Miracle-dz/UniFAR-FTUs huggingface dataset:
A mind-body interface alternates with effector-specific regions in motor cortex

Primary motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down precentral gyrus from foot to face representations1,2. The motor homunculus has remained a textbook pillar of functional neuroanatomy, despite evidence for concentric functional zones3 and maps of complex actions4. Using our highest precision functional magnetic resonance imaging (fMRI) data and methods, we discovered that the classic homunculus is interrupted by regions with sharpy distinct connectivity, structure, and function, alternating with effector-specific (foot, hand, mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, and to prefrontal, insular, and subcortical regions of the Cingulo-opercular network (CON), critical for executive action5 and physiological control6, arousal7, and processing of errors8 and pain9. This interdigitation of action control-linked and motor effector regions was independently verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant, child) precision fMRI revealed potential cross-species analogues and developmental precursors of the inter-effector system. An extensive battery of motor and action fMRI tasks documented concentric somatotopies for each effector, separated by the CON-linked inter-effector regions. The inter-effector regions lacked movement specificity and co-activated during action planning (coordination of hands and feet), and axial body movement (e.g., abdomen, eyebrows). These results, together with prior work demonstrating stimulation-evoked complex actions4 and connectivity to internal organs (e.g., adrenal medulla)10, suggest that M1 is punctuated by an integrative system for implementing whole-body action plans. Thus, two parallel systems intertwine in motor cortex to form an integrate-isolate pattern: effector-specific regions (foot, hand, mouth) for isolating fine motor control, and a mind-body interface (MBI) for the integrative whole-organism coordination of goals, physiology, and body movement.
Optical selection rules for electron-hole pair excitation in 3 D topological insulators

Experiments using ARPES, which is based on the photoelectric effect, have shown that the surface states in 3D topological insulators (TI) are helical. Here we consider Weyl interface fermions due to band inversion in narrow-bandgap semiconductors, such as Pb1−xSnxTe and Bi1−xSbx. We determine the optical selection rules of electron-hole pair excitation by means of the solutions of the 3D Dirac equation. While electron-hole pairs in graphene are generated through intraband transitions, we show that in 3D TI they are generated through both intraband and interband transitions. For their analysis, we calculate explicitly the electric dipole matrix elements by means of bandstructure calculations for Pb1−xSnxTe. While in graphene the pseudospin helicity operator is given by ĥg = − (1/ |p⊥|)σ · p, we define the spin helicity operator in 3D TI as ĥTI = − (1/ |p⊥|) (σ × p) · ẑ, where ẑ points perpendicular to the interface. Our results are crucial for future opto-electronic devices based on 3D TI.
An exploratory study of a simple approach for evaluating drug solubility in milk related vehicles

Milk related materials are frequently used as a vehicle for drug product administration. Therefore, drug solubility information in milk related vehicles is desirable for prediction of how they may influence in vivo drug release and bioavailability. However, there are very limited data published on this topic. This study explored a practical method to address the key challenges associated with solubility assessment in milk, including the sample equilibration time and cleanup procedures. Amitriptyline, acetaminophen, dexamethasone, nifedipine, piroxicam, and prednisolone were selected as model drugs to represent a wide range of physicochemical properties. Their solubilities were determined at room temperature in pH 6.8 phosphate buffer, skim milk, whole milk, reconstituted whole milk powder, and unprocessed raw milk. The overall results confirmed that milk greatly improves the solubility of poorly water-soluble drugs. However, the extent of improvement and mechanism of solubilization appeared unique for each drug, highlighting the importance of evaluating milk solubility experimentally. The method used in this exploratory study can be applied in future investigations of a broader range of drugs and milk-related vehicles.
On an Analogy Between Ephaptic Coupling in Large Tracts and Cross-Modal Integration During Illusory Percept

