bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed cerebrovascular dysfunction and social deficits after traumatic brain injury
Authors: Singh Aditya , Gong Steven , Vu Anh , Li Scott , Obenaus Andre
Published: February 2024

Traumatic brain injury (TBI) survivors face debilitating long-term psychosocial consequences, including social isolation and depression. Acute TBI modifies neurovascular physiology and behavior but a gap in our understanding are the chronic physiological implications of altered brain perfusion on behavioral activities, particularly social interactions.

We investigated longitudinal functional vascular networks across the brain for 2-months post- TBI and its impact on social behavior. Adult C57/BL6 male mice received a moderate cortical TBI. Behavior (foot-fault, open-field, 3-chamber social preference) was assessed at baseline, 3-, 7-, 14-, 30-, and 60-days post injury (dpi) followed by magnetic resonance imaging (MRI, 9.4T). Anatomical MRI (T2-weighted), dynamic susceptibility contrast (DSC) perfusion weighted MRI (PWI) were acquired at each temporal epoch. After the final 60dpi MRI, animals underwent transcardial perfusion fixation to map angioarchitecture. MRI data were analyzed using standardized protocols followed by cross-correlations between social behavior, cerebral perfusion, and vascular metrics.

Social behavior deficits at 60dpi emerged as reduced interaction with a familiar cage-mate (partner). We observed multiphasic decrements in cerebral blood flow (CBF) encompassing lesion and perilesional cortex where acute reductions at 3-14dpi partially recovered by 30dpi, followed by significant reductions in perfusion at 60dpi. The CBF perturbations extended antero-posteriorly from the ipsilateral TBI impact site but also adulterated contralateral brain regions. CBF reductions impacted regions known to regulate social behavior including hippocampus, hypothalamus, and rhinal cortex. Alongside perfusion deficits at 60dpi, social isolation in TBI-mice emerged with a significant decline in preference to spend time with a cage mate. Cortical vascular density was also reduced corroborating the decline in brain perfusion and social interaction.

Thus, the novel temporal neurovascular loss, and subsequent recovery followed by chronic decrements are broadly reflected by social interaction perturbations. Our correlations strongly implicate a linkage between vascular density, cerebral perfusion, and social interactions, where early evaluation can potentially predict long-term outcomes. Thus, our study provides a clinically relevant timeline of alterations in functional vascular recovery that can guide research for future therapeutics.
A Scalable Optimization Algorithm for Solving the Beltway and Turnpike Problems with Uncertain Measurements
Authors: Elder C.S. , Hoang Minh , Ferdosi Mohsen , Kingsford Carl
Published: February 2024

The Beltwayand Turnpikeproblems entail the reconstruction of circular and linear one-dimensional point sets from unordered pairwise distances. These problems arise in computational biology when the measurements provide distances but do not associate those distances with the entities that gave rise to them. Such applications include molecular structure determination, genomic sequencing, tandem mass spectrometry, and molecular error-correcting codes (since sequencing and mass spec technologies can give lengths or weights, usually without connecting them to endpoints). Practical algorithms for Turnpike are known when the distance measurements are accurate, but both problems become strongly NP-hard under any level of measurement uncertainty. This is problematic since all known applications experience some degree of uncertainty from uncontrollable factors. Traditional algorithms cope with this complexity by exploring a much larger solution space, leading to exponential blowup in terms of both time and space. To alleviate both issues, we propose a novel alternating optimization algorithm that can scale to large, uncertain distance sets with as many as 100,000 points. This algorithm is space and time-efficient, with each step running inO(mlog(m)) time and requiring onlyworking space for a distance set of sizem. Evaluations of this approach on synthetic and partial digest data showcase improved accuracy and scalability in the presence of uncertain, duplicated, and missing distances. Our implementation of the algorithm is available athttps://github.com/Kingsford-Group/turnpikesolvermm.
How the Anatomy of the Epidermal Cells Is Correlated to the Transient Response of Stomata
Authors: Zekri Maryam Alsadat , Tholen Daniel , Koller Lukas , Lang Ingeborg , Theroux-Rancourt Guillaume
Published: February 2024

