Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Brain Atrophy Patterns and Neurogenetic Profiles in Cognitively-Defined Alzheimer’s Disease Subgroups

Elucidating mechanisms underlying the clinical heterogeneity observed among individuals with Alzheimer’s disease (AD) is key to facilitate personalized treatments. We categorized 679 individuals with AD into subgroups based on a relative impairment in one cognitive domain (i.e. AD-Memory, AD-Executive-Functioning, AD-Language and AD-Visuospatial-Functioning). We compared atrophy patterns derived from MRI and identified patterns that closely matched the respective cognitive profiles, i.e. medial temporal lobe atrophy in AD-Memory, fronto-parietal in AD-Executive-Functioning, asymmetric left-temporal in AD-Language, and posterior in AD-Visuospatial-Functioning. We then determined spatial correlations between subgroup-specific atrophy and a transcriptomic atlas of gene expression, which revealed both shared (e.g. mitochondrial respiration and synaptic function/plasticity) and subgroup-specific (e.g. cell-cycle for AD-Memory, protein metabolism in AD-Language, and modification of gene expression in AD-Visuospatial-Functioning) biological pathways associated with each subgroup’s atrophy patterns. We conclude that cognitive heterogeneity in AD is related to neuroanatomical differences, and specific biological pathways may be involved in their emergence.
Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

Background Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that impair skeletal muscle growth may contribute to the disease severity. Methods We used human muscle stem cells (MuSCs) carrying 4 different LMNA mutations and two mouse models of muscle laminopathies, representing a spectrum of disease severity, to investigate the ability of skeletal muscle to differentiate and to hypertrophy in response to mechanical challenges. We extended these finding to individuals with LMNA-related muscular dystrophy using muscle biopsies. Results In vitro, we observe impaired myogenic differentiation with disorganized cadherin/β catenin adhesion complexes in MuSCs carrying LMNA-CMD. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective accretion of activated MuSCs, defective protein synthesis and defective remodeling of the neuro-muscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the Yes-Associated Protein (YAP), a key sensor and mediator of mechanical cues. We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely-related EDMD models. Conclusions Combining studies in vitro, in vivo and patient samples, we find that LMNA-CMD mutations interfere with mechano-signaling pathways in skeletal muscle, implicating defective skeletal muscle growth as a pathogenic contributor for the severity of LMNA-related muscular dystrophy.
Ventral Pallidum GABA Neurons Mediate Motivation Underlying Risky Choice

Pursuing rewards while avoiding danger is an essential function of any nervous system. Here, we examine a new mechanism helping rats negotiate the balance between risk and reward when making high-stakes decisions. Specifically, we focus on GABA neurons within an emerging mesolimbic circuit nexus: the ventral pallidum (VP). These neurons play a distinct role from other VP neurons in simple motivated behaviors in mice, but their role in more complex motivated behaviors is unknown. Here, we interrogate the behavioral functions of VPGABA neurons in male and female transgenic GAD1:Cre rats (and WT littermates), using a reversible chemogenetic inhibition approach. Using a behavioral assay of risky decision-making, and of the food-seeking and shock-avoidance components of this task, we show that engaging inhibitory Gi/o signaling specifically in VPGABA neurons suppresses motivation to pursue highly salient palatable foods, and possibly also motivation to avoid being shocked. In contrast, inhibiting these neurons did not affect seeking of low-value food, free consumption of palatable food, or unconditioned affective responses to shock. Accordingly, when rats considered whether to pursue food despite potential for shock in a risky decision-making task, inhibiting VPGABA neurons caused them to more readily select a small but safe reward over a large but dangerous one, an effect not seen in the absence of shock threat. Together, results indicate that VPGABA neurons are critical for high-stakes adaptive responding that is necessary for survival, but which may also malfunction in psychiatric disorders. SIGNIFICANCE STATEMENT In a dynamic world, it is essential to implement appropriate behaviors under circumstances involving rewards, threats, or both. Here, we demonstrate a crucial role for VPGABA neurons in high-stakes motivated behavior of several types. We show that this VPGABA role in motivation impacts decision-making, as inhibiting these neurons yields a conservative, risk-averse strategy not seen when the task is performed without threat of shock. These new roles for VPGABA neurons in behavior may inform future strategies for treating addiction, and other disorders of maladaptive decision-making.
Hybrid diffuse optical monitoring of hemodynamic changes following acute cerebral ischemia in a porcine model

