Miracle-dz/UniFAR-FTUs huggingface dataset:
Persistent Memory Research in the Post-Optane Era

After over a decade of researcher anticipation for the arrival of persistent memory (PMem), the first shipments of 3D XPoint-based Intel Optane Memory in 2019 were quickly followed by its cancellation in 2022. Was this another case of an idea quickly fading from future to past tense, relegating work in this area to the graveyard of failed technologies? The recently introduced Compute Express Link (CXL) may offer a path forward, with its persistent memory profile offering a universal PMem attachment point. Yet new technologies for memory-speed persistence seem years off, and may never become competitive with evolving DRAM and flash speeds. Without persistent memory itself, is future PMem research doomed? We offer two arguments for why reports of the death of PMem research are greatly exaggerated. First, the bulk of persistent-memory research has not in fact addressed memory persistence, but rather in-memory crash consistency, which was never an issue in prior systems where CPUs could not observe post-crash memory states. CXL memory pooling allows multiple hosts to share a single memory, all in different failure domains, raising crash-consistency issues even with volatile memory. Second, we believe CXL necessitates a "disaggregation" of PMem research. Most work to date assumed a single technology and set of features, i.e., speed, byte addressability, and CPU load/store access. With an open interface allowing new topologies and diverse PMem technologies, we argue for the need to examine these features individually and in combination. While one form of PMem may have been canceled, we argue that the research problems it raised not only remain relevant but have expanded in a CXL-based future.
Hybridization Mediated Range Expansion and Climate Change Resilience in Two Keystone Tree Species of Boreal Forests

Current global climate change is expected to affect biodiversity negatively at all scales leading to mass biodiversity loss. Many studies have shown that the distribution of allele frequencies across a species’ range is often influenced by specific genetic loci associated with local environmental variables. This association reflects local adaptation and allele changes at those loci could thereby contribute to the evolutionary response to climate change. However, predicting how species will adapt to climate change from this type of data alone remains challenging. In the present study, we combined exome capture sequences and environmental niche reconstruction, to test multiple methods for assessing local adaptation and climate resilience in two widely distributed conifers, Norway spruce and Siberian spruce. Both species are keystone species of the boreal forest and share a vast hybrid zone. We show that local adaptation in conifers can be detected through allele frequency variation, population-level ecological preferences, and historical niche movement. Moreover, we integrated genetic and ecological information into genetic offset predictive models to show that hybridization plays a central role in expanding the niche breadth of the two conifer species and may help both species to cope better with future changing climates. This joint genetic and ecological analysis also identified genetically isolated populations that are at risk under current climate change.
Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2

The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the enzymes in charge of pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated quinone-based compounds, discovering potent HsDHODH inhibition (low nanomolar IC50) and promising in vitro anti-SARS-CoV-2 activity (low micromolar EC50). These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools like molecular docking and QSAR models to analyze protein-ligand interactions. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.
A novel in vivo system to study coral biomineralization in the starlet sea anemone (Nematostella vectensis)

Coral reefs are important for maintaining healthy marine ecosystems and are declining rapidly due to increasing environmental stresses. Coral conservation efforts require a mechanistic understanding of how these stresses may disrupt biomineralization, but progress in this area has been slow primarily because corals are not easily amenable to laboratory research. Some cellular characteristics of biomineralization are well characterized, such as the role of carbonic anhydrases, the polarized secretion of ions, and the secretion of “intrinsically disordered proteins” (IDPs) into extracellular microenvironments. We highlight how the starlet sea anemone (Nematostella vectensis) can serve as a tractable model to interrogate the cellular mechanisms of coral biomineralization. We have developed transgenic constructs using genes involved in biomineralization from several animal phyla that can be injected into Nematostella zygotes. These constructs are designed so translated proteins may be purified using TEV protease or Histidine tags to study their physicochemical properties. Using a fluorescent tag, we confirm ectopic expression of the coral biomineralizing protein SpCARP1 in live Nematostella embryos and adults and demonstrate via calcein staining that calcium ions co-localize with SpCARP1 in carbonate and calcium enriched seawater. Our findings suggest that SpCARP1 can induce the formation of amorphous calcium carbonate precursors in N. vectensis, consistent with its suspected role in the early stages of coral biomineralization. These results lay a fundamental groundwork for establishing N. vectensis as a novel in vivo system to explore the evolutionary and cellular mechanisms of biomineralization, improve coral conservation efforts, and even develop novel biomaterials. Graphical Abstract
Pan-Cancer Drug Response Prediction Using Integrative Principal Component Regression