Here, we show the possible correlation between the anatomical characteristics of epidermal cells ofArabidopsis thalianawith the stomata transient opening, which is commonly called the Wrong-Way Response (WWR). The WWR was induced by either reduced air humidity or leaf excision. Five genotypes ofA. thalianaCol8,epf1epf2, lcd1-1, SALK069, and UBP, respectively, with anatomical differences in epidermal cells such as stomatal density, stomata size, size, and shape of the pavement cells were selected. These genotypes allowed us to investigate the mutual effects of stomata density and size on WWR. Scanning Electron Microscopy (SEM) was applied for image acquisition of the abaxial and adaxial surface of the leaves and the main features of the epidermal cells were extracted by one of the additions to the MiToBo plugin of ImageJ/Fiji called PaCeQuant. The stomatal conductance to water vapor (gs) was measured using the portable photosynthesis measurement system LICor-6800. Our linear models showed that the size of the stomata explained the rate of WWR induced by reduced air humidity, so genotypes with smaller stomata showed a smaller rate of the WWR. After leaf excision, however, there was no correlation between the size of the stomata and the rate of the WWR. Moreover, we found that after both, reduced air humidity and leaf excision, the size of the pavement cells on the abaxial surface is correlated to the rate of the WWR; genotypes with smaller pavement cells on the abaxial surface had a smaller rate of WWR.
DiffGAN: a conditional generative adversarial network for phasing single molecule diffraction data to atomic resolution
Authors: Matinyan S. , Filipcik P. , Genderen E. van , Abrahams J.P.
Published: February 2024

Introduction

Proteins that adopt multiple conformations pose significant challenges in structural biology research and pharmaceutical development, as structure determination via single particle cryo-electron microscopy (cryo-EM) is often impeded by data heterogeneity. In this context, the enhanced signal-to-noise ratio of single molecule cryo-electron diffraction (simED) offers a promising alternative. However, a significant challenge in diffraction methods is the loss of phase information, which is crucial for accurate structure determination.

Methods

Here, we present DiffGAN, a conditional generative adversarial network (cGAN) that estimates the missing phases at high resolution from a combination of high-resolution single particle diffraction data and low-resolution image data.

Results

For simulated datasets, DiffGAN allows effectively determine protein structures at atomic resolution from diffraction patterns and noisy low-resolution images.

Discussion

Our findings suggest that combining single particle cryo-electron diffraction with advanced generative modeling, as in DiffGAN, could revolutionize the way protein structures are determined, offering a more accurate and efficient alternative to existing methods.
Unveiling Frailty: Comprehensive and Sex-Specific Characterization in Prematurely Aging PolgA Mice
Authors: Yılmaz Dilara , Singh Amit , Wehrle Esther , Kuhn Gisela A. , Mathavan Neashan , Müller Ralph
Published: February 2024

Frailty, a geriatric syndrome, is assessed using the frailty phenotype (FP) and frailty index (FI). While these approaches have been applied to aging mice, their effectiveness in prematurely aging mouse models such as PolgAD257A/D257A(PolgA) has not been completely explored. We demonstrated that frailty became evident in PolgA mice around 40 weeks, validated through body weight loss, reduced walking speed, decreased physical activity, and weaker grip strength. Moreover, we also identified sex differences in these mice with females exhibiting higher frailty compared to males. Frailty prevalence in PolgA mice at 40 weeks parallels that observed in naturally aging mice at 27 months and aging humans at 65-70 years. These findings contribute to understanding frailty onset and sex-specific patterns, emphasizing the significance of the PolgA mouse model in investigating aging and related disorders.
Interpretable Atomistic Prediction and Functional Analysis of Conformational Ensembles and Allosteric States in Protein Kinases Using AlphaFold2 Adaptation with Randomized Sequence Scanning and Local Frustration Profiling
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Tian Hao , Xiao Sian , Tao Peng , Verkhivker Gennady
Published: February 2024

