Miracle-dz/UniFAR-FTUs huggingface dataset:
Overlapping community detection in complex networks using fuzzy theory, balanced link density, and label propagation

Complex networks represent various real‐world systems. Overlapping community detection is one of the critical tasks in studying these networks and has significance to a wide variety of applications, including the exploration of online social networks because of the natural attitude of persons to participate in multiple communities at the same time. Despite a large number of existing community detection algorithms for detecting disjoint communities, the efficient and fast uncovering of overlapping communities has remained a challenging problem. To provide an efficient solution, on the one hand, the balanced link density label propagation (BLDLP) algorithm, proposed by the authors of the current study, is a fast, stable, and efficient method for disjoint community detection. On the other hand, the fuzzy theory is a worthwhile approach for overlapping community detection since it provides the membership rate of the overlapping nodes as well as the detection of overlapping communities. Hence, in this paper, based on the synergy of the BLDLP algorithm and the fuzzy theory, a novel method, called fuzzy BLDLP, for overlapping community detection is proposed. Fuzzy BLDLP is fast and efficient. The proposed method needs no prior information about the number of network communities to discover them. The experiments on both synthetic and real‐world known networks, including Zachary, Dolphins, and COVID‐19 Co‐authorship, have revealed that the proposed method successfully detects the overlapping nodes and communities and hence is comparable with the state‐of‐the‐art overlapping community detection algorithms in terms of recall, precision, F‐score and overlapping normalized mutual information.
Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation

cAMP is a key player in many physiological processes. Classically considered to originate solely from the plasma membrane, this view was recently challenged by observations showing that GPCRs can sustain cAMP signaling from intracellular compartments associated with nuclear PKA translocation and activation of transcriptional events. In this report we show that neither PKA translocation nor cAMP diffusion, but rather nuclear sAC activation represents the only source of nuclear cAMP accumulation, PKA activation, and CREB phosphorylation. Both pharmacological and genetic sAC inhibition, that did not affect the cytosolic cAMP levels, completed blunted nuclear cAMP accumulation, PKA activation and proliferation, while an increase in sAC nuclear expression significantly enhanced cell proliferation. Moreover, utilizing novel compartment-specific optogenetic actuators we showed that light-dependent nuclear cAMP synthesis can stimulate PKA, CREB and trigger cell proliferation. Thus, our results show that sAC-mediated nuclear accumulation is not only necessary but sufficient and rate-limiting for cAMP-dependent proliferation.
A framework to trace microbial engraftment at the strain level during fecal microbiota transplantation

Background Fecal microbiota transplantation (FMT) may treat microbiome-associated diseases effectively. However, the mechanism and pattern of the FMT process require expositions. Previous studies indicated the necessity to track the FMT process at the microbial strain level. At this moment, shotgun metagenomic sequencing enables us to study strain variations during the FMT. Result We implemented a software package PStrain-tracer to study microbial strain variations during FMT from the shotgun metagenomic sequencing data. The package visualizes the strain alteration and traces the microbial engraftment during the FMT process. We applied the package to two typical FMT datasets: one ulcerative colitis (UC) dataset and one Clostridium difficile infection (CDI) dataset. We observed that when the engrafted species has more than one strain in the source sample, 99.3% of the engrafted species will engraft only a subset of strains. We further confirmed that the all-or-nothing manner unsuited the engraftment of species with multiple strains by heterozygous single-nucleotide polymorphisms (SNPs) count, revealing that strains prefer to engraft independently. Furthermore, we discovered a primary determinant of strain engrafted success is their proportion in species, as the engrafted strains from the donor and the pre-FMT recipient with proportions 33.10 % (p-value = 6e − 06) and 37.08 % (p-value = 9e − 05) significantly higher than ungrafted strains on average, respectively. All the datasets indicated that the diversity of strains bursts after FMT and decreases to one after eight weeks for twelve species. Previous studies neglected strains with their corresponding species showing insignificant differences between different samples. With the package, from the UC dataset, we successfully determined the strain variations of the species Roseburia intestinalis, a beneficial species reducing intestinal inflammation, colonized in the cured UC patient being engrafted from the donor, even if the patient hosted the same species yet before treatment. We found seven strains in donors from the CDI dataset and one strain in pre-FMT recipients from eight species that associated CDI FMT failure. Conclusion PStrain-tracer is the first framework that tracks strain alterations in metagenomic sequencing data of FMT. PStrain-tracer implemented several methods specialized for FMT experiment samples, such as visualization of strains abundance alteration in the FMT experiment and determinant strains detection in FMT failure. We applied PStrain-tracer on two published datasets, uncovered novel strains related to FMT failure, and demonstrated the necessity of analyzing the whole-genome shotgun metagenomic data of FMT at the strain level. We also developed an online visualizer of PStrain-tracer for the users to adjust their visualized results online. The package is available at https://github.com/deepomicslab/PStrain-tracer.
Effects of Familial Alzheimer’s Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide

Familial Alzheimer’s disease (FAD) mutations of the amyloid β-peptide (Aβ) are known to lead to early onset and more aggressive Alzheimer’s disease. FAD mutations such as “Iowa” (D23N), “Arctic” (E22G), “Italian” (E22K), and “Dutch” (E22Q) have been shown to accelerate Aβ aggregation relative to the wild-type (WT). The mechanism by which these mutations facilitate increased aggregation is unknown, but each mutation results in a change in net charge of the peptide. Previous studies have used nonpolarizable force fields to study Aβ, providing some insight into how this protein unfolds. However, nonpolarizable force fields have fixed charges that lack the ability to redistribute in response to changes in local electric fields. Here, we performed polarizable molecular dynamics (MD) simulations on the full-length Aβ42 of WT and FAD mutations and calculated folding free energies of the Aβ15-27 fragment via umbrella sampling. By studying both the full-length Aβ42 and a fragment containing mutations and the central hydrophobic cluster (residues 17-21), we were able to systematically study how these FAD mutations impact secondary and tertiary structure and the thermodynamics of folding. Electrostatic interactions, including those between permanent and induced dipoles, affected sidechain properties, salt bridges, and solvent interactions. The FAD mutations resulted in shifts in the electronic structure and solvent accessibility at the central hydrophobic cluster and the hydrophobic C-terminal region. Using umbrella sampling, we found that the folding of the WT and E22 mutants are enthalpically driven, whereas the D23N mutant is entropically driven, arising from a different unfolding pathway and peptide-bond dipole response. Together, the unbiased, full-length and umbrella sampling simulations of fragments reveal that the FAD mutations perturb nearby residues and others in hydrophobic regions to potentially alter solubility. These results highlight the role electronic polarizability plays in amyloid misfolding and the role of heterogeneous microenvironments that arise as conformational change takes place.
Cytoplasmic TDP-43 accumulation drives changes in C-bouton number and size in a mouse model of sporadic Amyotrophic Lateral Sclerosis

An altered neuronal excitability of spinal motoneurones has consistently been implicated in Amyotrophic Lateral Sclerosis (ALS) leading to several investigations of synaptic input to these motoneurones. One such input that has repeatedly been shown to be affected is a population of large cholinergic synapses terminating mainly on the soma of the motoneurones referred to as C-boutons. Most research on these synapses during disease progression has used transgenic Superoxide Dismutase 1 (SOD1) mouse models of the disease which have not only produced conflicting findings, but also fail to recapitulate the key pathological feature seen in ALS; cytoplasmic accumulations of TAR DNA-binding protein 43 (TDP-43). Additionally, they fail to distinguish between slow and fast motoneurones, the latter of which have more C-boutons but are lost earlier in the disease. To circumvent these issues, we quantified the frequency and volume of C-boutons on traced soleus and gastrocnemius motoneurones, representing predominantly slow and fast motor pools respectively. Experiments were performed using the TDP-43ΔNLS mouse model that carries a transgenic construct of TDP-43 devoid of its nuclear localization signal, preventing its nuclear import. This results in the emergence of pathological TDP-43 inclusions in the cytoplasm, modelling the main pathology seen in this disorder, accompanied by a severe and lethal ALS phenotype. Our results confirmed changes in both the number and volume of C-boutons with a decrease in number on the more vulnerable, predominantly fast gastrocnemius motoneurones and an increase in number on the less vulnerable, predominantly slow soleus motoneurones. Importantly, these changes were only found in male mice. However, both sexes and motor pools showed a decrease in C-bouton volume. Our experiments confirm that cytoplasmic TDP-43 accumulation is sufficient to drive C-bouton changes.
Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy

LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by the severe muscular dystrophy but also involves other tissues. In the dyW/dyW mouse model for LAMA2 MD, amelioration of muscle function by skeletal muscle-specific expression of the two linker proteins, mini-agrin and αLNNd, is sufficient to greatly increase survival. In such survivors, the phenotype is dominated by the hindlimb paralysis. We now show that ubiquitous expression of the two linker proteins in dyW/dyW mice improves muscle function and prevents hindlimb paralysis. The same ameliorating effect of the linker proteins was seen in dy3K/dy3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in many, if not all tissues affected in LAMA2 MD.
An apical protein, Pcr2, is required for persistent movement by the human parasite Toxoplasma gondii

