bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD46 targeted212Pb alpha particle radioimmunotherapy for prostate cancer treatment
Authors: Li Jun , Huang Tao , Hua Jun , Wang Qiong , Su Yang , Chen Ping , Bidlingmaier Scott , Li Allan , Xie Zhongqiu , Bidkar Anil , Shen Sui , Shi Weibin , Seo Youngho , Flavell Robert R. , Gioeli Daniel , Dreicer Robert , Li Hui , Liu Bin , He Jiang 
Published: October 2022

ABSTRACTWe recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated212Pb, anin vivogenerator of alpha-emitting212Bi and212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate,212Pb-TCMC-YS5. We characterized212Pb-TCMC-YS5in vitroand established a safe dosein vivo. We next studied therapeutic efficacy of a single dose of212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 20 μCi212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (10 μCi212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.SignificanceThis study reports a novel CD46 targeted212Pb alpha particle radioimmunotherapy,212Pb-TCMC-YS5, that is well tolerated and shows potent anti-tumor activity (tumor growth inhibition and increase of animal survival)in vivoin three prostate cancer small animal models, i.e., a subcutaneous and an intraprostate orthotopic mCRPC cell line-derived xenograft models, and a prostate cancer patient-derived xenograft model. Given that YS5 is a clinical stage human antibody, this YS5-based212Pb alpha particle therapy has potential of translation to the clinic for treatment of mCRPC patients.
Diet Induced Obesity and Diabetes Enhance Mortality and Reduces Vaccine Efficacy for SARS-CoV-2
Authors: Johnson Robert M , Ardanuy Jeremy , Hammond Holly , Logue James , Jackson Lian , Baracco Lauren , McGrath Marisa , Dillen Carly , Patel Nita , Smith Gale , Frieman Matthew 
Published: October 2022

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), emerged in Wuhan, China, in December 2019. As of October 2022, there have been over 625 million confirmed cases of COVID-19, including over 6.5 million deaths. Epidemiological studies have indicated that comorbidities of obesity and diabetes mellitus are associated with increased morbidity and mortality following SARS-CoV-2 infection. We determined how the comorbidities of obesity and diabetes affect morbidity and mortality following SARS-CoV-2 infection in unvaccinated and adjuvanted spike nanoparticle (NVX-CoV2373) vaccinated mice. We find that obese/diabetic mice infected with SARS-CoV-2 have increased morbidity and mortality compared to age matched normal mice. Mice fed a high-fat diet (HFD) then vaccinated with NVX-CoV2373 produce equivalent neutralizing antibody titers to those fed a normal diet (ND). However, the HFD mice have reduced viral clearance early in infection. Analysis of the inflammatory immune response in HFD mice demonstrates a recruitment of neutrophils that was correlated with increased mortality and reduced clearance of the virus. Depletion of neutrophils in diabetic/obese vaccinated mice reduced disease severity and protected mice from lethality. This model recapitulates the increased disease severity associated with obesity and diabetes in humans with COVID-19 and is an important comorbidity to study with increasing obesity and diabetes across the world.ImportanceSARS-CoV-2 has caused a wide spectrum of disease in the human population, from asymptomatic infections to death. It is important to study the host differences that may alter the pathogenesis of this virus. One clinical finding in COVID19 patients, is that people with obesity or diabetes are at increased risk of severe illness from SARS-CoV-2 infection. We used a high fat diet model in mice to study the effects of obesity and Type 2 diabetes on SARS-CoV-2 infection as well as how these comorbidities alter the response to vaccination. We find that diabetic/obese mice have increased disease after SARS-CoV-2 infection and they have slower clearance of virus. We find that the lungs of these mice have increased neutrophils and that removing these neutrophils protect diabetic/obese mice from disease. This demonstrates why these diseases have increased risk of severe disease and suggests specific interventions upon infection.
Encoding surprise by retinal ganglion cells
Authors: Despotović Danica , Joffrois Corentin , Marre Olivier , Chalk Matthew 
Published: October 2022