The groundbreaking achievements of AlphaFold2 (AF2) approaches in protein structure modeling marked a transformative era in structural biology. Despite the success of AF2 tools in predicting single protein structures, these methods showed intrinsic limitations in predicting multiple functional conformations of allosteric proteins and fold-switching systems. The recent NMR-based structural determination of the unbound ABL kinase in the active state and two inactive low-populated functional conformations that are unique for ABL kinase presents an ideal challenge for AF2 approaches. In the current study we employ several implementations of AF2 methods to predict protein conformational ensembles and allosteric states of the ABL kinase including (a) multiple sequence alignments (MSA) subsampling approach; (b) SPEACH_AF approach in which alanine scanning is performed on generated MSAs; and (c) introduced in this study randomized full sequence mutational scanning for manipulation of sequence variations combined with the MSA subsampling. We show that the proposed AF2 adaptation combined with local frustration mapping of conformational states enable accurate prediction of the ABL active and intermediate structures and conformational ensembles, also offering a robust approach for interpretable characterization of the AF2 predictions and limitations in detecting hidden allosteric states. We found that the large high frustration residue clusters are uniquely characteristic of the low-populated, fully inactive ABL form and can define energetically frustrated cracking sites of conformational transitions, presenting difficult targets for AF2 methods. This study uncovered previously unappreciated, fundamental connections between distinct patterns of local frustration in functional kinase states and AF2 successes/limitations in detecting low-populated frustrated conformations, providing a better understanding of benefits and limitations of current AF2-based adaptations in modeling of conformational ensembles.
A low-abundance class of Dicer-dependent siRNAs produced from a variety of features inC. elegans
Authors: Knittel Thiago L. , Montgomery Brooke E. , Tate Alex J. , Deihl Ennis W. , Nawrocki Anastasia S. , Hoerndli Frederic J. , Montgomery Taiowa A.
Published: February 2024

Canonical small interfering RNAs (siRNAs) are processed from double-stranded RNA (dsRNA) by the endoribonuclease Dicer. siRNAs are found in plants, animals, and some fungi where they associate with Argonautes to direct RNA silencing. InCaenorhabditis elegans, some endogenous small RNAs, such as 22G-RNAs and 26G-RNAs, share certain attributes with canonical siRNAs but exhibit unique characteristics known only to occur in nematodes. For instance, 22G-RNAs do not originate from dsRNA and are not processed by Dicer, whereas 26G-RNAs require Dicer but lack the typical duplex intermediate with symmetrical 3’-overhangs and are produced only antisense to their mRNA templates. To identify canonical siRNAs inC. elegans, we first characterized the siRNAs produced from exogenous dsRNA. As predicted based on earlier studies, exogenous dsRNA is processed into ∼23-nt duplexes with 2-4-nt 3’-overhangs, ultimately yielding siRNAs devoid of 5’ G-containing sequences that bind with high affinity to the Argonaute RDE-1. Leveraging these characteristics, we searched for their endogenous counterparts and identified thousands of endogenous loci representing dozens of unique elements that give rise to mostly low to moderate levels of siRNAs, called 23H-RNAs. These loci include repetitive elements, alleged coding genes, pseudogenes, non-coding RNAs, and unannotated features, many of which adopt hairpin structures reminiscent of the hpRNA/RNA interference (RNAi) pathway in flies and mice. Our results expand the known repertoire ofC. eleganssmall RNAs and demonstrate that key features of the endogenous siRNA pathway are relatively unchanged in animals.
Salbutamol, a short acting beta-2 agonist, reduces risk and improves prognosis of prostate cancer
Authors: Lehrer Steven , Rheinstein Peter H.
Published: February 2024

Background

Beta-blockers, a class of drugs commonly used to manage blood pressure, have been the subject of research regarding their relationship to prostate cancer risk, prognosis, and treatment. Beta blockers reduce risk and improve prognosis of prostate cancer. Perioperative use of a non-selective beta blocker improves outcome after radical prostatectomy. But a related class of drugs, beta 2 adrenergic agonists, has received little attention in prostate cancer.

Methods

We studied the relationship of the beta 2 adrenergic agonist salbutamol to prostate cancer risk and survival. We analyzed FDA MedWatch data to determine whether salbutamol could influence the risk of prostate cancer. We used UK Biobank (UKBB) data to assess the effect of salbutamol on prostate cancer (PC) survival.

Results

Salbutamol significantly reduces prostate cancer risk, Proportional Reporting Ratio (PRR) and 95% confidence interval (lower bound; upper bound): 0.131 (0.11; 0.155) and improves prognosis. Mean survival was 7.35 years for subjects not taking salbutamol, 10.5 years for subjects taking salbutamol (p = 0.041, log rank test. To adjust for the effect of age we performed proportional hazards regression, survival time dependent variable, age and salbutamol use independent variables. Salbutamol use was significantly related to survival time (p = 0.016) and independent of the significant effect of age (p < 0.001).

