bluuebunny/crossref_metadata_2025 huggingface dataset:
Cx43 Enhances Response to BRAF/MEK Inhibitors by Reducing DNA Repair Capacity
Authors: Varela-Vázquez Adrián , Guitián-Caamaño Amanda , Carpintero-Fernández Paula , Álvarez Vanesa , Carneiro-Figueira Alexander , Varela-Eirín Marta , Calleja-Chuclá Teresa , Bravo-López Susana B , Vidal Anxo , Sendón-Lago Juan , Rodríguez-Candela Mateos Marina , Caeiro José R , Blanco Miguel G. , Sabio Guadalupe , Quindós María , Rivas Carmen , Santamaría David , Fernandez-Lozano Carlos , Fonseca Eduardo , Huertas Pablo , Sánchez-Laorden Berta , Alabert Constance , Mayán María D.
Published: July 2024

BRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major handicaps for successful treatments. Here, by using relevant preclinical models, we found that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, increases effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could lead to a novel therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed an innovative drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a new player on DNA repair and BRAF/MEKi response, underlining the therapeutical potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours.
Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines
Authors: Fantin Raianna F. , Clark Jordan J. , Cohn Hallie , Jaiswal Deepika , Bozarth Bailey , Civljak Alesandro , Rao Vishal , Lobo Igor , Nardulli Jessica R. , Srivastava Komal , Yong Jeremy , Andreata-Santos Robert , Bushfield Kaitlyn , Lee Edward S. , Singh Gagandeep , Group PVI Study , Kleinstein Steven H. , Krammer Florian , Simon Viviana , Bajic Goran , Coelho Camila H.
Published: July 2024

The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicitde novoB-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was ade novo,antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs’ specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.

GRAPHICAL ABSTRACT
A peptide-neurotensin conjugate that crosses the blood-brain barrier induces pharmacological hypothermia associated with anticonvulsant, neuroprotective and anti-inflammatory properties following status epilepticus in mice
Authors: Ferhat Lotfi , Soussi Rabia , Masse Maxime , Kyriatzis Grigorios , Girard Stéphane D. , Gassiot Fanny , Gaudin Nicolas , Laurencin Mathieu , Bernard Anne , Bôle Angélique , Ferracci Géraldine , Smirnova Maria , Roman François , Dive Vincent , Cisternino Salvatore , Temsamani Jamal , David Marion , Lécorché Pascaline , Jacquot Guillaume , Khrestchatisky Michel
Published: July 2024

Preclinical and clinical studies show that mild to moderate hypothermia is neuroprotective in sudden cardiac arrest, ischemic stroke, perinatal hypoxia/ischemia, traumatic brain injury and seizures. Induction of hypothermia largely involves physical cooling therapies, which induce several clinical complications, while some molecules have shown to be efficient in pharmacologically induced hypothermia (PIH). Neurotensin (NT), a 13 amino-acid neuropeptide that regulates body temperature, interacts with various receptors to mediate its peripheral and central effects. NT induces PIH when administered intracerebrally. However, these effects are not observed if NT is administered peripherally, due to its rapid degradation and poor passage of the blood brain barrier (BBB). We conjugated NT to peptides that bind the low-density lipoprotein receptor (LDLR) to generate “vectorized” forms of NT with enhanced BBB permeability. We evaluated their effects in epileptic conditions following peripheral administration. One of these conjugates, VH-N412, displayed improved stability, binding potential to both the LDLR and NTSR-1, rodent/human cross-reactivity and improved brain distribution. In a mouse model of kainate (KA)-induced status epilepticus (SE), VH-N412 elicited rapid hypothermia associated with anticonvulsant effects, potent neuroprotection and reduced hippocampal inflammation. VH-N412 also reduced sprouting of the dentate gyrus mossy fibers and preserved learning and memory skills in the treated mice. In cultured hippocampal neurons, VH-N412 displayed temperature-independent neuroprotective properties. To the best of our knowledge, this is the first report describing the successful treatment of SE with PIH. In all, our results show that vectorized NT may elicit different neuroprotection mechanisms mediated either by hypothermia and/or by intrinsic neuroprotective properties.
Criticality explains structure-function relationships in the human brain
Authors: Angiolelli Marianna , Scarpetta Silvia , Sorrentino Pierpaolo , Lopez Emahnuel Troisi , Quarantelli Mario , Granata Carmine , Sorrentino Giuseppe , Palmieri Vincenzo , Messuti Giovanni , Stefano Mattia , Filippi Simonetta , Cherubini Christian , Loppini Alessandro , Chiodo Letizia
Published: July 2024