AbstractThe efficient coding hypothesis posits that early sensory neurons transmit maximal information about sensory stimuli, given internal constraints. A central prediction of this theory is that neurons should preferentially encode stimuli that are most surprising. Previous studies suggest this may be the case in early visual areas, where many neurons respond strongly to rare or surprising stimuli. For example, previous research showed that when presented with a rhythmic sequence of full-field flashes, many retinal ganglion cells (RGCs) respond strongly at the instance the flash sequence stops, and when another flash would be expected. This phenomenon is called the ‘omitted stimulus response’. However, it is not known whether the responses of these cells varies in a graded way depending on the level of stimulus surprise. To investigate this, we presented retinal neurons with extended sequences of stochastic flashes. With this stimulus, the surprise associated with a particular flash/silence, could be quantified analytically, and varied in a graded manner depending on the previous sequences of flashes and silences. Interestingly, we found that RGC responses could be well explained by a simple normative model, which described how they optimally combined their prior expectations and recent stimulus history, so as to encode surprise. Further, much of the diversity in RGC responses could be explained by the model, due to the different prior expectations that different neurons had about the stimulus statistics. These results suggest that even as early as the retina many cells encode surprise, relative to their own, internally generated expectations.
Investigating the role of binding free energy, binding affinity and antibody escape in the evolution of SARS-CoV-2 spike protein
Authors: Young Matthew , Lycett Samantha J 
Published: October 2022

AbstractSARS-CoV-2 is considered a pandemic virus and presents a major strain on public health globally. SARS-CoV-2 infects mammalian cells by binding to its receptor, ACE2 which is mediated by the viral spike glycoprotein, specifically the receptor binding domain (RBD) within the spike protein. Recent development of vaccines against SARS-CoV-2 spike protein are currently the best strategy to reduce morbidity and mortality from infection. Like all viruses, SARS-CoV-2 evolves which may result in mutations which are benign or alter its viral fitness. The evolution of SARS-CoV-2 may increase the virulence, possibly by increasing the infectivity of the virus through strengthening the binding of the RBD to ACE2 or enabling the virus to evade naturally or vaccine induced immune responses. To address the need to characterise the evolution of SARS-CoV-2, this study has compared SARS-CoV2 sequences globally to the Wuhan reference strain at different time points. Additionally, by assigning scores to sequence data, which quantify each sequences binding strength to ACE2 and ability to evade patient derived antibodies, we have demonstrated that over time SARS-CoV-2 has evolved in less than one year to increase its ability to evade antibodies and increase the binding free energy between the RBD and ACE2.
Circadian clock disruption promotes the degeneration of dopaminergic neurons
Authors: Dorcikova Michaëla Majcin , Duret Lou C. , Pottié Emma , Nagoshi Emi 
Published: October 2022

AbstractSleep and circadian rhythm disruptions are frequent comorbidities of Parkinson’s disease (PD), a disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although sleep/circadian disturbances can be observed years before diagnosing PD, it remains unclear whether circadian clocks have a causal role in the degenerative process. We demonstrated here that circadian clocks regulate the rhythmicity and magnitude of the vulnerability of DA neurons to oxidative stress inDrosophila. Circadian pacemaker neurons are presynaptic to a subset of DA neurons and rhythmically modulate their susceptibility to degeneration. The arrhythmicperiod(per) gene null mutation exacerbates the age-dependent loss of DA neurons and, in combination with brief oxidative stress, causes premature animal death. These findings suggest that circadian clock disruption promotes dopaminergic neurodegeneration.
Ixodes ricinustick bacteriome alterations based on a climatically representative survey in Hungary
Authors: Gréta Tóth Adrienn , Farkas Róbert , Papp Márton , Kilim Oz , Yun Haeun , Makrai László , Maróti Gergely , Gyurkovszky Mónika , Krikó Eszter , Solymosi Norbert 
Published: October 2022

ABSTRACTBackgroundThe microbial communities of disease vectors may represent a key feature in several biological functions and thus deserve special attention in light of climate change and the consequent need to develop novel control strategies. Nevertheless, vector-borne microbial networks are still poorly understood. Assessing vectors’ microbial interactions and climatic dependencies may contribute to better-estimating pathogen transmission characteristics, public health risks and the urgency for control steps to be taken.MethodsIn a climatically representative country-wide survey,Ixodes ricinusticks were collected from 17 locations in Hungary. Using shotgun metagenomic sequencing, the bacteriome composition was analyzed by investigating the relationship between the abundances of nymphs and females in various climatic environments.ResultsBacterial composition on the genus level revealed a significant difference between the samples from females and nymphs. Within the core bacteriome, females and nymphs showed significant variation in the following genera:Arsenophonus, Bacillus, Candidatus Midichloria, Rhodococcus, Sphingomonas, Staphylococcus, Wolbachia. Among females, according to temperature strata, the following were found differentiating:Curtobacterium, Pseudomonas, Sphingomonas. There was no genus with a significant difference in precipitation categories for females. In the nymphs,Curtobacteriumshowed significant variation between temperature andBacillusandCurtobacteriumfor various precipitation levels. Based on the full sample set,ArsenophonusandWolbachiacorrelated positively which we assumed to have occurred due to the presence ofI. hookeri.ConclusionsThe composition of vector-borne bacteriome members showed significant alterations at sampling points with different climatic conditions and development stages of the tick hosts. Our findings not only pave the way towards understanding tick-borne bacterial networks and interdependencies but also shed light on the high potential for the presence of a possible biological tick control species, the tick parasitoid,Ixodiphagus hookeribased on related bacteriome patterns. The results of conscious tick microbiome assessment studies may contribute to precision tick control strategies of the future.
HumanBrainAtlas: an in vivo MRI dataset for detailed segmentations
Authors: Schira Mark M. , Isherwood Zoey J , Kassem Mustafa (Steve) , Barth Markus , Shaw Thomas B. , Roberts Michelle M , Paxinos George 
Published: October 2022