Conclusion

Salbutamol and other beta-adrenergic agonists could represent a new class of drugs for treatment of prostate cancer.
An interim exploratory biomarker analysis of a Phase 2 clinical trial to assess the impact of CT1812 in Alzheimer’s disease
Authors: Lizama BN , North HA , Pandey K , Williams C , Duong D , Cho E , Di Caro V , Ping L , Blennow K , Zetterberg H , Lah J , Levey AI , Grundman M , Caggiano AO , Seyfried NT , Hamby ME
Published: February 2024

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer’s disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing Phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in patients with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics can detect more than 2,000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

HIGHLIGHTS

Effects of CT1812 on AD patients were investigated in a randomized Phase 2 clinical trial

Pharmacodynamic biomarkers of CT1812 were identified through unbiased analysis of proteomics quantitation data acquired using TMT Mass Spectrometry (TMT-MS)

CT1812 normalized a set of biomarkers altered in AD

Findings provide proof of mechanism that CT1812 impacts synapse, inflammation, amyloid-related processes
The Topology of Representational Geometry
Authors: Brown Shael , Farivar Reza
Published: February 2024

Representational similarity analysis (RSA) is a powerful tool for abstracting and then comparing neural representations across brains, regions, models and modalities. However, typical RSA analyses compares pairs of representational dissimilarities to judge similarity of two neural systems, and we argue that such methods can not capture the shape of representational spaces. By leveraging tools from computational topology, which can probe the shape of high-dimensional data, we augment RSA to be able to detect more subtle yet real differences and similarities of representational geometries. This new method could be used in conjunction with regular RSA in order to make new inferences about neural function.

Significance Statement

Big data in high-dimensional spaces, like neuroimaging datasets, contain important shape structures. These shape structures can be analyzed to identify the underlying features and dynamics which drive the system. We showed that such analyses, applied to neural activity patterns elicited by viewing various objects, can identify real but subtle and complex features of those objects which are encoded in the brain.
Computer vision analysis of mother-infant interaction identified efficient pup retrieval in V1b vasopressin receptor knockout mice
Authors: Sajjaviriya Chortip , Fujianti  , Azuma Morio , Tsuchiya Hiroyoshi , Koshimizu Taka-aki
Published: February 2024

Close contact between lactating rodent mothers and their infants is essential for effective nursing. Whether the mother’s effort to retrieve the infants to their nest requires the vasopressin-V1b vasopressin receptor axis has not been fully defined. To address this question, V1b receptor knockout (V1bKO) and control mice were analyzed in pup retrieval test. Because an exploring mother in a new test cage randomly accessed to multiple infants in changing backgrounds over time, a computer vision-based deep learning analysis was applied to continuously calculate the distances between the mother and the infants as a parameter of their relationship. In an open-field, a virgin female V1bKO mice entered fewer times into the center area and moved shorter distances than wild-type (WT). While this behavioral pattern persisted in V1bKO mother, the pup retrieval test demonstrated that total distances between a V1bKO mother and infants came closer in a shorter time than with a WT mother. Moreover, in the medial preoptic area, parts of the V1b receptor transcripts were detected in galanin- andc-fos-positive neurons following maternal stimulation by infants. This research highlights the effectiveness of deep learning analysis in evaluating the mother-infant relationship and the critical role of V1b receptor in pup retrieval during the early lactation phase.

Highlights

(1)

Mother-infant relationship was calculated as distances by computer vision and object detection analysis.

(2)

V1b knockout female mice tended to avoid entering centerfield in a new cage compared to control female.

(3)

Lack of V1b vasopressin receptor in mice facilitated the pup retrieval in early infancy, even with shorter distances of total movements.
PyF2F: A robust and simplified fluorophore-to-fluorophore distance measurement tool for Protein interactions from Imaging Complexes after Translocation experiments
Authors: Hernandez Altair C. , Ortiz Sebastian , Betancur Laura I. , Dojčilović Radovan , Picco Andrea , Kaksonen Marko , Oliva Baldo , Gallego Oriol
Published: February 2024