In this paper, the authors report simulations analogous to cross-modal integration which can be modeled by thinking of large (in terms of numbers of axons) axon tracts with distinctly demarcated subsets of axons. In such a tract, when the demarcated regions are separately stimulated they fire in response to the stimulation. Due to extracellular current-based coupling, at a later time, unstimulated axons also begin to cross-talk. The simulation graphical result, though on a faster time scale, is analogous to the multi-channel MEG recordings of “AV-(A+V)” obtained by Shams et. al. When the coupling parameter is weakened, this cross-talk disappears. In Shams et. al., the appearance and disappearance of cross-talk are related to the perception of an illusory flash by the subject. Our extrapolated conclusion is that ephaptic coupling might be a part of the mechanism for cross-talk between brain regions mediating, say, audio and visual-processing. We also study noisy ephaptic coupling and additionally do a comparative study with the Kuramoto model, which yields insight into the exact and detailed mechanism of ephaptic synchronization.
Thiovibrio frasassiensis gen. nov., sp. nov., an autotrophic, elemental sulfur disproportionating bacterium isolated from sulfidic karst sediment, and proposal of Thiovibrionaceae fam. nov.

A novel, autotrophic, mesophilic bacterium, strain RS19-109T, was isolated from sulfidic stream sediments in the Frasassi Caves, Italy. The cells of this strain grew chemolithoautotrophically under anaerobic conditions while disproportionating elemental sulfur (S0) and thiosulfate, but not sulfite with bicarbonate/CO2 as a carbon source. Autotrophic growth was also observed with molecular hydrogen as an electron donor, and S0, sulfate, thiosulfate, nitrate, and ferric iron as electron acceptors. Oxygen was not used as an electron acceptor and sulfide was not used as an electron donor. Weak growth was observed with sulfate as an electron acceptor and organic carbon as electron donors and carbon sources. The strain also showed weak growth by fermentation of tryptone. Strain RS19-109T was found to be phylogenetically distinct based on 16S rRNA gene sequence similarity (89.2%) to its closest relative, Desulfurivibrio alkaliphilus AHT2T. The draft genome sequence for strain RS19-109T had average nucleotide identity, average amino acid identity, and in silico DNA-DNA hybridization values of 72.2%, 63.0%, and 18.3%, respectively, compared with the genome sequence of D. alkaliphilus AHT2T. On the basis of its physiological and genomic properties, strain RS19-109T is proposed as the type strain of a novel species of a novel genus, Thiovibrio frasassiensis gen. nov., sp. nov. A novel family, Thiovibrionaceae fam. nov., is proposed to accommodate Thiovibrio within the order Desulfobulbales.
SalienceNet: an unsupervised Image-to-Image translation method for nuclei saliency enhancement in microscopy images

Automatic segmentation of nuclei in low-light microscopy images remains a difficult task, especially for high-throughput experiments where need for automation is strong. Low saliency of nuclei with respect to the background, variability of their intensity together with low signal-to-noise ratio in these images constitute a major challenge for mainstream algorithms of nuclei segmentation. In this work we introduce SalienceNet, an unsupervised deep learning-based method that uses the style transfer properties of cycleGAN to transform low saliency images into high saliency images, thus enabling accurate segmentation by downstream analysis methods, and that without need for any parameter tuning. We have acquired a novel dataset of organoid images with soSPIM, a microscopy technique that enables the acquisition of images in low-light conditions. Our experiments show that SalienceNet increased the saliency of these images up to the desired level. Moreover, we evaluated the impact of SalienceNet on segmentation for both Otsu thresholding and StarDist and have shown that enhancing nuclei with SalienceNet improved segmentation results using Otsu thresholding by 30% and using StarDist by 26% in terms of IOU when compared to segmentation of non-enhanced images. Together these results show that SalienceNet can be used as a common preprocessing step to automate nuclei segmentation pipelines for low-light microscopy images.
The class XIV myosin of Toxoplasma gondii, TgMyoA, is druggable in an animal model of infection