AbstractWe introduce HumanBrainAtlas, an initiative to construct a highly detailed, open-access atlas of the living human brain that combines high-resolutionin vivoMR imaging and detailed segmentations previously possible only in histological preparations. Here, we present and evaluate the first step of this initiative: a comprehensive dataset of two healthy male volunteers reconstructed to a 0.25 mm3isotropic resolution for T1w, T2w and DWI contrasts. Multiple high-resolution acquisitions were collected for each contrast and each participant, followed by averaging using symmetric group-wise normalisation (Advanced Normalisation Tools). The resulting image quality permits structural parcellations rivalling histology-based atlases, while maintaining the advantages ofin vivoMRI. For example, components of the thalamus, hypothalamus, and hippocampus - difficult or often impossible to identify using standard MRI protocols, can be identified within the present data. Our data are virtually distortion free, fully 3D, and compatible with existingin vivoNeuroimaging analysis tools. The dataset is suitable for teaching and is publicly available via our website (www.hba.neura.edu.au), which also provides data processing scripts. Instead of focusing on coordinates in an averaged brain space, our approach focuses on providing an example segmentation at great detail in the high quality individual brain, this serves as an illustration on what features contrasts and relations can be used to interpret MRI datasets, in research, clinical and education settings.
Measuring the co-localization and dynamics of mobile proteins in live cells undergoing signaling responses
Authors: Shelby Sarah A. , Shaw Thomas R. , Veatch Sarah L. 
Published: October 2022

ii.Summary/AbstractSingle molecule imaging in live cells enables the study of protein interactions and dynamics as they participate in signaling processes. When combined with fluorophores that stochastically transition between fluorescent and reversible dark states, as in super-resolution localization imaging, labeled molecules can be visualized in single cells over time. This improvement in sampling enables the study of extended cellular responses at the resolution of single molecule localization. This chapter provides optimized experimental and analytical methods used to quantify protein interactions and dynamics within the membranes of adhered live cells. Importantly, the use of pair-correlation functions resolved in both space and time allows researchers to probe interactions between proteins on biologically relevant distance and time-scales, even though fluorescence localization methods typically require long times to assemble well-sampled reconstructed images. We describe an application of this approach to measure protein interactions in B cell receptor signaling and include sample analysis code for post-processing of imaging data. These methods are quantitative, sensitive, and broadly applicable to a range of signaling systems.
Effective Molecular Dynamics from Neural-Network Based Structure Prediction Models
Authors: Jussupow Alexander , Kaila Ville R. I. 
Published: October 2022

ABSTRACTRecent breakthroughs in neural-network based structure prediction methods, such as AlphaFold2 and RoseTTAFold, have dramatically improved the quality of computational protein structure prediction. These models also provide statistical confidence scores that can estimate uncertainties in the predicted structures, but it remains unclear to what extent these scores are related to the intrinsic conformational dynamics of proteins. Here we compare AlphaFold2 prediction scores with >60 μs of explicit molecular dynamics simulations of 28 one- and two-domain proteins with varying degree of flexibility. We demonstrate a strong correlation between the statistical prediction scores and the explicit motion derived from extensive atomistic molecular dynamics simulations, and further derive an elastic network model based on the statistical scores of AlphFold2 (AF-ENM), which we benchmark in combination with coarse-grained molecular dynamics simulations. We show that our AF-ENM method reproduces the global protein dynamics with improved accuracy, providing a powerful way to derive effective molecular dynamics using neural-network based structure prediction models.
A modular cloning toolbox including CRISPRi for the engineering of the human fungal pathogen and biotechnology hostCandida glabrata
Authors: Billerbeck Sonja , Prins Rianne C , Marquardt Malte 
Published: October 2022