The pursuit of precision oncology heavily relies on large-scale genomic and pharmacological data garnered from preclinical cancer model systems such as cell lines. While cell lines are instrumental in understanding the interplay between genomic programs and drug response, it well-established that they are not fully representative of patient tumors. Development of integrative methods that can systematically assess the commonalities between patient tumors and cell-lines can help bridge this gap. To this end, we introduce the Integrative Principal Component Regression (iPCR) model which uncovers both joint and model-specific structured variations in the genomic data of cell lines and patient tumors through matrix decompositions. The extracted joint variation is then used to predict patient drug responses based on the pharmacological data from preclinical models. Moreover, the interpretability of our model allows for the identification of key driver genes and pathways associated with the treatment-specific response in patients across multiple cancers. We demonstrate that the outputs of the iPCR model can assist in inferring both model-specific and shared co-expression networks between cell lines and patients. We show that iPCR performs favorably compared to competing approaches in predicting patient drug responses, in both simulation studies and real-world applications, in addition to identifying key genomic drivers of cancer drug responses.
Heterogeneity in functional connectivity: Dimensional predictors of individual variability during rest and task fMRI in psychosis

Background Individuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. We examined the relationship between behavioral data and individual variability of functional connectivity at rest and during an emotional-processing task. Methods Neuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global ‘variability score’. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability. Results SSD showed greater MCD during rest (p = 0.00013) and task (p = 0.022). In the hierarchical regression, diagnosis remained significant when social cognition was included during rest (p = 0.008), but not during task (p = 0.50); social cognition was significant during both rest and task (both p = 0.01). Conclusions Diagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes.
SCUBE-1 in The Diagnosis and Follow-Up Of Subclinical Atherosclerosis in The Experimental Diabetes Mellitus and Obesity Model

BACKGROUND Obesity and diabetes mellitus (DM) is a metabolic disease that is a global problem, the most crucial complication of which is atherosclerotic cardiovascular disease resulting from endothelial dysfunction and accompanying platelet hyperactivity. The presence of the SCUBE-1 protein has been observed within vascular endothelial cells and platelets, both recognized for their pivotal involvement in the arterial thrombosis mechanism. The objective of this research is to examine the utility of serum SCUBE-1 levels in diagnosing and monitoring subclinical atherosclerosis in experimentally induced DM and obese rats. METHODS The study comprised a cohort of 28 male Sprague‒Dawleyrats, which encompassed the following groups: the obese group subjected to a high-fat diet (HFD), the TII-DM group administered HFD in combination with a single dose of streptozocin (STZ), the TI-DM group treated solely with STZ, and the control group. Serum SCUBE1 was analyzed using the enzyme-linked immunosorbent assay method, and caspase-3 (Cas-3), interleukin-6 (IL-6), interferon-gamma (INF-gamma) and superoxide dismutase (SOD) expression in the liver and pancreas of rats were evaluated using immunohistochemical methods. RESULTS Serum SCUBE1 levels were significantly higher in the obese and DM groups than in the control group, but there was no significant difference among the obese, TI-DM and TII-DM groups. The study identified a significant relationship between serum SCUBE1 level and hepatic CAS3, IL-6 and SOD expression and pancreatic SOD expression. CONCULISON SCUBE1 can be used as a promising novel marker for the diagnosis and monitoring of subclinical atherosclerosis in individuals with obesity, TI-DM, and TII-DM
Estimation By Multiple Views Of Outdoor Terrain Modeled By Stochastic Processes