Healthy brain exhibits a rich dynamical repertoire, with flexible spatiotemporal patterns replays on both microscopic and macroscopic scales. How do fixed structural connections yield a diverse range of dynamic patterns in spontaneous brain activity? We hypothesize that the observed relationship between empirical structure and functional patterns is best explained when the microscopic neuronal dynamics is close to a critical regime. Using a modular Spiking Neuronal Network model based on empirical connectomes, we posit that multiple stored functional patterns can transiently reoccur when the system operates near a critical regime, generating realistic brain dynamics and structural-functional relationships. The connections in the model are chosen as to force the network to learn and propagate suited modular spatiotemporal patterns. To test our hypothesis, we employ magnetoencephalography and tractography data from five healthy individuals. We show that the critical regime of the model is able to generate realistic features, and demonstrate the relevance of near-critical regimes for physiological brain activity.
Neophobic response of bull ants (Myrmecia midas) to odours introduced on their foraging route
Authors: Kambala Venkata Manvitha , Ahmed Yousef , Lee Jasmine , Jose Anwin , Nadir Sahera Syed , Priyanka B C , Gabir Ali , Sun Yingdie , Cheng Ken , Deeti Sudhakar
Published: July 2024

Goal-oriented learning and navigation is well known in eusocial insects. The solitary foraging of nocturnal bull antsMyrmecia midasin their visually complex environment relies on path integration and landmark learning. While this species seems to be ‘sensitive’ to handling and reacts to visual changes in their surroundings, not much is known about how added olfactory stimuli impact their route navigation on a vertical surface. In the current study, we added one of five different invisible odours on the trees on which foragers normally forage. We found that the bull ants showed neophobic responses to all the odours. The Tea-tree and Lavender odours showed the strongest impact on the bull ants’ navigation by causing detours, U-turns, and avoidance of the sensory stimuli, with the ants meandering more and scanning more frequently. The odours of Olive oil, Flax-seed oil, and Eucalyptus oil had a moderate impact on the ants’ navigation. These findings showed the widespread influence of non-visual chemical cues in shaping bull ant navigation and highlight the induction of neophobic responses stemming from chemical alterations on learned routes. Overall, this study contributes to the understanding of the effects of foreign odours, adding to our understanding of the complex learning processes of bull ants in their vertical navigation.
On the synergy between myelin proteins P0, MBP, and P2 in peripheral nerve major dense line formation
Authors: Krokengen Oda C. , Raasakka Arne , Klenow Martin Berg , Pal Antara , Hetland Øystein , Mularski Anna , Ruskamo Salla , Pedersen Jan Skov , Simonsen Adam Cohen , Kursula Petri
Published: July 2024

Myelin is a proteolipid membrane multilayer held together by a set of proteins. The proper formation and function of the myelin sheath relies on the coordinated action of several key myelin proteins. Research exploring how proteins from the peripheral myelin cytoplasmic apposition – myelin basic protein (MBP), the cytoplasmic tail of myelin protein zero (P0ct), and peripheral myelin protein 2 (P2) – interact with each other and with myelin-like membranes was conducted using various techniques, such as small-angle X-ray diffraction (SAXD), differential scanning calorimetry (DSC), surface plasmon resonance (SPR), as well as electron and live epifluorescence microscopy. DSC revealed changes in lipid interactions depending on the protein combination, with MBP and P0ct binding more tightly to lipid membranes than P2, resulting in altered membrane fluidity and stability. These results were supported by SPR, which indicated that the myelin proteins may compete for membrane surface binding. Analysis of the Bragg peaks induced by the myelin proteins in lipidic environments showed both lamellar and non-lamellar phases in protein-lipid complexes. The results indicate both synergy and competition between the three main proteins residing in the PNS myelin major dense line. Furthermore, the observed direct effects of myelin proteins on lipid membrane properties may be relevant to their function in myelinating cells.
BMAP: a comprehensive and reproducible biomedical data analysis platform
Authors: Ren Yongyong , Cheng Zhiwei , Li Leijie , Zhang Yuening , Dai Fang , Deng Luojia , Wu Yijie , Gu Jianlei , Lin Qingmin , Wang Xiaolei , Kong Yan , Lu Hui
Published: July 2024

In the realm of biomedical research, efficient data analysis and processing are crucial due to the escalating volume and complexity of data generated by research teams. Managing these vast arrays of localized data presents significant challenges, necessitating precise, efficient, and reproducible analysis methodologies to ensure the integrity and reliability of scientific outcomes. Traditional management of analysis codes, computing environments, and the inherent difficulties in result traceability due to team dynamics often lead to inefficiencies and potential risks in maintaining academic integrity. Furthermore, while online storage platforms such as Dryad, GitHub, and Docker facilitate data, code, and environment management, they do not inherently guarantee the reproducibility of results, with issues like data incompleteness, forgotten parameters, or software discrepancies posing additional challenges. To address these critical gaps, we developed a BioMedical data Analysis Platform (BMAP) to offer online and localized categorized management of research assets. BMAP enhances workflow efficiency by transforming complex pipelines into user-friendly web applications, promoting consistency and standardization across team analyses. Its comprehensive web analysis module and seamless integration with data and computing resources support automated result reproducibility and visualization. According to the assessment, 1,692 omics-related figures from 101 recent articles, across 45 visualization types, were tested with BMAP, which could cover 37.8% of the types and 64.3% of the figures. BMAP also enables the sharing and enhancement of research methods through its cloud platform, allowing researchers to utilize the previously developed and validated tools, thereby reducing redundant effort and minimizing analytical discrepancies due to methodological differences.
Comprehensive elucidation of glutathione import inEscherichia coli
Authors: Knoke Lisa R. , Muskietorz Maik , Kühn Lena , Leichert Lars I.
Published: July 2024

