling systems enabling high filtration volumes and rapid sample collection in the field have thus far hindered broad scale eDNA studies in the ocean specifically for small and medium scale organizations. To overcome these challenges, several modular water sampling systems that utilize hollow-membrane filtration cartridges were developed by RKS laboratories and tested by the Fisheries and Oceans, Canada, Molecular Genetics Laboratory. Compared to Sterivex filters, an industry standard for eDNA filtration, the hollow-membrane filtration cartridges allowed for a six-fold increase in filtration volume and threefold increase in filtration speed. The field sampling systems, which combine pumps, a programmable controller, an air pump, an ozone generator, and up to eight filters at once, enabled efficient direct eDNA filtration from diverse aquatic environments, from creeks to the open ocean. To evaluate ease of deployment, we present the results of a three day workshop where technical staff of an Indigenous resource management organization, without any prior knowledge in eDNA sampling, were trained and performed independent eDNA sample collection. The samples were analyzed by metabarcoding and qPCR to reveal the distributions of salmon and other species co-occurring in salmon ecosystems, from large ephemeral predators, to the planktonic prey of salmon, even including their pathogens. In this example study, we further observed a substantial shift in community composition in the vicinity of aquaculture facilities where marine species associated with aquaculture feed were detected in freshwater at high relative abundance. This study demonstrates how these sampling systems provide an efficient entry point for small and medium scale organizations to utilize eDNA to fulfill their research and monitoring objectives.
Influence of the Glymphatic System on α-Synuclein Propagation: Role of Aquaporin-4 and the Dystrophin-Associated Protein Complex
Authors: Lopes Douglas M , Llewellyn Sophie K , Bury Sheila E , Wang Jiazheng , Wells Jack A , Gegg Matthew E , Verona Guglielmo , Lythgoe Mark F , Harrison Ian F
Published: September 2024

Propagation and aggregation of prion proteins, such as tau and α-synuclein (αSyn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinson’s disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences αSyn propagation dynamics, and the role of propagating αSyn itself on glymphatic function.

In this study, we used a mouse model of αSyn propagation to elucidate the impact of αSyn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of αSyn pre-formed fibrils leads to reduced expression of the AQP4 endfoot complex, but propagation of endogenous αSyn induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing endogenous αSyn load. To determine the influence of glymphatic dysfunction on αSyn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF αSyn clearance, and chronic treatment exacerbated αSyn pathology, neurodegeneration, and motor behavioural deficits in mice. Together our findings show that αSyn clearance and propagation are modulated by glymphatic function and suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinson’s diseases.

Summary for the non-scientific community

The glymphatic system clears brain waste during sleep. Lopes et al. show that α-synuclein, a protein linked to Parkinson’s, is cleared by this system. Using a mouse model of the disease, they suggest that aquaporin-4 water channels may impair glymphatic function, contributing to α-synuclein buildup in patients’ brains.