An approach to 3-D surface estimation is introduced where surfaces are modelled as patches of primitive parameterized surfaces, and these parameters are estimated from images taken by cameras in two or more positions. Appropriate parameterized patches for modelling manufactured objects include planar, cylindrical, spherical and unrestricted quadric patches. Any parameterized function can be used. A complex 3-D object can be described as a collection of such patches. For more irregular surfaces such as outdoor terrain, we use a collection of primitive patches linked together as a stochastic process. More specifically, in this paper we use planar primitive patches, and describe their dependence by Markov Random Fields. We then treat 3-D terrain height estimation as stochastic pro-cess estimation given two or more image data sets. To the extent that the models used are appropriate, this should result in the most accurate surface height estimation, object recognition for objects such as boulders, crevices, mountains, etc, occulded surface height estimation, and other information extraction. A simple geometric explanation is given for the estimation algorithm. This paper is one aspect of a new Bayesian approach to stereo vision as presented in [4,5,6].
Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments may result from saturation of the plasticity mechanism making it unavailable to be recruited at the appropriate synapses to support learning (Nguyen-Vu et al., 2017). This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb−/−), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here we extend this work by testing predictions of the saturation hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on an oculomotor learning task in which PF-Purkinje cell LTD has been implicated, with no impairment on an LTD-independent oculomotor learning task. Consistent with the saturation hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb−/−mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficit in L7-Fmr1 KO mice. These results support the hypothesis that the enhancement of synaptic plasticity can lead to its saturation in vivo and inability to support learning, providing a novel mechanistic perspective that could inform the development of new clinical approaches for autism and other disorders of the nervous system.
Single nuclei chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry

Single nuclei analysis is allowing robust classification of cell types in an organ that helps to establish relationships between cell-type specific gene expression and chromatin accessibility status of gene regulatory regions. Using breast tissues of 92 healthy donors of various genetic ancestry, we have developed a comprehensive chromatin accessibility and gene expression atlas of human breast tissues. Integrated analysis revealed 10 distinct cell types in the healthy breast, which included three major epithelial cell subtypes (luminal hormone sensing, luminal adaptive secretory precursor, and basal-myoepithelial cells), two endothelial subtypes, two adipocyte subtypes, fibroblasts, T-cells, and macrophages. By integrating gene expression signatures derived from epithelial cell subtypes with spatial transcriptomics, we identify specific gene expression differences between lobular and ductal epithelial cells and age-associated changes in epithelial cell gene expression patterns and signaling networks. Among various cell types, luminal adaptive secretory cells and fibroblasts showed genetic ancestry dependent variability. A subpopulation of luminal adaptive secretory cells with alveolar progenitor (AP) cell state were enriched in Indigenous American (IA) ancestry and fibroblast populations were distinct in African ancestry. ESR1 expression pattern was distinctly different in cells from IA compared to the rest, with a high level of ESR1 expression extending to AP cells and crosstalk between growth factors and Estrogen Receptor signaling being evident in these AP cells. In general, cell subtype-specific gene expression did not uniformly correlate with cell-specific chromatin accessibility, suggesting that transcriptional regulation independent of chromatin accessibility governs cell type-specific gene expression in the breast.
CaCO3 Nanoparticles Delivering MicroRNA-200c Suppress Oral Squamous Cell Carcinoma

