VirusRecom: an information-theory-based method for recombination detection of viral lineages and its application on SARS-CoV-2.

Genomic recombination is an important driving force for viral evolution, and recombination events have been reported for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the Coronavirus Disease 2019 pandemic, which significantly alter viral infectivity and transmissibility. However, it is difficult to identify viral recombination, especially for low-divergence viruses such as SARS-CoV-2, since it is hard to distinguish recombination from in situ mutation. Herein, we applied information theory to viral recombination analysis and developed VirusRecom, a program for efficiently screening recombination events on viral genome. In principle, we considered a recombination event as a transmission process of ``information'' and introduced weighted information content (WIC) to quantify the contribution of recombination to a certain region on viral genome; then, we identified the recombination regions by comparing WICs of different regions. In the benchmark using simulated data, VirusRecom showed a good balance between precision and recall compared to two competing tools, RDP5 and 3SEQ. In the detection of SARS-CoV-2 XE, XD and XF recombinants, VirusRecom providing more accurate positions of recombination regions than RDP5 and 3SEQ. In addition, we encapsulated the VirusRecom program into a command-line-interface software for convenient operation by users. In summary, we developed a novel approach based on information theory to identify viral recombination within highly similar sequences, providing a useful tool for monitoring viral evolution and epidemic control.

A Bioinspired Gradient Design Strategy for Cellulose-Based Electromagnetic Wave Absorbing Structural Materials.

Cellulose nanofiber (CNF) possesses excellent intrinsic properties, and many CNF-based high-performance structural and functional materials have been developed recently. However, the coordination of the mechanical properties and functionality is still a considerable challenge. Here, a CNF-based structural material is developed by a bioinspired gradient structure design using hollow magnetite nanoparticles and the phosphorylation-modified CNF as building blocks, which simultaneously achieves a superior mechanical performance and electromagnetic wave absorption (EMA) ability. Benefiting from the gradient design, the flexural strength of the structural material reached ∼205 MPa. Meanwhile, gradient design improves impedance matching, contributing to the high EMA ability (-59.5 dB) and wide effective absorption width (5.20 GHz). Besides, a low coefficient of thermal expansion and stable storage modulus was demonstrated as the temperature changes. The excellent mechanical, thermal, and EMA performance exhibited great potential for application in stealth equipment and electromagnetic interference protecting electronic packaging materials.

vsRNAfinder: a novel method for identifying high-confidence viral small RNAs from small RNA-Seq data.

Virus-encoded small RNAs (vsRNA) have been reported to play an important role in viral infection. Unfortunately, there is still a lack of an effective method for vsRNA identification. Herein, we presented vsRNAfinder, a de novo method for identifying high-confidence vsRNAs from small RNA-Seq (sRNA-Seq) data based on peak calling and Poisson distribution and is publicly available at https://github.com/ZenaCai/vsRNAfinder. vsRNAfinder outperformed two widely used methods namely miRDeep2 and ShortStack in identifying viral miRNAs with a significantly improved sensitivity. It can also be used to identify sRNAs in animals and plants with similar performance to miRDeep2 and ShortStack. vsRNAfinder would greatly facilitate effective identification of vsRNAs from sRNA-Seq data.

Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

Probiotic Clostridium butyricum ameliorates cognitive impairment in obesity via the microbiota-gut-brain axis.

Obesity is a risk factor for cognitive dysfunction and neurodegenerative disease, including Alzheimer's disease (AD). The gut microbiota-brain axis is altered in obesity and linked to cognitive impairment and neurodegenerative disorders. Here, we targeted obesity-induced cognitive impairment by testing the impact of the probiotic Clostridium butyricum, which has previously shown beneficial effects on gut homeostasis and brain function. Firstly, we characterized and analyzed the gut microbial profiles of participants with obesity and the correlation between gut microbiota and cognitive scores. Then, using an obese mouse model induced by a Western-style diet (high-fat and fiber-deficient diet), the effects of Clostridium butyricum on the microbiota-gut-brain axis and hippocampal cognitive function were evaluated. Finally, fecal microbiota transplantation was performed to assess the functional link between Clostridium butyricum remodeling gut microbiota and hippocampal synaptic protein and cognitive behaviors. Our results showed that participants with obesity had gut microbiota dysbiosis characterized by an increase in phylum Proteobacteria and a decrease in Clostridium butyricum, which were closely associated with cognitive decline. In diet-induced obese mice, oral Clostridium butyricum supplementation significantly alleviated cognitive impairment, attenuated the deficit of hippocampal neurite outgrowth and synaptic ultrastructure, improved hippocampal transcriptome related to synapses and dendrites; a comparison of the effects of Clostridium butyricum in mice against human AD datasets revealed that many of the genes changes in AD were reversed by Clostridium butyricum; concurrently, Clostridium butyricum also prevented gut microbiota dysbiosis, colonic barrier impairment and inflammation, and attenuated endotoxemia. Importantly, fecal microbiota transplantation from donor-obese mice with Clostridium butyricum supplementation facilitated cognitive variables and colonic integrity compared with from donor obese mice, highlighting that Clostridium butyricum's impact on cognitive function is largely due to its ability to remodel gut microbiota. Our findings provide the first insights into the neuroprotective effects of Clostridium butyricum on obesity-associated cognitive impairments and neurodegeneration via the gut microbiota-gut-brain axis.