Toxoplasma gondii is a widespread apicomplexan parasite that can cause severe disease in its human hosts. The ability of T. gondii and other apicomplexan parasites to invade into, egress from, and move between cells of the hosts they infect is critical to parasite virulence and disease progression. An unusual and highly conserved parasite myosin motor (TgMyoA) plays a central role in T. gondii motility. The goal of this work was to test whether pharmacological inhibition of TgMyoA can alter disease progression in an animal model of infection. To this end, we sought to identify small molecule inhibitors of TgMyoA by screening a collection of 50,000 structurally diverse small molecules for inhibitors of the recombinant motors actin-activated ATPase activity. The top hit to emerge from the screen, KNX-002, inhibited TgMyoA with little to no effect on any of the vertebrate myosins tested. KNX-002 was also active against parasites, inhibiting parasite motility and growth in culture in a dose-dependent manner. We used chemical mutagenesis, selection in KNX-002, and targeted sequencing to identify a mutation in TgMyoA (T130A) that renders the recombinant motor less sensitive to compound. Compared to wild-type parasites, parasites expressing the T130A mutation showed reduced sensitivity to KNX-002 in motility and growth assays, confirming TgMyoA as a biologically relevant target of KNX-002. Finally, KNX-002 was shown to slow disease progression in mice infected with wild-type parasites, but not parasites expressing the resistance-conferring TgMyoA T130A mutation. These data demonstrate the specificity of KNX-002 for TgMyoA, both in vitro and in vivo, and validate TgMyoA as a druggable target for toxoplasmosis. Since TgMyoA is essential for virulence, conserved in apicomplexan parasites, and distinctly different from the myosins found in humans, pharmacological inhibition of MyoA offers a promising new approach to treating the devastating diseases caused by T. gondii and other apicomplexan parasites.
The Effectiveness of Humble Leadership to Mitigate Employee Burnout in the Healthcare Sector: A Structural Equation Model Approach

The discussion on employee burnout (BOT) has existed in academic literature for a long time. While BOT was identified as a personal issue, there is a lack of a system approach solution. In this regard, a milestone was achieved in 2019 when the World Health Organization (WHO) introduced a new definition of BOT, recognising it as an occupational phenomenon, thereby placing a greater responsibility on organisational leadership to manage it. Since then, different leadership models have been proposed by scholars to reduce the effect of BOT in an organisation. Humble leadership (HL), as a people-first approach, has recently gained importance in organisational management literature. Studies have indicated that HL significantly influences different employee outcomes. However, research on the significance of HL to mitigate BOT of employees was scarce—similarly, on the underlying mechanisms of how and why. While HL has the potential to reduce BOT in an organisation, little or no research has studied it. Acknowledging these knowledge gaps, the basic aim of this study is to enrich the existing body of knowledge by proposing HL as an effective organisational management strategy to reduce the effect of BOT in the healthcare sector. The study introduces two mediators, work engagement (WREN) and subjective wellbeing (SUBW), to explain the underlying mechanism between HL and BOT. The conditional indirect role of altruism (ALM) was also tested. The data were obtained from hospital employees by employing a survey method (questionnaire, n = 303). Structural equation model (SEM) was considered for testing the hypothesised model to study the interrelationships between variables. The results confirmed that the manifestation of HL in an organisation reduces BOT significantly, and WREN and SUBW mediate this relationship. The study also demonstrates the buffering effect of ALM in the above-proposed relationships. The empirical findings offer multiple contributions in theory and practice, among which the most important one was to realise the profound importance of HL in reducing the effect of BOT in healthcare management.
Antimicrobial Activity of Methanolic Root Extract of D ecalepis hamiltonii

: The present study was quantitative analysis and antimicrobial activity of petroleum ether, chloroform, ethyl acetate, methanol root extracts. The gram positive and gram negative bacterial and fungal species by the disc diffusion method at various concentration (250µl-1000µl). The results was present in the phenolic and flavonoid content compared to extracts. All the root extract against to Bacillus subtilis and Streptococcus pyogenes and fungal species Candida albicans at highest inhibition at concentration of methanolic root extract of zone formation. The preliminary studies on Decalepis hamiltonii root extract exhibited their antimicrobial potential which could be exploited further and future pharmaceutical, therapeutic efficiency and food preservation and applications
Case report: Metastatic urothelial cancer with an exceptional response to immunotherapy and comprehensive understanding of the tumor and the tumor microenvironment