MicroRNA (miR)-200c suppresses the initiation and progression of oral squamous cell carcinoma (OSCC), the most prevalent head and neck cancer with high recurrence, metastasis, and mortality rates. However, miR-200c-based gene therapy to inhibit OSCC growth and metastasis has yet to be reported. To develop an miR-based gene therapy to improve the outcomes of OSCC treatment, this study investigates the feasibility of plasmid DNA encoding miR-200c delivered via non-viral CaCO3-based nanoparticles to inhibit OSCC tumor growth. CaCO3-based nanoparticles with various ratios of CaCO3 and protamine sulfate (PS) were utilized to transfect pDNA encoding miR-200c into OSCC cells and the efficiency of these nanoparticles was evaluated. The proliferation, migration, and associated oncogene production, as well as in vivo tumor growth for OSCC cells overexpressing miR-200c were also quantified. It was observed that, while CaCO3-based nanoparticles improve transfection efficiencies of pDNA miR-200c, the ratio of CaCO3 to PS significantly influences the transfection efficiency. Overexpression of miR-200c significantly reduced proliferation, migration, and oncogene expression of OSCC cells, as well as the tumor size of cell line-derived xenografts (CDX) in mice. In addition, a local administration of pDNA miR-200c using CaCO3 delivery significantly enhanced miR-200c transfection and suppressed tumor growth of CDX in mice. These results strongly indicate that the nanocomplexes of CaCO3/pDNA miR-200c may potentially be used to reduce oral cancer recurrence and metastasis and improve clinical outcomes in OSCC treatment. (227 words)
Characterization of Gαs and Gαolf activation by catechol and non-catechol dopamine D1 receptor agonists

The dopamine D1 receptor (D1R) couples to Gαs and Gαolf and plays a crucial role in regulating voluntary movement and other cognitive functions, making it a potential therapeutic target for several neurological and neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia. In the central nervous system, Gαs is widely expressed in the cortex and Gαolf is predominantly found in the striatum. We used two different configurations of bioluminescence resonance energy transfer (BRET) assays and a fluorescence-based cyclic AMP (cAMP) production functional assay to test a series of tetracyclic catechol (dihydrexidine, methyl-dihydrexidine, doxanthrine) and non-catechol (tavapadon, PF-8294, PF-6142) D1R agonists for their activity at these G proteins. We discovered that these tetracyclic catechol compounds, PF-8294 and PF-6142 exerted full agonism when D1R coupled to Gαs but partial agonism when D1R coupled to Gαolf. In contrast, tavapadon acted as a full agonist at Gαolf and a partial agonist at Gαs. The effects of these compounds on the cortical and nigral electrophysiological events agree with their selectivity profiles. This suggests the possibility of achieving region-specific pharmacology and opens new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.
THE EFFECT OF THE ASPECT RATIO ON CRACK-INDUCED ANISOTROPY1

Media containing aligned cracks show anisotropy with respect to elastic wave propagation. There are several models describing the wave propagation in cracked media, most of them only valid for cracks with small aspect ratios. One of these models (Crampin's model) is compared with a model valid for all aspect ratios (Nishizawa's model). The elastic constants and the group velocities are compared for both dry and liquid-filled inclusions with aspect ratios ranging from 0.0001 (flat cracks) up to 1 (spheres). The difference between both models is small for small aspect ratios but becomes larger for increasing aspect ratios. At a crack density of 0.05 both models give-within an error of 5%–the same results for aspect ratios up to 0.3. Therefore Crampin's model can be applied to a large range of cracked media even if the aspect ratio of the inclusions is not small. The variation of the anisotropy as a function of the aspect ratio can be studied using Thomsen's dimensionless parameters δ, E and y. They show how inclusions with large aspect ratios result in elliptical anisotropy.
Profiling Chromatin Accessibility in Humans Using Adenine Methylation and Long-Read Sequencing

Chromatin accessibility demonstrates accessible DNA regions that usually have regulatory function. Several studies have demonstrated DNA accessibility profiling using nanopore sequencing and GpC or adenine modification. However, the GpC dinucleotide is not evenly distributed across the genome and there are regions sparse in GpC. 6mA studies have demonstrated chromatin accessibility in yeast using nanopore based sequencing, although a high-false positive in 6mA detection rate and low coverage have previously precluded the effective use in mammalian sized genomes. Here, we have developed accurate 6mA base calling and demonstrated high-resolution profiling of accessible regions and simultaneous CpG methylation detection in humans using long read sequencing.
Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity from synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We further demonstrate that neuronal activity stimulates autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a novel trans-synaptic signaling mechanism modulating structural plasticity.