Glutathione is the major thiol-based antioxidant in a wide variety of biological systems, ranging from bacteria to eukaryotes. As a redox couple, consisting of reduced glutathione (GSH) and oxidized glutathione disulfide (GSSG), it is crucial for the maintenance of the cellular redox balance. Glutathione transport out of and into cellular compartments and the extracellular space is a determinant of the thiol-disulfide redox state of the organelles and bodily fluids in question, but is currently not well understood. Here we use the genetically-encoded, glutathione-measuring redox probe Grx1-roGFP2 to comprehensively elucidate the import of extracellular glutathione into the cytoplasm of the model organismEscherichia coli. The elimination of only two ATP-Binding Cassette (ABC) transporter systems, Gsi and Opp, completely abrogates glutathione import intoE. coli’s cytoplasm, both in its reduced and oxidized form. The lack of only one of them, Gsi, completely prevents import of oxidized glutathione (GSSG), while the lack of the other, Opp, substantially retards the uptake of reduced glutathione (GSH).
Congruent timing in Human, Nightingale, Parotid Wasp and Hawaiian Planthopper vocalisations
Authors: Fourcin Adrian
Published: July 2024

Earlier multi-speaker, multi-language measurements found that in purposeful fluent speech, total voice duration was half that of the whole – a maximum Shannon entropy criterion for two state signals. The present aim is to discover whether other species’ vocalisations are similarly associated with maximum timing entropy control. Data selection has been based on the use of courtship songs since they are purposeful and fluent. These songs are intended for con-specific females and, at present, often too complex for reliable acoustic signal analysis. In consequence it has been necessary, for this preliminary study, to find courtship songs in which the echemes are well demarcated from silence – this has led to a curtailment of potential signal resources.

The vocalisation timings in examples of the courtship songs of Nightingale, Parotid Wasp and Hawaiian Planthopper have been analysed. The resulting measurements are compared with those for voice timing in purposeful fluent, human speech. There are three primary findings:

The same Shannon timing entropy maximising rule is intrinsic to all four vocalisations.

Gaussian distributions of voice/vocalisation timings are present for each of the four signal types.

In each case, maximum entropy of voice/vocalisation timing tends to be maintained continually throughout the production of the whole signal.
HINT1 Inhibitors as Selective Modulators of MOR-NMDAR Cross Regulation and Non-Opioid Analgesia
Authors: Dillenburg Maxwell , Peterson Cristina D. , Dolat Rafal , Ligori Kostana , Kitto Kelley F , Wilcox George L , Fairbanks Carolyn A. , Wagner Carston R.
Published: July 2024

The Human Histidine Triad Nucleotide Binding Protein 1 (HINT1) has recently become a protein of interest due to its involvement in several CNS processes, including neuroplasticity and the development of several neuropsychiatric disorders. Crucially, HINT1 behaves as a mediator for the cross-regulation of the mu opioid receptor (MOR) andN-methyl-D-aspartate receptor (NMDAR). Active site inhibition of HINT1 using small molecule inhibitors has been demonstrated to have a significant impact on this cross-regulatory relationshipin vivo. Herein, we describe the development of a series of ethenoadenosine HINT1 inhibitors to further evaluate the effect of HINT1 inhibition on morphine’s blockade of NMDA-evoked behaviors, the development of acute endomorphin-2 tolerance and analgesia. X-ray crystallographic analysis and HINT1 binding experiments demonstrate that modifications to the inhibitor nucleobase greatly impact the inhibitor binding interactions with HINT1. Our results reveal a complex structural-activity relationship for HINT1 inhibitors in which minor modifications to the ethenoadenosine scaffold resulted in dramatic changes to their activity in these assays modeling MOR-NMDAR interaction. Specifically, we observed the ability of HINT1 inhibitors to selectively affect individual pathways of MOR-NMDAR crosstalk. Furthermore, we observed that a carbamate ethenoadenosine inhibitor of HINT1 can induce analgesia, while not affecting opioid tolerance. Additionally, although past studies have indicated that that loss of HINT1 expression can result in the downregulation of p53, we have shown that inhibition of HINT1 has no effect on either the expression of HINT1 or p53. These studies highlight the critical role of HINT1 in MOR-NMDAR crosstalk and demonstrate the intriguing potential of using HINT1 active-site inhibitors as tools to probe its role in these biochemical pathways and its potential as a novel pain target.
Antigen-Specific modulation of Chronic Experimental Autoimmune Encephalomyelitis in Humanized Mice by TCR-like Antibody Targeting Auto-Reactive T-Cell Epitope
Authors: Goor Ilana , Altman Efrat , Arman Inbar , Haus-Cohen Maya , Reiter Yoram
Published: July 2024

The development and application of human T-cell receptor (TCR)-like antibodies (TCRL) recognizing disease-specific peptide-MHC complexes may prove an important tool for basic research and therapeutic applications.

