bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice
Authors: Korkmaz Funda , Sims Steven , Sen Fazilet , Sultana Farhath , Laurencin Victoria , Cullen Liam , Pallapati Anusha , Liu Avi , Rojekar Satish , Penev George , Cheliadinova Ulliana , Vasilyeva Darya , Burganova Guzel , Macdonald Anne , Saxena Mansi , Goosens Ki , Rosen Clifford , Barak Orly , Lizneva Daria , Gumerova Anisa , Ye Keqiang , Ryu Vitaly , Yuen Tony , Frolinger Tal , Zaidi Mone 
Published: February 2024

ABSTRACTAlzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post–menopausal levels of the pituitary gonadotropin follicle–stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampalFshrto drive AD–like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female3xTg;Fshr+/+, 3xTg;Fshr+/–and3xTg;Fshr-/-mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham–operated3xTg;Fshr-/-mice were implanted with 17β-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects ofFshrdepletion.3xTg;Fshr+/+mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in3xTg;Fshr-/-mice and, to a lesser extent, in3xTg;Fshr+/-mice–– thus documenting a clear gene–dose–dependent prevention of hippocampal–dependent spatial memory impairment. At 5 and 10 months, sham–operated3xTg;Fshr-/-mice showed better memory performance during the acquisition and/or retrieval phases, suggesting thatFshrdeletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10–month–old3xTg;Fshr-/-mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized3xTg;Fshr-/-mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene–dose–dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16–month–oldAPP/PS1mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH–blocking agent for the early prevention of cognitive decline in postmenopausal women.
When most fMRI connectivity cannot be detected: insights from time course reliability
Authors: Koten Jan Willem , Manner Hans , Pernet Cyril , Schüppen Andre , Szücs Dénes , Wood Guilherme , Ioannidis John P. A. 
Published: February 2024

ABSTRACTThe level of correlation between two phenomena is limited by the accuracy at which these phenomena are measured. Despite numerous group reliability studies, the strength of the fMRI connectivity correlation that can be detected given underlying within subject time course reliability remains elusive. Moreover, it is unclear how within subject time course reliability limits the robust detection of connectivity on the group level. We estimated connectivity from 50 individuals engaged in a working memory task. The grand mean connectivity of the connectome equaled r =0.41 (95% CI 0.31-0.50) for the test run and r =0.40 (95% CI 0.29-0.49) for the retest run. However, mean connectivity was reduced to r=0.09 (95% C.I. 0.03-0.16) when test-retest reliability and residual auto-correlations of single time courses were considered, suggesting that less than a quarter of the observed connectivity is reliably detectable. Null hypothesis significance testing (NHST)-based analysis revealed that within subject time course reliability markedly affects the significance levels at which paths can be detected at the group level. This was in particular the case when samples were small or connectome coordinates were randomly selected. With a sample of 50 individuals, the connectome of a test session was completely reproduced in retest sessions at P < 2.54e-6. Despite perfect group reproducibility at conservative p-values, on average only 0.81 percent of the observed connectivity could be attributed to working memory-related time course fluctuations after corrections. Time course reliability can offer valuable insights on the detectable connectivity and should be assessed more frequently in fMRI investigations.
The bispectral EEG (BSEEG) method quantifies post-operative delirium-like states in young and aged mice after head mount implantation surgery
Authors: Nishiguchi Tsuyoshi , Shibata Kazuki , Yamanishi Kyosuke , Dittrich Mia Nicole , Islam Noah Yuki , Patel Shivani , Phuong Nathan James , Marra Pedro S. , Malicoat Johnny R. , Seki Tomoteru , Nishizawa Yoshitaka , Yamanashi Takehiko , Iwata Masaaki , Shinozaki Gen 
Published: February 2024