Rapid screening for stroke in pre-hospital settings may improve patient outcomes by allowing early deployment of thrombolytic therapies. Near-infrared hybrid diffuse optical screening devices may fill this need. This study seeks to determine whether hybrid diffuse optical measurements can measure hemodynamic changes associated with cerebral ischemia within the first few hours of the onset of acute ischemia in a large animal model. A hybrid diffuse optical device combining of near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) was fabricated to measure total hemoglobin concentration (HbT), tissue oxygen saturation (StO2) and blood flow index (BFI). Cerebral ischemia was induced by ligation of the bilateral common carotid arteries (CCA) in five miniature pigs. Additionally, a fatal stroke was induced in two pigs by injecting 5ml air emboli into both CCA. Cerebral hemodynamic parameters were monitored continuously throughout the study with the hybrid optical device. Relative changes BFI showed the good repeatability both of the ligation and fatal stroke experiments. During bilateral CCA ligation, the BFI decreased by up to about 66% of baseline values; during the fatal stroke experiment, the BFI decreased by up to about 95%, with a temporal resolution of 20 seconds. To the best of our knowledge, there are not existing methods which can measure the cerebral ischemia within the first few hours of the onset noninvasively. The MRI scanning was conducted at 24 h post injury. However, the images showed no abnormality. The results show the hybrid diffuse optical method can immediately measure the hemodynamic changes of miniature pigs in the first few hours of each single cerebral ischemia onset, and the BFI may be the promising biomarker to distinguish the cerebral ischemia and cerebral death.
Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

Kidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.
Hyperprolactinemia in a male pituitary androgen receptor knockout mouse model is associated with a female-like pattern of lactotroph development

Circulating prolactin concentration in rodents and humans is sexually dimorphic. Estrogens are a well-characterised stimulator of prolactin release. Circulating prolactin fluctuates throughout the menstrual/estrous cycle of females in response to estrogen levels, but remains continually low in males. We have previously identified androgens as an inhibitor of prolactin release through characterisation of males of a mouse line with a conditional pituitary androgen receptor knockout (PARKO) which have an increase in circulating prolactin, but unchanged lactotroph number. In the present study we aimed to specify the cell type that androgens act on to repress prolactin release. We examined lactotroph-specific, Pit1 lineage-specific and neural-specific conditional AR knockouts, however they did not duplicate the high circulating prolactin seen in the pituitary androgen receptor knockout line, suggesting that the site of androgen repression of prolactin production was another cell type. Using electron microscopy to examine ultrastructure we showed that pituitary androgen receptor knockout male mice develop lactotrophs that resemble those seen in female mice, and that this is likely to contribute to the increase in circulating prolactin. When castrated, pituitary androgen receptor knockout males have significantly reduced circulating prolactin compared to intact males, which suggests that removal of circulating estrogens as well as androgens reduces the stimulation of pituitary prolactin release. However, when expression of selected estrogen-regulated anterior pituitary genes were examined there were no differences in expression level between controls and knockouts. Further investigation is needed into prolactin regulation by changes in androgen-estrogen balance, which has implications not only in the normal sexual dimorphism of physiology but also in diseases such as hyperprolactinemia.
Classic articles in Apoptotic Research: A Bibliometric Analysis