Multiple Sclerosis is characterized by aberrant CD4 T cell response to self-antigens presented by class II MHC molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG35-55 derived from Myelin Oligodendrocyte Glycoprotein (MOG) presented on HLA-DR2 which is associated with Multiple Sclerosis (MS).

We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/ MOG35-55 derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in humanized EAE transgenic mouse model. The TCRLs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG35-55 stimulation in an antigen-specific manner. Most significant, administration of TCRL to MOG35-55 induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with reduction of autoreactive pathogenic T cells infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglia APCs.

Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE.

Our study constitutes an in vivo proof-of-concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as multiple sclerosis (MS), validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases.
Proxi-RIMS-seq2 applied to native microbiomes uncovers hundreds of known and novelm5C methyltransferase specificities
Authors: Yang Weiwei , Luyten Yvette , Reister Emily , Mangelson Hayley , Sisson Zach , Auch Benjamin , Liachko Ivan , Roberts Richard J. , Ettwiller Laurence
Published: July 2024

Methylation patterns in bacteria can be used to study Restriction-Modification (RM) or other defense systems with novel properties. Whilem4C andm6A methylation is well characterized mainly through PacBio sequencing, the landscape ofm5C methylation is under-characterized. To bridge this gap, we performed RIMS-seq2 on microbiomes composed of resolved assemblies of distinct genomes through proximity ligation. This high-throughput approach enables the identification ofm5C methylated motifs and links them to cognate methyltransferases directly on native microbiomes without the need to isolate bacterial strains. Methylation patterns can also be identified on viral DNA and compared to host DNA, strengthening evidence for virus-host interaction. Applied to three different microbiomes, the method unveils over 1900 motifs that were deposited in REBASE. The motifs include a novel 8-base recognition site (CATm5CGATG) that was experimentally validated by characterizing its cognate methyltransferase. Our findings suggest that microbiomes harbor arrays of untappedm5C methyltransferase specificities, providing insights to bacterial biology and biotechnological applications.
Persistent activity during working memory maintenance predicts long-term memory formation in the human hippocampus
Authors: Daume Jonathan , Kamiński Jan , Salimpour Yousef , Anderson William S. , Valiante Taufik A. , Mamelak Adam N. , Rutishauser Ueli
Published: July 2024

Working Memory (WM) and Long-Term Memory (LTM) are often viewed as separate cognitive systems. Little is known about how these systems interact when forming memories. We recorded single neurons in the human medial temporal lobe while patients maintained novel items in WM and a subsequent recognition memory test for the same items. In the hippocampus but not the amygdala, the level of WM content-selective persist activity during WM maintenance was predictive of whether the item was later recognized with high confidence or forgotten. In contrast, visually evoked activity in the same cells was not predictive of LTM formation. During LTM retrieval, memory-selective neurons responded more strongly to familiar stimuli for which persistent activity was high while they were maintained in WM. Our study suggests that hippocampal persistent activity of the same cell supports both WM maintenance and LTM encoding, thereby revealing a common single-neuron component of these two memory systems.
An essential role for the Hv1 voltage-gated proton channel inPseudomonas aeruginosacorneal infection
Authors: Rodriguez Priscila , Abbondante Serena , Marshall Michaela , Abdelmeseh Jessica , Tombola Francesco , Pearlman Eric
Published: July 2024

Assembly of NADPH oxidase 2 (NOX2) proteins in neutrophils plays an essential role in controlling microbial infections by producing high levels of reactive oxygen species (ROS). In contrast, the role of the Hv1 voltage-gated proton channel that is required for sustained NOX2 activity is less well characterized. We examined the role of Hv1 in a murine model of blindingPseudomonas aeruginosacorneal infection and found that in contrast to C57BL/6 mice,Hvcn1-/-mice exhibit an impaired ability to kill bacteria and regulate disease severity.In vitro, we used a novel Hv1 Inhibitor Flexible (HIF) to block ROS production by human and murine neutrophils and found that HIF inhibits ROS production in a dose-dependent manner following stimulation with PMA or infection withP. aeruginosa. Collectively, these findings demonstrate an important role for Hv1 on controlling bacterial growth in a clinically relevant bacterial infection model.
Identifying candidate items for a prototype index on propensity to integrate research evidence into clinical decision-making in rehabilitation
Authors: Roberge-Dao Jacqueline , Thomas Aliki , Rochette Annie , Shikako Keiko , Mayo Nancy
Published: July 2024

Purpose

Existing measures of evidence-based practice (EBP) in rehabilitation provide a fragmented interpretation of EBP competencies as performance is rated on discrete domains without a harmonized measure to represent the multidimensionality of EBP. Building on previous work, this study aimed to provide evidence that a brief multidimensional index can be formed to determine a clinician’s propensity to integrate research evidence into decision-making to inform the subsequent development process.