Structural knowledge of protein assemblies in their physiological environment is paramount to understand cellular functions at the molecular level. Protein interactions from Imaging Complexes after Translocation (PICT) is a live-cell imaging technique for the structural characterization of macromolecular assemblies in living cells. PICT relies on the measurement of the separation between labelled molecules using fluorescence microscopy and cell engineering. Unfortunately, the required computational tools to extract molecular distances involve a variety of sophisticated software that challenge reproducibility and limit their implementation by highly specialised researchers. Here we introduce PyF2F, a Python-based software that provides a workflow for measuring molecular distances from PICT data, with minimal user programming expertise. We used a published dataset to validate PyF2F performance.
Apnoea suppresses brain activity in infants
Authors: Zandvoort Coen S. , Dereymaeker Anneleen , Baxter Luke , Jansen Katrien , Naulaers Gunnar , de Vos Maarten , Hartley Caroline
Published: February 2024

Apnoea – the cessation of breathing – is commonly observed in premature infants. These events can reduce cerebral oxygenation and are associated with poorer neurodevelopmental outcomes. However, relatively little is known about how apnoea and shorter pauses in breathing impact brain function in infants, which will provide greater mechanistic understanding of how apnoea affects brain development. We analysed simultaneous recordings of respiration, electroencephalography (EEG), heart rate, and peripheral oxygen saturation in 124 recordings from 118 infants (post-menstrual age: 38.6 ± 2.7 weeks [mean ± standard deviation]) during apnoeas (pauses in breathing greater than 15 seconds) and shorter pauses in breathing between 5 and 15 seconds. EEG amplitude significantly decreased during both apnoeas and shorter pauses in breathing compared with normal breathing periods. Change in EEG amplitude was significantly associated with change in heart rate during apnoea and breathing pauses and, during apnoeas only, with oxygen saturation change. No associations were found between EEG amplitude and pause duration or post-menstrual age. The decrease in EEG amplitude may be a result of the changing metabolism and/or homeostasis following changes in oxygen and carbon dioxide concentrations, which alters the release of neurotransmitters. As apnoeas often occur in premature infants, frequent disruption to brain activity may impact neural development and result in long-term neurodevelopmental consequences.
Secure Discovery of Genetic Relatives across Large-Scale and Distributed Genomic Datasets
Authors: Hong Matthew M. , Froelicher David , Magner Ricky , Popic Victoria , Berger Bonnie , Cho Hyunghoon
Published: February 2024

Finding relatives within a study cohort is a necessary step in many genomic studies. However, when the cohort is distributed across multiple entities subject to data-sharing restrictions, performing this step often becomes infeasible. Developing a privacy-preserving solution for this task is challenging due to the significant burden of estimating kinship between all pairs of individuals across datasets. We introduce SF-Relate, a practical and secure federated algorithm for identifying genetic relatives across data silos. SF-Relate vastly reduces the number of individual pairs to compare while maintaining accurate detection through a novel locality-sensitive hashing approach. We assign individuals who are likely to be related together into buckets and then test relationships only between individuals in matching buckets across parties. To this end, we construct an effective hash function that captures identity-by-descent (IBD) segments in genetic sequences, which, along with a new bucketing strategy, enable accurate and practical private relative detection. To guarantee privacy, we introduce an efficient algorithm based on multiparty homomorphic encryption (MHE) to allow data holders to cooperatively compute the relatedness coefficients between individuals, and to further classify their degrees of relatedness, all without sharing any private data. We demonstrate the accuracy and practical runtimes of SF-Relate on the UK Biobank and All of Us datasets. On a dataset of 200K individuals split between two parties, SF-Relate detects 94.9% of third-degree relatives, and 99.9% of second-degree or closer relatives, within 15 hours of runtime. Our work enables secure identification of relatives across large-scale genomic datasets.
Towards Effective CAIX-targeted Radionuclide and Checkpoint Inhibition Combination Therapy for Advanced Clear Cell Renal Cell Carcinoma
Authors: Kleinendorst Simone C. , Oosterwijk Egbert , Molkenboer-Kuenen Janneke , Frielink Cathelijne , Franssen Gerben M. , Boreel Daan F. , Tamborino Giulia , Gloudemans Manon , Hendrikx Merel , Kroon Dennis , Hillen Jopp , Bussink Johan , Muselaers Stijn , Mulders Peter , Konijnenberg Mark W. , Wheatcroft Michael P. , Twumasi-Boateng Kwame , Heskamp Sandra
Published: February 2024

Background

Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [177Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC.

Methods

In this study, we evaluated the therapeutic and immunological action of [177Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [177Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [177Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling.