Overexpression of forebrain PTP1B leads to synaptic and cognitive impairments in obesity.

Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.

First detection of Tetraparvovirus ungulate 1 in diseased cattle (Chinese Simmental) from Hunan province, China.

Tetraparvovirus is an emerging parvovirus infecting a variety of mammals and humans, and associated with human diseases including severe acute respiratory infection and acute encephalitis syndrome. In the present study, a Tetraparvovirus ungulate 1 (formerly known as bovine hokovirus) strain HNU-CBY-2023 was identified and characterized from diseased Chinese Simmental from Hunan province, China. The nearly complete genome of HNU-CBY-2023 is 5346 nt in size and showed genomic identities of 85-95.5% to the known Tetraparvovirus ungulate 1 strains from GenBank, indicating a rather genetic variation. Phylogenetic and genetic divergence analyses indicated that Tetraparvovirus ungulate 1 could be divided into two genotypes (I and II), and HNU-CBY-2023 was clustered into genotype II. This study, for the first time, identified Tetraparvovirus ungulate 1 from domestic cattle from mainland China, which will be helpful to understand the prevalence and genetic diversity of Tetraparvovirus ungulate 1.

Randomized trial comparing the effects of a 3D head-up system and microscope eyepiece-assisted simulated vitrectomy with intraocular illumination on the ocular surface of an operator.

BACKGROUND: To compare the effects of a 3D head-up system and microscope eyepiece-assisted simulated vitrectomy intraocular illumination on the ocular surface of an operator. METHODS: This was a prospective randomized controlled study. According to the application system, thirty ophthalmic operators (60 eyes) were randomly divided into 3D and eyepiece groups. Under different intensities of intraocular illumination, operators in both groups viewed the fundus model through a 3D display screen or microscopic eyepiece for 2 h. Objective examinations and a subjective symptom questionnaire were used immediately after the test to evaluate the ocular surface of the operators. Objective examinations included nonintrusion tear meniscus height (NIKTMH), nonintrusion break-up time (NIKBUT), and bulbar redness and strip meniscometry tube (SMTube) measurements. Statistical analyses were performed by using SPSS 26.0 software. RESULTS: After the test, the NIKTMH, NIKBUT and SMTube measurements decreased; however, the degree of change varied among the groups of different systems. The differences between the 3D group and the eyepiece group in NIKTMH measurements, SMTube measurements, subjective symptom scores (eye dryness, difficulty focusing, and cervical pain), and light intensity reaching the ocular surface of the operators were statistically significant (P < 0.05). All of the objective and subjective tests showed that the 3D group had fewer effects on the NIKTMH and SMTube measurements, and the subjective comfort of the 3D group was greater. CONCLUSION: For both 3D screens and eyepieces, simulated vitrectomy with intraocular illumination for two hours can lead to discomfort and abnormalities in the operator's ocular surface; however, these abnormalities are less severe in the 3D group. TRIAL REGISTRATION: This trial was registered on December 22, 2022, at the Chinese Clinical Trials Registry with NO. ChiCTR2200066989.

Correlation Between the Severity of Coronary Artery Disease and Retinal Artery Disease and the Therapeutic Effect of Captopril.

Objective: Investigate the Correlation Between the Severity of Coronary Artery Disease and Retinal Artery Disease, and assess the Efficacy of Angiotensin-Converting Enzyme Inhibitors (ACEIs) Application. Methods: One hundred patients diagnosed with primary hypertension at our hospital were chosen for the study. All patients underwent dual-source 64-layer spiral CT coronary angiography and fundus photography examination. Based on the extent of coronary artery stenosis, the patients were divided into Group A, Group B, Group C, and Group D. Results: In comparison with patients in Group A, individuals in Groups B, C, and D exhibited a notable increase in the severity of retinal artery stenosis and arteriovenous crossing signs (P < .05). Furthermore, the severity of retinal artery stenosis and arteriovenous crossing signs demonstrated an incremental trend with the severity of coronary artery stenosis (P < .05). The arteriovenous crossing sign exhibited a sensitivity of 47.87%, the specificity of 89.21%, positive predictive value of 89.76%, and the negative predictive value of 46.53% for predicting coronary artery stenosis. After treatment, the blood pressure levels of the patients, both systolic (SBP) and diastolic blood pressure (DBP) levels significantly decreased compared to before treatment. Conclusion: A significant positive correlation was observed between the severity of coronary artery lesions and retinal artery lesions. Assessing alterations in retinal blood vessels in hypertensive patients can effectively indicate the extent of coronary artery stenosis indirectly. Concerning medication, the antihypertensive drug captopril demonstrated the potential to alleviate the severity of coronary artery and retinal artery lesions in hypertensive patients. However, specific treatment methods should be tailored to individual patient circumstances.