Methods

Using a Canadian dataset of occupational and physical therapists (n=127) who responded to a survey containing 70 frequently used items to measure EBP (representing six domains), one item per key EBP domain was selected using Rasch measurement theory and expert consensus. A preliminary scoring algorithm was developed for testing purposes. The interpretability of the prototype index was examined across characteristics of the sample and compared to full EBP measures using generalized estimating equations.

Results

Five items were selected for inclusion in the prototype index representing the dimensions ofuse of research evidence, self-efficacy, resources, attitudes,andactivities. Testing demonstrated that the prototype behaves consistently regardless of age groups, gender, and setting, and provides comparable information to full EBP measures.

Conclusion

This study provides promising preliminary evidence to justify continuing the index development process. The benefits of having a global index of EBP as opposed to having multiple domain-specific measures are discussed in this paper.
Lateral Thinking: Pathway Specific Neurodegeneration of the Cortical Cholinergic System in Alzheimer’s Disease
Authors: Crockett Rachel A. , Casselton Charlotte , Howard Tatianna M. , Wilkins Kevin B. , Seo Gang , Brontë-Stewart Helen M. ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database
Published: July 2024

INTRODUCTION

Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer’s disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression.

METHODS

187 participants were included in this study who were either healthy controls (HC; n=50) or had early mild cognitive impairment (EMCI; n=50), late MCI (LMCI; n=37), or AD (n=50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed.

RESULTS

NBM volume was smallest in AD followed by LMCI (p<0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (p<0.001). Both MCI groups had higher lateral tract MD compared to HC (p<0.05). Medial tract MD was higher in LMCI (p=0.008), but not EMCI (p=0.09) compared to HC. Higher lateral tract MD was associated with executive function (p=0.001) and language (p=0.02).

DISCUSSION

Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.
Association of CSF α-Synuclein Seed Amplification Assay Positivity with Disease Progression and Cognitive Decline: A Longitudinal Alzheimer’s Disease Neuroimaging Initiative Study
Authors: Tosun Duygu , Hausle Zachary , Thropp Pamela , Concha-Marambio Luis , Lamoureux Jennifer , Lebovitz Russ , Shaw Leslie M. , Singleton Andrew B. , Weiner Michael W. ,   the Alzheimer’s Disease Neuroimaging Initiative, Blauwendraat Cornelis
Published: July 2024

INTRODUCTION

CSF α-synuclein seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body (LB) co-pathology in AD.

METHODS

1637 cross-sectional and 407 longitudinal CSF samples from ADNI were tested with SAA. We examined longitudinal dynamics of Aβ, α-synuclein seeds, and p-tau181, along with global and domain-specific cognition in stable SAA+, stable SAA−, and those who converted to SAA+ from SAA−.

RESULTS

SAA+ individuals had faster cognitive decline than SAA−, notably in MCI, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42-positivity but did not impact progression of either Aβ42 or p-tau181 status. Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly Aβ42. In vitro α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline.

DISCUSSION

These results highlight the interplay between Aβ and α-synuclein and their association with disease progression.
Brain imaging phenotypes associated with polygenic risk for Essential Tremor
Authors: Medeiros Miranda , Pastor-Bernier Alexandre , Azizi Houman , Schmilovich Zoe , Castonguay Charles-Etienne , Savadjiev Peter , Poline Jean-Baptiste , St-Onge Etienne , Zhang Fan , O’Donnell Lauren J. , Pasternak Ofer , Zeighami Yashar , Dion Patrick A. , Dagher Alain , Rouleau Guy A.
Published: July 2024

Essential tremor (ET) is a common movement disorder with a strong genetic basis. Magnetic resonance imaging (MRI), particularly diffusion-weighted MRI (dMRI) and T1 MRI has been used to identify brain abnormalities of ET patients. However, the mechanisms by which genetic risk affects the brain to render individuals vulnerable to ET remain unknown.

We aim to understand how ET manifests by identifying presymptomatic brain vulnerabilities driven by ET genetic risk.

We probe the vulnerability of healthy people towards ET by investigating the association of morphometry, and white and grey matter dMRI with ET in polygenic risk scores (PRS) in roughly 30,000 individuals from the UK Biobank (UKB).

Our results indicate significant effects of ET-PRS with mean diffusivity, fractional anisotropy, free water, radial diffusivity, and axial diffusivity in white matter tracts implicated in movement control. We found significant associations between ET-PRS and grey matter tissue microstructure, including the red nucleus, caudate, putamen, and motor thalamus. ET-PRS was associated with reduced grey matter volumes in several cortical and subcortical areas including the cerebellum. Identified anomalies include networks connected to surgical sites effective in ET treatment. Finally, in a secondary analysis, low PRS individuals compared to a small number of patients with ET (N=49) in the UKB revealed many structural differences.