The phylum Apicomplexa includes thousands of species of unicellular parasites that cause a wide range of human and animal diseases such as malaria and toxoplasmosis. To infect, the parasite must first initiate active movement to disseminate through tissue and invade into a host cell, and then cease moving once inside. The parasite moves by gliding on a surface, propelled by an internal cortical actomyosin-based motility apparatus. One of the most effective invaders in Apicomplexa is Toxoplasma gondii, which can infect any nucleated cell and any warm-blooded animal. During invasion, the parasite first makes contact with the host cell “head-on” with the apical complex, which features an elaborate cytoskeletal apparatus and associated structures. Here we report the identification and characterization of a new component of its apical complex, Preconoidal region protein 2 (Pcr2). Pcr2 knockout parasites replicate normally, but they are severely diminished in their capacity for host tissue destruction due to significantly impaired invasion and egress, two vital steps in the lytic cycle. When stimulated for calcium-induced egress, Pcr2 knockout parasites become active, and secrete effectors to lyse the host cell. Calcium-induced secretion of the major adhesin, MIC2, also appears to be normal. However, the movement of the Pcr2 knockout parasite is spasmodic and unproductive, which drastically compromises egress. In addition to faulty motility, the ability of the Pcr2 knockout parasite to assemble the moving junction is impaired. Both defects likely contribute to the poor efficiency of invasion. Interestingly, actomyosin activity, as indicated by the motion of mEmerald tagged actin chromobody, appears to be largely unperturbed in the absence of Pcr2, raising the possibility that Pcr2 may act downstream of or in parallel with the actomyosin machinery.
Efficiency Improvement of a Dual PV Water Pumping System on a Desert Well by Solar Matched Load Control

Two similar PV powered water pumping systems (PVPS) with a programmable control system, which enables matching between the loads (pumps) and the generated PV power according to solar radiation intensity, are treated in this paper. Testing results show an annual gain of 7.4% in water pumped through using the control system. Moreover, up to 16% increment in daily water pumped, especially in winter days of moderate solar radiation (≈2.8 kWh/m 2 .day), has been measured. This means that a considerable reduction of the water cost is achieved and thereby the feasibility of PVPS is increased. Further increments of total system efficiency achieved by utilizing PV modules of higher efficiency and by mounting the PV array on a support structure with adjustable tilt angle are discussed. Decreasing the hydraulic output of the pumping system, due to the increase of temperature in summer, is demonstrated through field testing results.
Frontal cortex learns to add evidence across modalities

To make accurate perceptual decisions, the brain often combines information across sensory modalities. For instance, localizing objects by integrating their image and sound. However, the cortical substrates underlying this audiovisual integration remain uncertain. Here, we show that mouse frontal cortex combines auditory and visual evidence; that this combination is additive, mirroring behavior; and that it evolves with learning. Scanning optogenetic inactivation demonstrated that inactivating frontal cortex impaired choices based on either sensory modality. Recordings from >10,000 neurons indicated that after task learning, activity in frontal area MOs (secondary motor cortex) encodes an additive combination of visual and auditory signals, consistent with the mice’s behavioral strategy. An accumulator model applied to these sensory representations reproduced both the observed choices and reaction times. These results indicate that frontal cortex adapts through learning to combine evidence across sensory cortices, providing a signal that is transformed into a binary decision by a downstream accumulator.
Direct and indirect phenotypic effects on sociability indicate potential to evolve

The decision to leave or join a group is important as group size influences many aspects of organisms’ lives and their fitness. This tendency to socialise with others, sociability, should be influenced by genes carried by focal individuals (direct genetic effects) and by genes in partner individuals (indirect genetic effects), indicating the trait’s evolution could be slower or faster than expected. However, estimating these genetic parameters is difficult. Here, in a laboratory population of the cockroach Blaptica dubia, I estimate phenotypic parameters for sociability: repeatability (R) and repeatable influence (RI), that indicate whether direct and indirect genetic effects respectively are likely. I also estimate the interaction coefficient (Ψ), which quantifies how strongly a partner’s trait influences the phenotype of the focal individual and is key in models for the evolution of interacting phenotypes. Focal individuals were somewhat repeatable for sociability across a three-week period (R = 0.083), and partners also had marginally consistent effects on focal sociability (RI = 0.055). The interaction coefficient was non-zero, although in opposite sign for the sexes; males preferred to associate with larger individuals (Ψmale = −0.129) while females preferred to associate with smaller individuals (Ψfemale = 0.068). Individual sociability was consistent between dyadic trials and in social networks of groups. These results provide phenotypic evidence that direct and indirect genetic effects have limited influence on sociability, with perhaps most evolutionary potential stemming from heritable effects of the body mass of partners. Sex-specific interaction coefficients may produce sexual conflict and the evolution of sexual dimorphism in social behaviour.
Nucleotide resolution genetic mapping in pigs by publicly accessible whole genome imputation