Results

Biodistribution studies showed high tumor uptake of [177Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [177Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [177Lu]Lu-DOTA-hG250 + a-PD1.Ex vivoanalyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment.

Conclusions

Subtherapeutic [177Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.

Abstract Figure
Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering
Authors: Schiffer M. , Wagner K. , Carls E. , Nicke J. , Hesse M. , Fratila R. , Hildebrand S. , Pfeifer A. , Eberbeck D. , Malek Mohammadi M. , De la Fuente J.M. , Fleischmann B.K. , Roell W.
Published: February 2024

1

The cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB)in vitro, load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers (∼4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by ∼4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43+mFB provides strong protection against post-infarct ventricular tachycardia (VT)in vivo, as VT incidence is reduced by ∼50 % at two and eight weeks after cell injection. Thus,ex vivogene and subsequentin vivocell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.
Cross-species modeling and enhancement of cognitive control with striatal brain stimulation
Authors: Reimer Adriano E , Dastin-van Rijn Evan M , Kim Jaejoong , Mensinger Megan E , Sachse Elizabeth M , Wald Aaron , Hoskins Eric , Singh Kartikeya , Alpers Abigail , Cooper Dawson , Lo Meng-Chen , Ribeiro de Oliveira Amanda , Simandl Gregory , Stephenson Nathaniel , Widge Alik S
Published: February 2024

Brain disorders, particularly mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. We show a path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result, showing that DBS-like stimulation of the mid-striatum improves cognitive control in rats. Using this model, we identify a mechanism, improvement in domain-general cognitive control, and rule out competing hypotheses such as impulsivity. The rat findings explain prior human results and have immediate implications for clinical practice and future trial design.

One Sentence Summary:Developing a reliable animal model of a human brain stimulation therapy reveals that this therapy works by enhancing the brain’s ability to process conflicting pieces of evidence.
First chromosome-level genome assembly of a ribbon worm from the Hoplonemertea clade,Emplectonema gracile, and its structural annotation
Authors: Valero-Gracia Alberto , Roberts Nickellaus G. , Yap-Chiongco Meghan , Capucho Ana Teresa , Kocot Kevin M. , Matschiner Michael , Struck Torsten H.
Published: February 2024

Genome-wide information has so far been unavailable for ribbon worms of the clade Hoplonemertea, the most species-rich class within the phylum Nemertea. While species within Pilidiophora, the sister clade of Hoplonemertea, possess a pilidium larval stage and lack stylets on their proboscis, Hoplonemertea species have a planuliform larva and are armed with stylets employed for the injection of toxins into their prey. To further compare these developmental, physiological, and behavioral differences from a genomic perspective, the availability of a reference genome of a Hoplonemertea species is crucial. To this end, we herein present the annotated chromosome-level genome assembly forEmplectonema gracile(Nemertea; Hoplonemertea; Monostilifera; Emplectonematidae), an easily collected nemertean well-suited for laboratory experimentation. The genome is 157.9 Mbp in span. Hi-C scaffolding yielded 15 putative chromosomes with a scaffold N50 of 10.0 Mbp and a BUSCO completeness score of 95.3%. Structural annotation predicted 20,684 protein-coding genes. The high-quality reference genome reaches an Earth BioGenome standard level of 7.C.Q50. These data will be highly useful for future investigations towards a better understanding of the evolution, development, morphology, and toxicology of Nemertea.

Significance

The genome ofEmplectonema gracileis highly contiguous, well annotated, and shorter than those of the other two ribbon worm species sequenced to date. This genome is a valuable resource for studies on molecular ecology, venom evolution, and regeneration in marine invertebrates.
Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression
Authors: Sonkar Ravi , Ma Hong , Waxman David J.
Published: February 2024

Constitutive Androstane Receptor (CAR,Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to subsequent disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP, a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase levels, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared to males. Early (1-day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipid and xenobiotic metabolism and oxidative stress protection pathways; late (2-wk) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for immune response, macrophage activation, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to pro-inflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle activated carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Thus, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary expression changes in liver non-parenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP gene responses include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.
A Multi-objective Simulation-Optimization Framework for the Design of a Compliant Gravity Balancing Orthosis
Authors: Chishty Haider A. , Sergi Fabrizio
Published: February 2024

Flexion-synergy is a stereotypical movement pattern that inhibits independent joint control for those who have been affected by stroke; this abnormal co-activation of elbow flexors with shoulder abductors significantly reduces range of motion when reaching against gravity. While wearable orthoses based around compliant mechanisms have been shown to accurately compensate for the arm at the shoulder, it is unclear if accurate compensation can also be achieved while minimizing device bulk.