AbstractDelirium, a syndrome characterized by an acute change in attention, awareness, and cognition, is commonly observed in older adults and has multiple potential triggers, including illness, drug, trauma, and surgery. There are few quantitative monitoring methods in clinical settings. We developed the bispectral electroencephalography (BSEEG) method in clinical research that can detect the presence of and quantify the severity of delirium using a novel algorithm. In the pre-clinical model, we reported that the BSEEG method can capture a delirium-like state in mice following LPS administration. However, its application to post-operative delirium (POD) has not yet been validated in animal experiments. Therefore, this study aimed to create a POD model mouse with the BSEEG method by monitoring BSEEG scores after EEG head-mount implantation surgery throughout the recovery phase. We compared the BSEEG scores of C57BL/6J young (2-3 months old) with aged (18-19 months old) mice for quantitative evaluation of the delirium-like state after the surgery. Postoperatively, both groups showed increased BSEEG scores and a loss of regular diurnal changes in BSEEG scores every daytime and night. In young mice, BSEEG scores and regular diurnal changes recovered relatively quickly to baseline by around postoperative day 3. On the other hand, aged mice had prolonged increases in postoperative BSEEG scores and it reached steady state only after around postoperative day 8. This study suggests the BSEEG method can be utilized to quantitatively evaluate POD and also assess the effect of aging on recovery from POD in pre-clinical model.
Discovery of free glycated amines and glycated urea as potential markers of diabetic nephropathy
Authors: Shaikh Rashdajabeen Q , Das Sancharini , Chaurasiya Arvindkumar , Ashtamy MG , Sheikh Amreen B , Fernandes Moneesha , Tiwari Shalbha , Unnikrishnan AG , Kulkarni Mahesh J 
Published: February 2024

AbstractThe role of protein glycation in the pathogenesis of diabetes is well established. Akin to proteins, free amino acids and other small-molecule amines are also susceptible to glycation in hyperglycemic conditions and may have a role in the pathogenesis of the disease. However, the information on glycation of free amino acids and other small- molecule amines is relatively obscure. In the quest to discover small molecule glycated amines in the plasma, we have synthesized glycated amino acids, glycated creatine, and glycated urea, and by using a high-resolution accurate mass spectrometer, a mass spectral library was developed comprising the precursor and predominant fragment masses of glycated amines. Using this information, we report the discovery of glycation of free lysine, arginine, and leucine/isoleucine from the plasma of diabetic patients. This has great physiological significance as glycation of these amino acids may create their deficiency and affect vital physiological processes such as protein synthesis, cell signaling and insulin secretion. Also, these glycated amino acids could serve as potential markers of diabetes and its complications. On the other hand, accumulation of creatinine and urea in the plasma act as biomarkers of diabetic nephropathy diagnosis. For the first time, we report the detection of glycated urea in diabetes, which is confirmed by matching the precursor and fragment masses with thein vitrosynthesized glycated urea by using12C6 and13C6-glucose. Further, we quantified glycated urea detected in two forms, monoglycated urea (MGU) and diglycated urea (DGU), by a targeted mass spectrometric approach in the plasma of healthy, diabetes, and diabetic nephropathy subjects. Both MGU and DGU showed a positive correlation with clinical parameters such as blood glucose and HbA1c. Given that urea gets converted to glycated urea in hyperglycemic conditions, it is crucial to quantify MGU and DGU along with the urea for the diagnosis of diabetic nephropathy.
Selection on sporulation strategies in a metapopulation can lead to coexistence
Authors: Proulx Stephen R. , Sakal Taom , Thomasson Kelly 
Published: February 2024

AbstractIn constant environments the coexistence of similar species or genotypes is generally limited. In a metapopulation context, however, types that utilize the same resource but are distributed along a competition-coexistence trade-off, can coexist. Much thought in this area focuses on a generic trade-off between within-deme competitive ability and between-deme dispersal ability. We point out that the sporulation program in yeasts and other microbes can create a natural trade-off such that strains which initiate sporulation at higher rates suffer in terms of within-deme competition but benefit in terms of between deme dispersal. We develop simple metapopulation models where the within-deme behavior follows simple chemostat dynamics. We first show that the rate of sporulation determines the colonization ability of the strain, with colonization ability increasing with sporulation rate up to a point. Metapopulation stability of a single strain exists in a defined range of sporulation rates. We then use pairwise invasability plots to show that coexistence of strains with different sporulation rates generally occurs, but that the set of sporulation rates that can potentially coexist is smaller than the set that allows for stable metapopulations. We then extend our pairwise results to show how a continuous set of strains can coexist and verify our conclusions with numerical calculations. Our results show that stable variation in sporulation rates is expected under a wide range of ecological conditions.
Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity
Authors: Chevalier Sarah , Decourt Mélina , Francheteau Maureen , Balbous Anaïs , Fernagut Pierre-Olivier , Benoit-Marand Marianne 
Published: February 2024