Genetic mapping to identify genes and alleles associated with or causing economically important quantitative trait variation in livestock animals such as pigs is a major goal in the genetic improvement animals. Despite recent advances in high throughput genotyping technologies, resolution of genetic mapping in pigs remains poor due in part to the low density of genotyped variant sites. In this study, we overcame this limitation by developing a reference haplotype panel for pigs based on 2,259 whole genome sequenced animals representing 44 pig breeds. We optimized the imputation procedure to achieve an average concordance rate in excess of 97%, non-reference concordance rate 91%, and r2 0.89. We demonstrated that genotype imputation using this resource can dramatically improve resolution of genetic mapping. Finally, we developed a public web server (swimgeno.org) to allow the pig genetics community to fully utilize this resource. We expect the resource and server to significantly facilitate genetic mapping and accelerate genetic improvement in pigs.
The canonical Wnt signaling pathway is not a promising therapeutic target for PNS regeneration enhancement

PNS injury initiates transcriptional changes in Schwann cells, satellite glial cells and PNS neurons that facilitate regeneration. The signaling pathways that control these transcriptional changes are not fully understood. The canonical Wnt signaling pathway is active during early stages of PNS development, where it controls radial axonal sorting and the onset of PNS myelination. Upon PNS injury, the Wnt signaling pathway is re-activated, suggesting that Wnt signaling plays an important role in PNS regeneration. To explore the potential of the Wnt pathway as a therapeutic target for enhancement of PNS recovery, we used a combination of genetic and pharmacological approaches to either activate or inhibit the Wnt signaling pathway during PNS recovery. We found that manipulating the Wnt signaling pathway does not alter PNS regeneration. Our data suggests that the Wnt signaling pathway is not a strong therapeutic target for the enhancement of PNS regeneration.
Epigenetic plasticity via adaptive DNA hypermethylation and clonal expansion underlie resistance to oncogenic pathway inhibition in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis. Drug resistance is the major cause for therapeutic failure in PDAC patients with progressive disease. The mechanisms underlying resistance formation are complex and remain poorly understood. To gain insights into molecular changes during the formation of resistance to oncogenic MAPK pathway inhibition we utilized short-term passaged primary tumor cells from ten PDACs of genetically engineered mice. We followed gain and loss of resistance upon MEKi exposure and withdrawal by longitudinal integrative analysis of whole genome sequencing, whole genome bisulfite sequencing, RNA-sequencing and mass spectrometry data. We found that resistant cell populations under increasing MEKi treatment evolved by the expansion of a single clone but were not a direct consequence of known resistance-conferring mutations. Rather, resistant cells showed adaptive DNA hypermethylation of 209 and hypomethylation of 8 genomic sites, most of which overlap with regulatory elements known to be active in murine PDAC cells. Both DNA methylation changes and MEKi resistance were transient and reversible upon drug withdrawal. The effector caspase CASP3 is one of the 114 genes for which transcriptional downregulation inversely correlated with the methylation status of the associated DNA region. CASP3 inactivation in resistant cells led to attenuation of drug-induced apoptosis which could be reversed by DNA methyltransferase inhibition with remarkable sensitivity exclusively in the resistant cells. Overall, our data provide a context for characterization and targeting of epigenetically mediated resistance mechanisms in PDAC.
Ultra-small bispecific fusion protein augments tumor penetration and treatment efficacy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Due to drugs’ low intrinsic anticancer activity and the unique physiological barrier of PDAC tumors, the once highly anticipated antibody-based pathway-targeted therapies have not achieved promising improvement in outcomes. Here, an ultra-small-sized bispecific fusion protein, termed Bi-fp50, that could largely enrich deep tumor tissue and effectively inhibit PDAC tumor growth was reported. The bispecific Bi-fp50 protein was constructed by a typical synthetic biology method that could efficiently target EGFR and VEGF of PDAC cells simultaneously in vitro and in vivo. For Bxpc3 and Aspc1 PDAC cells, the Bi-fp50 achieved a significant and synergistic therapeutic effect. Owing to the small size of only 50 kDa and the function of reducing the interstitial fluid pressure by vascular normalization, the Bi-fp50 showed enhanced penetration, considerable accumulation, and uniform distribution in tumor and subsequently led to effective inhibition of the growth of Bxpc3 cells-induced PDAC tumor in vivo. Furthermore, no noticeable side effect of Bi-fp50 was found in vitro and in vivo. This work demonstrates that the synthetic Bi-fp50 fusion protein could be used as a new effective pathway-specific targeted therapy for PDACs.