Although immune checkpoint inhibitors (ICIs) are increasingly used as second-line treatments for urothelial cancer (UC), only a small proportion of patients respond. Therefore, understanding the mechanisms of response to ICIs is critical to improve clinical outcomes for UC patients. The tumor microenvironment (TME) is recognized as a key player in tumor progression and the response to certain anti-cancer treatments. This study aims to investigate the mechanism of response using integrated genomic and transcriptomic profiling of a UC patient who was part of the KEYNOTE-045 trial and showed an exceptional response to pembrolizumab. Diagnosed in 2014 and receiving first-line chemotherapy without success, the patient took part in the KEYNOTE-045 trial for 2 years. She showed dramatic improvement and has now been free of disease for over 6 years. Recently described by Bagaev et al., the Molecular Functional (MF) Portrait was utilized to dissect genomic and transcriptomic features of the patient’s tumor and TME. The patient’s tumor was characterized as Immune Desert, which is suggestive of a non-inflamed microenvironment. Integrated whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis identified an ATM mutation and high TMB level (33.9 mut/mb), which are both positive biomarkers for ICI response. Analysis further revealed the presence of the APOBEC complex, indicating the potential for use of APOBEC signatures as predictive biomarkers for immunotherapy response. Overall, comprehensive characterization of the patient’s tumor and TME with the MF Portrait revealed important insights that could potentially be hypothesis generating to identify clinically useful biomarkers and improve treatment for UC patients.
Clinicopathological characteristics and outcomes of synchronous renal cell carcinoma and urothelial carcinoma: A population-based analysis

Background To better understand the characteristics, and survival outcomes of synchronous renal cell carcinoma (RCC) and urothelial carcinoma (UC), we described and analyzed the clinical features, factors, and prognosis of patients with synchronous RCC and UC using a large population-based database. Methods Within the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016), we identified patient with concurrent RCC and UC at initial diagnosis. Their clinicopathological features and prognosis were evaluated. A logistic regression model was used to examine risk factors for the occurrence of concomitant RCC and UC, and Kaplan-Meier survival curves were used to estimate overall survival. Results A total of 61,454 RCC patients were identified from the SEER database, 704 (1.1%) patients presented with synchronous RCC and UC. Among these patients, concurrent bladder tumors (566/704) are more common. Subsequently, subgroup analysis based on the location of UC indicated that patients with concurrent RCC and upper tract urothelial carcinoma (UTUC) had unfavorable UC characteristics (higher tumor stage and grade), compared with patients with concomitant bladder cancer. An increased risk of concurrent UC was observed among older age, male sex, and white race. Meanwhile, papillary RCC histology [odds ratio (OR) 3.23; 95% confidence interval (CI) 2.13–4.90], and smaller tumor (OR 6.63; 95% CI 4.46–9.87) were independent risk factors for concomitant UTUC. In addition, we found that synchronous RCC and UTUC was associated with worse survival by using Kaplan-Meier and multivariable analysis [hazard ratio (HR) 2.36, 95% CI 1.89–2.95]. However, concomitant bladder cancer did not affect survival outcomes of patients with RCC (HR 1.00, 95% CI 0.86–1.17). Conclusion We found that synchronous concurrent RCC and UC is relatively uncommon and mostly located in the bladder. Older age, male sex, and white race increase the risk of synchronous RCC and UC. Meanwhile, patients with papillary RCC histology, and smaller tumors are more likely to have concomitant RCC and UTUC. Furthermore, our findings suggest that synchronous RCC and UTUC has a worse prognosis, while, concomitant bladder tumor did not affect the oncological outcomes of RCC.
Modulation of PC1/3 activity by a rare double-site homozygous mutation