In this work, we present a novel, multi-objective simulation-optimization framework towards the goal of designing practical gravity-balancing orthoses for the upper-limb. Our framework includes a custom built VB.NET application to run nonlinear finite element simulations in SolidWorks, and interfaces with a MATLAB-based particle swarm optimizer modified for multiple objectives. The framework is able to identify a set of Pareto-optimal compliant mechanism designs, confirming that compensation accuracy and protrusion minimization are indeed conflicting design objectives.

The preliminary execution of the simulation-optimization framework demonstrates a capability of achieving designs that compensate for almost 90% of the arm’s gravity or that exhibit an average protrusion of less than 5% of the arm length, with different trade-offs between these two objectives.
Associations between regional blood-brain barrier disruption, aging, and Alzheimer’s disease biomarkers in cognitively normal older adults
Authors: Denkinger Marisa , Baker Suzanne , Inglis Ben , Kobayashi Sarah , Juarez Alexis , Mason Suzanne , Jagust William
Published: February 2024

Background

Blood-brain barrier disruption (BBBd) has been hypothesized as a feature of aging that may lead to the development of Alzheimer’s disease (AD). We sought to identify the brain regions most vulnerable to BBBd during aging and examine their regional relationship with neuroimaging biomarkers of AD.

Methods

We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktransvalues, as a measure of BBBd, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)-PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBd than YA. In OA, Ktransvalues were compared based on sex, Aβ positivity status, and APOE4carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktransand AD biomarkers.

Results

OA showed greater BBBd than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktransvalues based on sex or Aβ positivity, but OA who were APOE4carriers had significantly higher Ktransvalues. There was no direct relationship between averaged Ktransand global Aβ pathology, but there was a trend for an Aβ status by tau interaction on Ktransin this region. SCCA showed increased Ktranswas associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktransand FTP SUVR.

Discussion

Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBd in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.
NeuroMDAVIS: Visualization of single-cell multi-omics data under deep learning framework
Authors: Maitra Chayan , Seal Dibyendu B. , Das Vivek , De Rajat K.
Published: February 2024

Single-cell technologies have favoured extensive advancements in cell-type discovery, cell state identi-fication, development of lineage tracing and disease understanding among others. Further, single-cell multi-omics data generated using modern technologies provide several views of omics contribution for the same set of cells. However, dimension reduction and visualization of biological datasets (single or multi-omics) remain a challenging task since obtaining a low-dimensional embedding that preserves information about local and global structures in data, is difficult. Further, combining different views obtained from each omics layer to interpret the underlying biology is even more challenging. Earlier, we have developed NeuroDAVIS which can perform the task of visualization of high-dimensional datasets of a single modality while preserving cluster-structures within the data. Nevertheless, there is no model so far that supports joint visualization of multi-omics datasets. Joint visualization refers to transforming the feature space of each individual modality and combining them to produce a latent embedding that supports visualization of the multi-modal dataset in the newly transformed feature space. In this work, we introduce NeuroMDAVIS which is a generalized version of NeuroDAVIS for visualization of biological datasets having multiple modalities. To the best of our knowledge, NeuroMDAVIS is the first of its kind multi-modal data visualization model. It is able to learn both local and global relationships in the data while generating a low-dimensional embedding useful for downstream tasks. NeuroMDAVIS competes against state-of-the-art visualization models like t-Distributed Stochastic Neighbor Embedding (t-SNE), Uniform Manifold Approximation and Projection (UMAP), Fast interpolation-based t-SNE (Fit-SNE), and the Siamese network-based visualization method (IVIS).
Cingulate cortex shapes early postnatal development of social vocalizations
Authors: Nagarajan Gurueswar , Matrov Denis , Pearson Anna C. , Yen Cecil , Bradley Sean P. , Chudasama Yogita
Published: February 2024