Brain structural vulnerabilities in healthy people at risk of developing ET correspond to areas known to be involved in the pathology of ET. High genetic risk of ET seems to disrupt ET brain networks even in the absence of overt symptoms of ET.
P-BODY AND CYTOSKELETON REMODELING BY ORTHOHANTAVIRUSES
Authors: Schwarzer-Sperber Hannah Sabeth , Petrich Annette , Schade Matthias , Nilson Niklaas , Chibrac-Ahad Linah , Lehmann Maik Joerg , Paulick Katharina , Weiss Sabrina , Bourquain Daniel , Witkowski Peter T. , Krüger Detlev H. , Herrmann Andreas , Schwarzer Roland
Published: July 2024

Orthohantaviruses, are emerging zoonotic pathogens causing life-threatening diseases in humans. The orthohantavirus genome consists of three RNA segment (vRNAs) of negative polarity, which are encapsidated by the viral nucleoprotein (N). To date, the precise subcellular behavior of vRNAs and N has not been fully elucidated. Here, we present a comprehensive analysis of orthohantavirus infections using Fluorescencein situHybridization (FISH) and multiple sequential FISH (Mu-Seq FISH), which enables simultaneous detection of viral RNAs, viral mRNAs, N, and cellular factors. Our experiments revealed distinct patterns of viral RNA clustering with varying degrees of N association. Moreover, we found a significant spatial correlation of virus vRNAs and N with cellular processing (P)-bodies, underlining their key role in orthohantavirus replication. Throughout the course of an infection, we observed an increasing dominance of N expression, while concomitantly P-body numbers grew significantly. We also found indications for a preferential 5’-end degradation of viral mRNAs in P-bodies. Furthermore, we report that orthohantavirus infection is accompanied by a significant redistribution of cellular components: while filamentous actin and microtubules become enriched in the perinuclear region, P-bodies move to the cell periphery. Finally, co-localization analyses suggest a formation of viral factories containing N, vRNAs, and viral mRNAs, indicating an intricate orthohantavirus assembly hierarchy.

AUTHOR SUMMARY

In this study we used advanced imaging techniques to observe the dynamics of viral components and key cellular structures during orthohantavirus infections. Our experiments show that orthohantaviruses cause significant changes within the cell, particularly involving P-bodies and components of the cytoskeleton, such as actin and microtubules. We also provided comprehensive spatiotemporal maps of orthohantaviral components, including visualization of the viral nucleoprotein, genomic RNA and mRNAs. Finally, we found indications for a 5’end degradation of virus mRNA in P-bodies, thus adding to our understanding of intracellular host-pathogen crosstalk. In summary, our work highlights the intricate relationship between viruses and host cells, emphasizing the dynamic changes that occur during orthohantaviral infections.
Amyloid-β can activate JNK signalling via WNT-5A/ROR2 to reduce synapse formation in Alzheimer’s disease
Authors: Fang Kevin , Pishva Ehsan , Piers Thomas , Scholpp Steffen
Published: July 2024

Wnt signalling is an essential signalling system in neurogenesis, and recent studies have highlighted the critical role of this signalling network in regulating synaptic plasticity, neuronal survival, and neurogenesis, processes that are disrupted in Alzheimer’s disease (AD). From the Wnt network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical pathway, which operates independently of β-catenin and involves the planar cell polarity (PCP), remains to be determined in AD.

In this work, we analyse the function of the orphan receptor tyrosine kinase ROR2, an essential co-receptor of the Wnt/PCP signalling pathway. We find that activation of WNT-5A/ROR2 signalling activates JNK signalling, reducing pre- and postsynaptic clusters on neurites in mature SH-SY5Y neurons. This observation is similar to SH-SY5Y neurons treated with the Amyloid-β peptide Aβ1-42or DKK1, which are both increased in AD. Surprisingly, the effect of Aβ1-42and DKK1 signalling on synaptogenesis can be mitigated by blocking ROR2 and JNK signalling, suggesting that Aβ and DKK1 signalling depends on ROR2/JNK signalling. Finally, we find an increase of WNT-5A/ROR2 clusters on neurites of iPSC-derived cortical neurons carrying the PSEN1 A75V mutation, known to enhance the pathological Aβ42/40ratio. Simultaneously, the number of pre- and post-synaptic clusters decreased in the mutant line. Inhibition of ROR2/JNK signalling in PSEN1A75Vcortical neurons partially rescues the reduction in synaptogenesis, suggesting that ROR2 signalling may act in a positive feedback loop with Aβ1-42and DKK1 signalling to augment JNK signalling as seen in AD.
Hearing and cognitive decline in aging differentially impact neural tracking of context-supported versus random speech across linguistic timescales
Authors: Bolt Elena , Kliestenec Katarina , Giroud Nathalie
Published: July 2024