Objectives Preprotein convertase 1/3 deficiency is a rare autosomal recessive disorder in which patients present with malabsorptive diarrhea and a series of symptoms of endocrine disorders such as polydipsia, reactive hypoglycemia, growth hormone deficiency, hypothyroidism, adrenal insufficiency, and early onset obesity. In its essence, pituitary hormone deficiency is caused by insufficient cleavage of pituitary prohormones. Here, we describe a female child with a rare double-site homozygous mutation in PCSK1 (Proprotein convertase subtilisin/kexin-type 1) gene, and thereby intend to investigate the relationship between these novel mutation sites and changes in protein synthesis and function. Methods We tested this patient's blood and urine fecal indicators of infection, blood electrolytes, and relevant endocrine hormone levels in the laboratory. Next Generation Sequencing was applied to screen the patient's DNA. Western Blot was performed to evaluate the mutant protein's expression. The enzymatic activity was measured as the rate of cleavage of a synthetic fluorogenic substrate in a specific solution. Results We found that this patient presented shortly after birth with uncorrectable diarrhea and symptoms of metabolic acidosis with hypothyroidism. Next Generation Sequencing revealed that a rare double-site homozygous missense mutation, c.763G > A (p.G255R) and c.758C > T (p.S253L), were detected in exon 7 of PCSK1 (Proprotein convertase subtilisin/kexin-type 1) gene on chromosome 5 of the patient. Western blotting revealed that there was no significant decrease in protein synthesis levels in the mutant phenotype compared to the wild type. Compared with WT type, the proteins expressed by the mutations showed a significant decrease in the enzyme activity towards the fluorescent substrates. However, neither the single site mutation p.S253L or p.G255R, nor the double-site mutation of both, all showed no significant differences from each other. Conclusions These two missense mutations have not been reported before, and it is even rarer to find homozygous variation of two sites in one patient. This study identifies two novel mutations for the first time and further investigates the changes in protein synthesis and enzyme activity, providing a new pathway to continue to explore the pathogenesis of diseases associated with the function of PC1/3.
AIM2 inflammasome activation benefits the therapeutic effect of BCG in bladder carcinoma

A large proportion of bladder cancer (BLCA) patients suffer from malignant progression to life-threatening muscle-invasive bladder cancer (MIBC). Inflammation is a critical event in cancer development, but little is known about the role of inflammation in BLCA. In this study, the expression of the innate immune sensor AIM2 is much lower in high-grade BLCA and positively correlates with the survival rates of the BLCA patients. A novel AIM2 overexpressed BLCA model is proposed to investigate the impact of AIM2 on BLCA development. Mice inoculated with AIM2-overexpressed cells show tumor growth delay and prolonged survival compared to the control group. Meanwhile, CD11b+ cells significantly infiltrate AIM2-overexpressed tumors, and AIM2-overexpression in 5637 cells enhanced the inflammasome activation. In addition, oligodeoxynucleotide (ODN) TTAGGG (A151), an AIM2 inflammasome inhibitor, could abolish the elevation of AIM2-induced cleavage of inflammatory cytokines and pyroptosis. Orthotopic BLCA by AIM2-overexpressed cells exhibits a better response to Bacillus Calmette-Guérin (BCG) immunotherapy. Overall, AIM2 inflammasome activation can inhibit the BLCA tumorigenesis and enhance the therapeutic effect of BCG in BLCA. This study provides new insights into the anti-tumor effect of AIM2 inflammasome activation in BLCA and the immunotherapeutic strategy of BLCA development.
Nucleic acid-sensing toll-like receptors: Important players in Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects the salivary and lacrimal glands, as well as other organ systems like the lungs, kidneys and nervous system. SS can occur alone or in combination with another autoimmune disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. The etiology of SS is unknown but recent studies have revealed the implication of the activation of innate immune receptors, including Toll-like receptors (TLRs), mainly through the detection of endogenous nucleic acids, in the pathogenesis of systemic autoimmune diseases. Studies on SS mouse models suggest that TLRs and especially TLR7 that detects single-stranded RNA of microbial or endogenous origin can drive the development of SS and findings in SS patients corroborate those in mouse models. In this review, we will give an overview of the function and signaling of nucleic acid-sensing TLRs, the interplay of TLR7 with TLR8 and TLR9 in the context of autoimmunity, summarize the evidence for the critical role of TLR7 in the pathogenesis of SS and present a possible connection between SARS-CoV-2 and SS.