The social dynamics of vocal behavior has major implications for social development in humans. We asked whether early life damage to the anterior cingulate cortex (ACC), which is closely associated with socioemotional regulation more broadly, impacts the normal development of vocal expression. The common marmoset provides a unique opportunity to study the developmental trajectory of vocal behavior, and to track the consequences of early brain damage on aspects of social vocalizations. We created ACC lesions in neonatal marmosets and compared their pattern of vocalization to that of age-matched controls throughout the first 6 weeks of life. We found that while early life ACC lesions had little influence on the production of vocal calls, developmental changes to the quality of social contact calls and their associated sequential and acoustic characteristics were compromised. These animals made fewer social contact calls, and when they did, they were short, loud and monotonic. We further determined that damage to ACC in infancy results in a permanent alteration in downstream brain areas known to be involved in social vocalizations, such as the amygdala and periaqueductal gray. Namely, in the adult, these structures exhibited diminished GABA-immunoreactivity relative to control animals, likely reflecting disruption of the normal inhibitory balance following ACC deafferentation. Together, these data indicate that the normal development of social vocal behavior depends on the ACC and its interaction with other areas in the vocal network during early life.
Alternative Macrophage Activation Requires Granulocyte-Derived Lipids
Authors: Veremeyko Tatyana , Vik Anders , Hansen Trond Vidar , Ponomarev Eugene D.
Published: February 2024

Lipid metabolism is important for alternative (M2) macrophage activation, but it remains unclear whether it is essential for this process, and the underlying mechanisms have yet to be determined. It is also unclear how the M2 phenotype is induced during the resolution of inflammation and tissue repair. We used large-scale RNA-sequencing and high-throughput lipidomics approaches to identify that during blood coagulation, granulocytes release certain lipids that are loaded onto high-density lipoproteins (HDLs), which then act via scavenger receptors SR-B1 and SR-B3 - to mediate the expression of 26 of 32 M2-associated genes and oxidative phosphorylation (OXPHOS) in macrophages. We found that in the absence of these lipids, interleukin-4 (IL-4) induced only 6 of 32 M2 markers, and this cytokine alone failed to induce OXPHOS. We also found that the HDL-associated C18:0, C18:2, and C20:3 fatty acids (FAs) were the lipids that most potently induced the M1-to-M2 transition. Furthermore, we determined that during IL-4-mediated inflammation, the inhibition of blood coagulation, or platelet and granulocyte depletion, results in a substantial decrease in M2 marker expression. Thus, this study identified that granulocyte-derived FAs mediate the reprogramming of macrophages towards the M2 phenotype, thereby bridging the processes of blood coagulation, inflammation, and repair.

Highlights

Activation of macrophages with IL-4 or IL-13 requires indispensable cofactor

The cofactor consists of high-density lipoproteins (HDLs) complexed with lipids

During blood coagulation, granulocytes produce lipids that are loaded on HDLs

HDL-associated fatty acids were the most potent lipids to induce M2 phenotype

Graphic Abstract
An axonal brake on striatal dopamine output by cholinergic interneurons
Authors: Zhang Yan-Feng , Luan Pengwei , Qiao Qinbo , He Yiran , Zatka-Haas Peter , Zhang Guofeng , Lin Michael Z. , Lak Armin , Jing Miao , Mann Edward O. , Cragg Stephanie J.
Published: February 2024

Depolarisation of distal axons is necessary for neurons to translate somatic action potentials into neurotransmitter release. Studies have shown that striatal cholinergic interneurons (ChIs) can directly drive ectopic action potentials in dopamine (DA) axons and trigger DA release. However, here we show that this action occurs within a broader context of axonal signal integration whereby activation of ChIs and depolarisation of DA axons by nicotinic receptors (nAChRs) limits the subsequent depolarisation and release of DA in response to ensuing activity. We demonstrate that activation of ChIs and nAChRs inex vivomouse striatum, even when it does not trigger DA release that is detectable by fast-scan cyclic voltammetry, limits DA release for ∼100 ms by depressing subsequent axonal depolarisation and calcium summation. This axonal brake on DA release is stronger in dorsal than ventral striatum, and is unrelated to DA depletion.In vivo, antagonism of nAChRs in dorsal striatum elevated extracellular DA levels and promoted conditioned place-preference, underscoring its physiological relevance. Our findings reveal that under physiological conditionsin vivo,ChIs acting via nAChRs dynamically attenuate DA output driven by DA neuron activity, leading to a predominantly inverse relationship between ACh and DA signalling that varies continuously with ChI activity.