Cognitive decline and hearing loss are common in older adults and often co-occur while investigated separately, affecting the neural processing of speech. This study investigated the interaction between cognitive decline, hearing loss, and contextual cues in speech processing. Participants aged 60 years and older were assessed for cognitive decline using the Montreal Cognitive Assessment and for hearing ability using a four-frequency pure tone average. They listened to in-house-designed matrix-style sentences that either provided supportive context or were random, while we recorded their electroencephalography. Neurophysiological responses were analyzed through auditory evoked potentials and speech tracking at different linguistic timescales (i.e., phrase, word, syllable and phoneme rate) using phase-locking values. The results showed that cognitive decline was associated with a lower chance of correct responses in a speech recognition task. Cognitive decline significantly impacted the P2 component of auditory evoked potentials, while hearing loss influenced speech tracking at the word and phoneme rates, but not at the phrase or syllable rates. Contextual cues enhanced speech tracking at the syllable rate. These findings suggest that cognitive decline and hearing loss differentially affect the neural mechanisms underlying speech processing, with contextual cues playing a significant role in enhancing syllable rate tracking. This study emphasises the importance of considering both cognitive and auditory factors when studying speech processing in older people and highlights the need for further research to investigate the interplay between cognitive decline, hearing loss and contextual cues in speech processing.
Functional implications of the interaction of the SARS-CoV-2 Nucleocapsid protein with factors involved in nonsense-mediated mRNA decay
Authors: Mallick Megha , Boehm Volker , Xue Guangpu , Blackstone Mark , Gehring Niels H. , Chakrabarti Sutapa
Published: July 2024

The RNA genome of the SARS-CoV-2 virus encodes for four structural proteins, 16 non- structural proteins and nine putative accessory factors. A high throughput analysis of interactions between human and SARS-CoV-2 proteins identified multiple interactions of the structural Nucleocapsid (N) protein with RNA processing factors. The N-protein, which is responsible for packaging of the viral genomic RNA was found to interact with two RNA helicases, UPF1 and MOV10 that are involved in nonsense-mediated mRNA decay (NMD). Using a combination of biochemical and biophysical methods, we investigated the interaction of the SARS-CoV-2 N-protein with NMD factors at a molecular level. Our studies led us to identify the core NMD factor, UPF2, as an interactor of N. The viral N-protein engages UPF2 in multipartite interactions and can negate the stimulatory effect of UPF2 on UPF1 catalytic activity. N also inhibits UPF1 ATPase and unwinding activities by competing in binding to the RNA substrate. We further investigate the functional implications of inhibition of UPF1 catalytic activity by N in mammalian cells. The interplay of SARS-CoV-2 N with human UPF1 and UPF2 does not affect decay of host cell NMD targets but might play a role in stabilizing the viral RNA genome.
Identification ofV. parvulaandS. gordoniiadhesins mediating co-aggregation and its impact on physiology and mixed biofilm structure
Authors: Dorison Louis , Béchon Nathalie , Martin-Gallausiaux Camille , Chamorro-Rodriguez Susan , Vitrenko Yakov , Ouazahrou Rania , Villa Romain , Deschamps Julien , Briandet Romain , Gribaldo Simonetta , Ghigo Jean-Marc , Beloin Christophe
Published: July 2024

The dental plaque is a polymicrobial community where biofilm formation and co-aggregation, the ability to bind to other bacteria, play a major role in the construction of an organized consortium. One of its prominent members is the anaerobic didermVeillonella parvula,considered as a bridging species, which growth depends on lactate produced by oralStreptococci. Understanding howV. parvulaco-aggregates and the impact of aggregation has long been hampered due to the lack of appropriate genetic tools. Here we studied co-aggregation of the naturally competent strainV. parvulaSKV38 with various oral bacteria and its effect on cell physiology. We show thatV. parvularequires different trimeric autotransporters of the type V secretion system to adhere to oralStreptococciandActinomyces. In addition, we describe a novel adhesin ofStreptococcus gordonii,VisA (SGO_2004), as the protein responsible for co-aggregation withV. parvula. Finally, we show that co-aggregation does not impact cell-cell communication, which is mainly driven by environmental sensing, but plays an important role in the architecture and species distribution within the biofilm.
Chlamydia muridarumCauses Persistent Subclinical Infection and Elicits Innate and Adaptive Immune Responses in C57BL/6J, BALB/cJ and J:ARC(S) Mice Following Exposure to Shedding Mice
Authors: Mishkin Noah , Carrasco Sebastian E , Palillo Michael Beniamo , Momtsios Panagiota , Woods Cheryl , Henderson Kenneth S , Longhini Ana Leda F , Otis Chelsea , Gardner Rui , Joseph Ann M , Sonnenberg Gregory F , Palillo Jack , Ricart Arbona Rodolfo J , Lipman Neil S
Published: July 2024