ABSTRACTBACKGROUNDParkinson’s disease is characterized by the degeneration ofsubstantia nigra pars compacta(SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations due to the degenerative process or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops.OBJECTIVETo investigate the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity and markers of synaptic plasticity.METHODSBilateral nigrostriatal degeneration was induced by viral-mediated overexpression of human mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the dorsomedial striatum (DMS) were performed and spike probability in response to OFC stimulation was measured before and after a high frequency stimulation (HFS). Post-mortem analysis included stereological assessment of nigral neurodegeneration, BDNF and TrkB levels.RESULTSNigrostriatal neurodegeneration led to altered firing patterns of OFC neurons that were restored by PPX. HFS of the OFC led to an increased spike probability in the DMS, while dopaminergic loss had an opposite effect. PPX led to a decreased spike probability following HFS in control rats and failed to counteract the effect of dopaminergic neurodegeneration. These alterations were associated with decreased levels of BDNF and TrkB.CONCLUSIONSBoth nigral dopaminergic loss and PPX concur to alter fronstostriatal transmission, precluding adequate information processing in associative basal ganglia loops as a gateway for the development of non-motor symptoms or non-motor side-effects of DRT.
Genetic Modulation of Protein Expression in Rat Brain
Authors: Li Ling , Wu Zhiping , Guarracino Andrea , Villani Flavia , Kong Deihui , Mancieri Ariana , Zhang Aijun , Saba Laura , Chen Hao , Brozka Hana , Vales Karel , Senko Anna N. , Kempermann Gerd , Stuchlik Ales , Pravenec Michal , Prins Pjotr , Peng Junmin , Williams Robert W. , Wang Xusheng 
Published: February 2024

AbstractGenetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits. However, the fundamental genetic architecture and variation of protein expression have received comparatively less attention than either mRNA or classical phenotypes. In this study, we systematically quantified proteins in the brains of a large family of rats using tandem mass tag (TMT)-based quantitative mass-spectrometry (MS) technology. We identified and quantified a comprehensive proteome of 8,119 proteins from Spontaneously Hypertensive (SHR/Olalpcv), Brown Norway with polydactyly-luxate (BN-Lx/Cub), and 29 of their fully inbred HXB/BXH progeny. Differential expression (DE) analysis identified 597 proteins with significant differences in expression between the parental strains (fold change > 2 and FDR < 0.01). We characterized 95 variant peptides by proteogenomics approach and discovered 464 proteins linked to strongcis-acting quantitative trait loci (pQTLs, FDR < 0.05). We also explored the linkage of pQTLs with behavioral phenotypes in rats and examined the sex-specific pQTLs to reveal both distinct and sharedcis-pQTLs between sexes. Furthermore, by creating a novel view of the rat pangenome, we improved the ability to pinpoint candidate genes underlying pQTL. Finally, we explored the connection between the pQTLs in rat and human disorders, underscoring the translational potential of our findings. Collectively, this work demonstrates the value of large and systematic proteo-genetic datasets in understanding protein modulation in the brain and its functional linkage to complex central nervous system (CNS) traits.
Episodic recruitment of attractor dynamics in frontal cortex reveals distinct mechanisms for forgetting and lack of cognitive control in short-term memory
Authors: Oña-Jodar Tíffany , Prat-Ortega Genís , Li Chengyu , Dalmau Josep , Compte Albert , de la Rocha Jaime 
Published: February 2024

ABSTRACTShort-term memory (STM) is prone to failure, especially during prolonged memory maintenance or under limited cognitive control. Despite predictive mechanistic frameworks based on persistent neural activity and attractor states, a direct assessment of network dynamics during multifactorial STM failure is still missing. We addressed this in a delayed-response task where mice maintained a prospective response during a long variable delay. Mice behavior episodically switched between a task-engaged state described by an attractor model, and a task-disengaged state purely determined by previous choices. During task engagement, the anterolateral motor cortex (ALM) showed delay persistent activity stably encoding correct choices, whereas the encoding reversed during the delay in error trials. In contrast, in task-disengaged phases ALM showed no clear traces of attractor dynamics and instead exhibited enhanced synchrony at ∼ 4-5Hz. Thus, ALM switches between distinct error-generating dynamics: in control-capable trials, transitions between memory attractors cause forgetting errors, whereas non-memory errors are caused by the dissociation of ALM during the mnemonic period reflecting the lack of cognitive control.
Spatial Transcriptomics in Breast Cancer Reveals Tumour Microenvironment-Driven Drug Responses and Clonal Therapeutic Heterogeneity
Authors: Jiménez-Santos María José , García-Martín Santiago , Rubio-Fernández Marcos , Gómez-López Gonzalo , Al-Shahrour Fátima 
Published: February 2024