ABSTRACTThe yeastCandida glabratais an emerging, often drug-resistant opportunistic human pathogen, that can cause severe systemic infections in immunocompromised individuals. At the same time, it is a valuable biotechnology host that naturally accumulates high levels of pyruvate – a valuable chemical precursor. Tools for the facile engineering of this yeast could greatly accelerate studies on its pathogenicity and its optimization for biotechnology. While a few tools for plasmid-based expression and CRISPR/Cas-based genome engineering have been developed, there is no well-characterized cloning toolkit available that would allow the assembly of pathways or genetic circuits in a modular fashion. Here, by re-using and characterizing theSaccharomyces cerevisiae-based yeast molecular cloning toolkit (YTK) inC. glabrataand by adding missing components, we build a well-characterized CgTK (Candida glabratatoolkit). We used the CgTK to build a CRISPR interference system forC. glabratathat can be used to generate selectable phenotypes via single-gRNA targeting such as required for genome-wide library screens.
Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease
Authors: Ferreira Sara A. , Li Conghui , Klæstrup Ida H. , Vitic Zagorka , Rasmussen Rikke K. , Kirkegaard Asger , Toft Gitte U. , Betzer Cristine , Svendsen Pia , Jensen Poul H. , Luo Yonglun , Etzerodt Anders , Moestrup Søren K. , Romero-Ramos Marina 
Published: October 2022

ABSTRACTAlpha-synuclein (α-syn) aggregation and immune activation represent hallmark pathological events in Parkinson’s disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in the PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine α-syn pre-formed fibrils (PFF) in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to α-syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and α-syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a novel, sex-dimorphic neuroprotective role for CD163 during α-syn-induced neurodegeneration.
Nonionic surfactants can modify the thermal stability of globular and membrane proteins interfering with the thermal proteome profiling principles to identify protein targets
Authors: Berlin Emmanuel , Lizano-Fallas Veronica , Carrasco del Amor Ana , Fresnedo Olatz , Cristobal Susana 
Published: October 2022

ABSTRACTThe membrane proteins are essential targets to understand cellular function. The unbiased identification of membrane protein targets is still the bottleneck for a system-level understanding of cellular response to stimuli or perturbations. It has been suggested to enrich the soluble proteome with membrane proteins by introducing nonionic surfactants in the solubilization solution. This strategy was aiming to simultaneous identify the globular and membrane protein targets by thermal proteome profiling principles. However, the thermal shift assay would surpass the cloud point temperature from the nonionic surfactants frequently utilized for membrane protein solubilization. It is expected that around the cloud point temperature, the surfactant micelles would suffer structural modifications altering protein solubility. Here, we show that the presence of nonionic surfactants can alter protein thermal stability from a mixed, globular and membrane, proteome. In the presence of surfactant micelles, the changes in proteins solubility analyzed after the thermal shift assay were affected by the thermal dependent modification of the micellar size, and its interaction with proteins. We demonstrate that the introduction of nonionic surfactants for the solubilization of membrane proteins is not compatible with the principles of target identification by thermal proteome profiling methodologies. Our results lead to explore thermal-independent strategies for membrane protein solubilization to assure confident membrane protein target identification. The proteome-wide thermal shift methods have already shown their capability to elucidate mechanisms of action from pharma, biomedicine, analytical chemistry, or toxicology and finding strategies, free from surfactants, to identify membrane protein targets would be the next challenge.
Altered cohesin dynamics and histone H3K9 modifications contribute to mitotic defects in thecbf11Δlipid metabolism mutant
Authors: Vishwanatha Akshay , Princová Jarmila , Hohoš Patrik , Zach Róbert , Převorovský Martin 
Published: October 2022

ABSTRACTMitotic fidelity is crucial for the faithful distribution of genetic information into the daughter cells. Many fungal species, including the fission yeastSchizosaccharomyces pombe, undergo a closed form of mitosis, during which the nuclear envelope does not break down. InS. pombenumerous processes have been identified that contribute to successful completion of mitosis. Notably, perturbations of lipid metabolism can lead to catastrophic mitosis and the “cut” phenotype. It was suggested that these mitotic defects are caused by insufficient membrane phospholipid supply during the anaphase nuclear expansion. However, it is not clear whether additional factors are involved. In this study we characterized in detail the mitosis in anS. pombemutant lacking the Cbf11 transcription factor, which regulates lipid metabolism genes. We show that incbf11Δcells mitotic defects appear already prior to anaphase, before the nuclear expansion begins. Moreover, we identify altered cohesin dynamics and centromeric chromatin structure as additional factors affecting mitotic fidelity in cells with disrupted lipid homeostasis, providing new insights into this fundamental biological process.