Background Classic articles are defined as research papers with a total citation of one thousand or more. The present study is to identify and analyse the characteristics of the classic articles in apoptosis research. Method Classic articles with total of 1,000 or more citations from Web of Science Core Collection since year of publication to the end of 2017 were basically assessed regarding their document types, languages, journals, and Web of Science categories within 1900 to 2017. Result The study showed 418 classic documents in apoptotic research including 260 articles published between 1972 and 2012. The most productive Web of Science category was multidisciplinary sciences. Nature published most of these classic articles followed by Cell, and Science. The most productive country and institution were United States and Harvard University respectively. The author S.J. Korsmeyer from Harvard University was the most productive in apoptosis field and published 13 classic apoptosis articles while the author J.C Reed had more potential to publish classic apoptosis articles in future. The author J.C. Reed and V.A. Fadok had equal potential to publish the same number of classic articles as first- and corresponding-author. Article of Kerr et al. in 1972 was the most popular and cited apoptosis article. The most impact article in 2017 was article entitled “Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion” by Dong et al. in 2002. Conclusion This study seems to identify the most industrious authors, institutions, and countries in the field of apoptosis research. It also tends to reveal the historical and discoveries related to the pathophysiology of apoptosis as well as the most impact publications on apoptosis studies.
The impact of animals on crop yields in Malawian rural villages

It is essential that the net effect of biodiversity on crop yields is determined; particularly in developing nations, where both increasing food security and reducing biodiversity losses are of high importance. This study modelled the abundance of pests, pollinators and pest-control animals and determined their impact on crop yield within agroecosystems in four rural villages in Malawi. Data on the habitat area, survivorship, fecundity, birthing month and effect on crop yield for 14 animal functional groups were collated through a focused meta-analysis. Using this data, models were created to determine the abundance of each functional group using land cover as the sole input variable; with Participatory Rural Appraisals (PRA) utilised to validate the model prediction. Bees, birds and insects always improved crop yield, whereas monkeys, rodents and large herbivores always result in losses. Three out of four villages experienced a net benefit to crop yield from the animal biodiversity present. We conclude that models derived from meta-analyses appear useful for broadly predicting the local-scale abundance of functional groups and their qualitative impact on crop yield. However, long-term field observations should be conducted to ensure that the PRA values in this study correlate with direct observation. Key words: Africa, Malawi, Zomba, agriculture, pest, pest control, pollination, pollinator.
CBX2 and CBX7 antagonistically regulate metabolic reprogramming in breast cancer

Striking similarity exists between metabolic changes associated with embryogenesis and tumorigenesis. Chromobox proteins-CBX2/4/6/7/8, core components of canonical polycomb repressor complex 1 (cPRC1), play essential roles in embryonic development and aberrantly expressed in breast cancer. Understanding how altered CBX expression relates to metabolic reprogramming in breast cancer may reveal vulnerabilities of therapeutic pertinence. Using transcriptomic and metabolomic data from breast cancer patients (N>3000 combined), we identified outstanding roles of CBX2 and CBX7 in positive and negative regulation of glucose metabolism, respectively. Genetic ablation experiments validated the contrasting roles of two isoforms in cancer metabolism and cell growth. Furthermore, we determined that contrary effects of CBX2 and CBX7 on breast cancer metabolism were due to differential modulation of the mTORC1 signaling by two isoforms. Underpinning the biological significance of metabolic roles, CBX2 and CBX7 were found to be the most up- and down-regulated isoforms, respectively, in breast tumors compared to normal tissues. Moreover, CBX2 and CBX7 expression (not other isoforms) correlated strongly, but oppositely, with breast tumor aggressiveness. Genomic data showed higher amplification frequency of CBX2, not CBX7, in breast tumors. Highlighting the clinical significance of findings, survival and drug sensitivity analysis revealed that CBX2 and CBX7 predicted patient outcome and sensitivity to clinical drugs. In summary, this work identifies previously unknown antagonistic roles of CBX2 and CBX7 in breast tumor metabolism, and the results presented may have implications in strategies targeting breast cancer metabolism. Significance statement Metabolic reprogramming is a hallmark of cancer. Understanding how reprogramming of metabolism is regulated in cancer may reveal therapeutically relevant targets. Using integrative approach, we elucidate the hitherto unknown antagonistic roles of CBX2 and CBX7 in breast cancer metabolism. Highlighting the relevance of identified metabolic roles, we found that CBX2 and CBX7 (not other members) are the most differentially expressed isoforms in breast tumors (compared to normals) and the only isoforms which significantly correlate with breast cancer aggressiveness. Further, CBX2/7 predicted patient outcome and response to drugs used in breast cancer treatment, underscoring clinical significance of our study. In brief, this work unravels novel metabolic roles of CBX2/7 which may have implications in breast cancer treatment.
Rapid evolution promotes fluctuation-dependent species coexistence