AbstractBreast cancer is a heterogeneous disease that has the highest incidence and mortality rate among cancers in women worldwide. Breast cancer patients are stratified into three clinical subtypes with different treatment strategies and prognostic values. The development of targeted therapies against the biomarkers that define these strata constitutes one of the precedents of precision oncology, which aims to provide tailored treatments to cancer patients by targeting the molecular alterations found in each tumour. Although this approach has increased patient outcomes, many treatment failure cases still exist. Drug ineffectiveness and relapse have been associated with the coexistence of several malignant subpopulations with different drug sensitivities within the same lesion, a phenomenon known as intratumor heterogeneity. This heterogeneity has been extensively studied from a tumour-centric view, but recently, it has become evident that the tumour microenvironment plays a crucial role in intratumor heterogeneity. However, few studies consider the tumour-microenvironment interplay and its influence on drug sensitivity. In this work, we predict the sensitivity of 10x Visium spatial transcriptomics data from 9 breast cancer patients to >1,200 drugs and verify different response patterns across the tumour, interphase and microenvironment regions. We uncover a sensitivity continuum from the tumour core to the periphery accompanied by a functional gradient. Moreover, we identify conserved therapeutic clusters with distinct response patterns within the tumour region. We link the specific drug sensitivities of each therapeutic cluster to different ligand-receptor interactions that underpin distinct biological functions. Finally, we demonstrate that genetically identical cancer spots may belong to different therapeutic clusters and that this therapeutic heterogeneity is related to their location at the edge or core of tumour ducts. These results highlight the importance of considering the distance to the tumour core and the microenvironment composition when identifying suitable treatments to target intratumor heterogeneity.
Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer
Authors: Zhang Ruibo , Bozic Ivana 
Published: February 2024

AbstractCancers typically result from sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in home-ostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings.
A single E205D allele of a key P450CYP6P3is driving metabolic pyrethroid resistance in the major African malaria vectorAnopheles gambiae
Authors: Kengne-Ouafo Jonas A. , Kouamo Mersimine , Muhammad Abdullahi , Tepa Arnaud , Ntadoun Stevia , Mugenzi Leon , Tekoh Theofelix , Hearn Jack , Tchouakui Magellan , Wondji Murielle , Ibrahim Sulaiman S. , Wondji Charles S. 
Published: February 2024

AbstractDeciphering the molecular drivers of insecticide resistance is paramount to extend the effectiveness of malaria vector control tools. Here, we demonstrated that the E205D amino acid change in a key metabolic resistance P450CYP6P3drives pyrethroid resistance in the major malaria vector,Anopheles gambiae. Spatio-temporal whole genome Poolseq analyses in Cameroon detected a major P450-linked locus on chromosome 2R beside the sodium channel locus.In vitrometabolism assays with recombinantly expressedCYP6P3protein revealed that the catalytic efficiency of 205D was 2.5 times higher than E205 with α-cypermethrin. Similar patterns were observed for permethrin. Overexpression of the 205D allele in transgenic flies confers higher more pyrethroids and carbamates resistance, compared to controls. A DNA-based assay further supported that theCYP6P3-205D variant strongly correlates with pyrethroid resistance in field populations (OR=26.4; P<0.0001) and that it reduces the efficacy of pyrethroid-only LLINs with homozygote RR genotype exhibiting significantly higher survival following PermaNet 3.0 exposure compared to the SS genotype (OR: 6.1, p = 0.0113). Furthermore, theCYP6P3-E205D combines with thekdrtarget-site resistance mechanisms to worsen the loss of bednet efficacy. The 205D mutation is now predominant in West and Central Africa but less abundant or absent in East and South Africa with signs of introgression withAn. coluzziiin Ghana. This study highlights the importance of P450-based resistance and designs field-applicable tools to easily track the spread of metabolic resistance and assess its impact on control interventions.One Sentence Summary:The major obstacle to malaria control and elimination is the spread of parasite resistance to anti-malarial drugs, and mosquito resistance to insecticides. In this study, we identified a key point mutation E205D in the metabolic geneCYP6P3(cytochrome P450) conferring resistance to pyrethroids by enhancing the breakdown of insecticides used for bednets impregnation. DNA-based assays were then designed and used to determine the spread of the resistance across Africa and demonstrate that theCYP6P3-205D allele works together with the knockdown resistance in the voltage-gated Sodium channel to reduce the efficacy of insecticide-treated bednets.