Chlamydia muridarum(Cm) has reemerged as a moderately prevalent infectious agent in research mouse colonies. Despite its' experimental use, few studies evaluate Cm's effects on immunocompetent mice following its natural route of infection. A Cm field isolate was administered (orogastric gavage) to 8-week-old female BALB/cJ (C) mice. After confirming shedding (through 95d), these mice were cohoused with naive C57BL/6J (B6), C, and Swiss (J:ARC[S]) mice (n=28/strain) for 30 days. Cohoused mice (n=3-6 exposed and 1-6 control/strain) were evaluated 7, 14, 21, 63, 120, and 180 days post-cohousing (DPC) via hemograms, serum biochemistry analysis, fecal qPCR, histopathology, and Cm MOMP immunohistochemistry. Immunophenotyping was performed on spleen (B6, C, S; n=6/strain) and intestines (B6; n=6) at 14 and 63 DPC. Serum cytokine concentrations were measured (B6; n=6 exposed and 2 control) at 14 and 63 DPC. All B6 mice were shedding Cm by 3 through 180 DPI. One of 3 C and 1 of 6 S mice began shedding Cm at 3 and 14 DPC, respectively, with the remaining shedding thereafter. Clinical pathology was nonremarkable. Minimal-to-moderate enterotyphlocolitis and gastrointestinal associated lymphoid tissue (GALT) hyperplasia was observed in 15 and 47 of 76 Cm-infected mice, respectively. Cm antigen was frequently detected in GALT-associated surface intestinal epithelial cells. Splenic immunophenotyping revealed increased monocytes and shifts in T cell population subsets in all strains/timepoints. Gastrointestinal immunophenotyping (B6) revealed sustained increases in total inflammatory cells and elevated cytokine production in innate lymphoid cells and effector T cells (large intestine). Elevated concentrations of pro-inflammatory cytokines were detected in the serum (B6). Results demonstrate that while clinical disease was not appreciated, 3 commonly utilized strains of mice are susceptible to chronic enteric Cm infection which may alter various immune responses. Considering the widespread use of mice to model GI disease, institutions should consider excluding Cm from their colonies.
Identification and partial reconstitution of the biosynthetic pathway of bioactive meroterpenoids fromHericium erinaceus(Lion’s Mane mushroom)
Authors: Iacovelli Riccardo , Poon Fons , Haslinger Kristina
Published: July 2024

Hericium erinaceus(Lion’s Mane mushroom) is widely consumed for its numerous reported benefits for brain health. A growing body of evidence suggests that these benefits are likely attributable to aromatics contained in its fruiting bodies, including the meroterpenoids hericenones. Here, we report the identification and reconstitution of the first two steps of the biosynthetic pathway of hericenones via heterologous expression of the PKS HerA and the carboxylic acid reductase HerB inAspergillus oryzae. Furthermore, we investigate a putative prenyltransferase that might be responsible for the following biosynthetic step. Ongoing efforts to reconstitute the full pathway will enable large scale production of hericenones and other meroterpenoids in heterologous hosts.
A proteome-wide structural systems approach reveals insights into protein families of all human herpesviruses
Authors: Soh Timothy K. , Ognibene Sofia , Sanders Saskia , Schäper Robin , Kaufer Benedikt B. , Bosse Jens B.
Published: July 2024

Structure predictions have become invaluable tools, but viral proteins are absent from the EMBL/DeepMind AlphaFold database. Here, we provide proteome-wide structure predictions for all nine human herpesviruses and analyze them in depth with explicit scoring thresholds. By clustering these predictions into structural similarity groups, we identified new families, such as the HCMV UL112-113 cluster, which is conserved in alpha-and betaherpesviruses. A domain-level search found protein families consisting of subgroups with varying numbers of duplicated folds. Using large-scale structural similarity searches, we identified viral proteins with cellular folds, such as the HSV-1 US2 cluster possessing dihydrofolate reductase folds and the EBV BMRF2 cluster that might have emerged from cellular equilibrative nucleoside transporters. Our HerpesFolds database is available athttps://www.herpesfolds.org/herpesfoldsand displays all models and clusters through an interactive web interface. Here, we show that system-wide structure predictions can reveal homology between viral species and identify potential protein functions.
Purcell-modified Doppler cooling of quantum emitters inside optical cavities
Authors: Lyne J. , Bassler N. S. , Park S. , Pupillo G. , Genes C.
Published: July 2024

Standard cavity cooling of atoms or dielectric particles is based on the action of dispersive optical forces in high-finesse cavities. We investigate here a complementary regime characterized by large cavity losses, resembling the standard Doppler cooling technique. For a single two-level emitter a modification of the cooling rate is obtained from the Purcell enhancement of spontaneous emission in the large cooperativity limit. This mechanism is aimed at cooling quantum emitters without closed transitions, which is the case for molecular systems, where the Purcell effect can mitigate the loss of population from the cooling cycle. We extend our analytical formulation to the many-particle case governed by small individual coupling, but exhibiting large collective coupling.

Published by the American Physical Society
2024
Two-Higgs-doublet model matched to nonlinear effective theory
Authors: Buchalla G. , König F. , Müller-Salditt Ch. , Pandler F.
Published: July 2024

We use functional methods to match the two-Higgs-doublet model with heavy scalars in the nondecoupling regime to the appropriate nonlinear effective field theory, which takes the form of an electroweak chiral Lagrangian (HEFT). The effective Lagrangian is derived to leading order in the chiral counting. This includes the loop induced h→γγ and h→Zγ local terms, which enter at the same chiral order as their counterparts in the Standard Model. An algorithm is presented that allows us to compute the coefficient functions to all orders in h. Some of the all-orders results are given in closed form. The parameter regimes for decoupling, nondecoupling, and alignment scenarios in the effective field theory context and some phenomenological implications are briefly discussed.

Published by the American Physical Society
2024