Recent studies have demonstrated that rapid contemporary evolution can play a significant role in regulating population dynamics on ecological timescales. Here we identify a previously unrecognized mechanism by which rapid evolution promotes species coexistence via temporal fluctuations and a trade-off between competitive ability and the speed of adaptive evolution. This is a special case of relative nonlinearity in coexistence theory, and given the propensity for both oscillatory dynamics and divergent rates of adaptation in the real world, we propose that this mechanism may operate widely in nature.
High-Precision Protein-Tracking With Interferometric Scattering Microscopy

The mobility of proteins and lipids within the cell, sculpted oftentimes by the organisation of the membrane, reveals a great wealth of information on the function and interaction of these molecules as well as the membrane itself. Single particle tracking has proven to be a vital tool to study the mobility of individual molecules and unravel details of their behaviour. Interferometric scattering (iSCAT) microscopy is an emerging technique well suited for visualising the diffusion of gold nanoparticle-labelled membrane proteins to a spatial and temporal resolution beyond the means of traditional fluorescent labels. We discuss the applicability of interferometric single particle tracking (iSPT) microscopy to investigate the minutia in the motion of a protein through measurements visualising the mobility of the epidermal growth factor receptor in various biological scenarios on the live cell.
Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats

It has been postulated that activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor nω-propyl-L-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased of DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH, and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.
Control of aperture closure during reach-to-grasp movements in immersive haptic-free virtual reality

Virtual reality (VR) has garnered much interest as a training environment for motor skill acquisition, including for neurological rehabilitation of upper extremities. While the focus has been on gross upper limb motion, VR applications that involve reaching for, and interacting with, virtual objects are growing. The absence of true haptics in VR when it comes to hand-object interactions raises a fundamentally important question: can haptic-free immersive virtual environments (hf-VEs) support naturalistic coordination of reach-to-grasp movements? This issue has been grossly understudied, and yet is of significant importance in the development and application of VR across a number of sectors. In a previous study (Furmanek et al., J Neuroeng Rehabil 16:78, 2019), we reported that reach-to-grasp movements are similarly coordinated in both the physical environment (PE) and hf-VE. The most noteworthy difference was that the closure phase—which begins at maximum aperture and lasts through the end of the movement—was longer in hf-VE than in PE, suggesting that different control laws might govern the initiation of closure between the two environments. To do so, we reanalyzed data from Furmanek et al. (J Neuroeng Rehabil 16:78, 2019), in which the participants reached to grasp three differently sized physical objects, and matching 3D virtual object renderings, placed at three different locations. Our analysis revealed two key findings pertaining to the initiation of closure in PE and hf-VE. First, the respective control laws governing the initiation of aperture closure in PE and hf-VE both included state estimates of transport velocity and acceleration, supporting a general unified control policy for implementing reach-to-grasp across physical and virtual environments. Second, the aperture was less informative to the control law in hf-VE. We suggest that the latter was likely because transport velocity at closure onset and aperture at closure onset were less independent in hf-VE than in PE, ultimately resulting in an aperture at closure onset having a weaker influence on the initiation of closure. In this way, the excess time and muscular effort needed to actively bring the fingers to a stop at the interface of a virtual object was factored into the control law governing the initiation of closure in hf-VE. Critically, this control law remained applicable, albeit with different weights in hf-VE, despite the absence of terminal haptic feedback and potential perceptual differences.
Triploidy and its evolutionary significance in Cystopteris protrusa

The most widely recognized mode of polyploid formation in homosporous ferns is allopolyploidy. There are taxa, however, that appear to have arisen through autopolyploidy. Several widely separated collections of the normally diploid species Cystopteris protrusa were found to be triploid. Plants in these collections were morphologically similar to typical, diploid C. protrusa, exhibited a significant number of trivalents during meiosis, and corresponded allozymically to heterozygotes from diploid populations. These plants probably arose through outcrossing between normal, haploid gametes and unreduced, diploid gametes. It is hypothesized that this mechanism of autopolyploid formation is stimulated by environmental stress and may be an intermediate stage in the formation of sexually reproductive tetraploids.