Key mutations on spike protein altering ACE2 receptor utilization and potentially expanding host range of emerging SARS-CoV-2 variants.

Increasing evidence supports inter-species transmission of SARS-CoV-2 variants from humans to domestic or wild animals during the ongoing COVID-19 pandemic, which is posing great challenges to epidemic control. Clarifying the host range of emerging SARS-CoV-2 variants will provide instructive information for the containment of viral spillover. The spike protein (S) of SARS-CoV-2 is the key determinant of receptor utilization, and therefore amino acid mutations on S will probably alter viral host range. Here, to evaluate the impact of S mutations, we tested 27 pseudoviruses of SARS-CoV-2 carrying different spike mutants by infecting Hela cells expressing different angiotensin-converting enzyme 2 (ACE2) orthologs from 20 animals. Of these 27 pseudoviruses, 20 bear single mutation and the other 7 were cloned from emerging SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (B.1.429), and Mu (B.1.621). Using pseudoviral reporter assay, we identified that the substitutions of T478I and N501Y enabled the pseudovirus to utilize chicken ACE2, indicating potential infectivity to avian species. Furthermore, the S mutants of real SARS-CoV-2 variants comprising N501Y showed significantly acquired abilities to infect cells expressing mouse ACE2, indicating a critical role of N501Y in expanding SARS-CoV-2 host range. In addition, A262S and T478I significantly enhanced the utilization of various mammal ACE2. In summary, our results indicated that T478I and N501Y substitutions were two S mutations important for receptor adaption of SARS-CoV-2, potentially contributing to the spillover of the virus to many other animal hosts. Therefore, more attention should be paid to SARS-CoV-2 variants with these two mutations.

Key mutations in the spike protein of SARS-CoV-2 affecting neutralization resistance and viral internalization.

To control the ongoing COVID-19 pandemic, a variety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been developed. However, the rapid mutations of SARS-CoV-2 spike (S) protein may reduce the protective efficacy of the existing vaccines which is mainly determined by the level of neutralizing antibodies targeting S. In this study, we screened prevalent S mutations and constructed 124 pseudotyped lentiviral particles carrying these mutants. We challenged these pseudoviruses with sera vaccinated by Sinovac CoronaVac and ZF2001 vaccines, two popular vaccines designed for the initial strain of SARS-CoV-2, and then systematically assessed the susceptivity of these SARS-CoV-2 variants to the immune sera of vaccines. As a result, 14 S mutants (H146Y, V320I + S477N, V382L, K444R, L455F + S477N, L452M + F486L, F486L, Y508H, P521R, A626S, S477N + S698L, A701V, S477N + T778I, E1144Q) were found to be significantly resistant to neutralization, indicating reduced protective efficacy of the vaccines against these SARS-CoV-2 variants. In addition, F486L and Y508H significantly enhanced the utilization of human angiotensin-converting enzyme 2, suggesting a potentially elevated infectivity of these two mutants. In conclusion, our results show that some prevalent S mutations of SARS-CoV-2 reduced the protective efficacy of current vaccines and enhance the infectivity of the virus, indicating the necessity of vaccine renewal and providing direction for the development of new vaccines.

Atomically Precise Metal Nanocluster Photosystem: Electron Relay Boosts Photocatalytic Organic Transformation.

Atomically precise metal nanoclusters (NCs) demonstrate emerging potential as a new generation of photosensitizers in photoredox catalysis. However, metal NCs suffer from intrinsic poor instability, which leads to the loss of photosensitization effect and hampers their widespread applications in heterogeneous photocatalysis. Herein, we corroborate the design of a spatially directional charge transfer pathway over transition metal chalcogenide (TMC)-based heterostructures by way of a facile and efficient electrostatic self-assembly approach. Positively charged solid-state nonconjugated insulating polymer of poly(allylamine hydrochloride) (PAH) and negatively charged glutathione (GSH) capped metal NCs [Ag9@(GSH)6] as building blocks were controllably and highly ordered anchored on the TMC substrate. It was unveiled that owing to the appropriate energy level alignment and interface configuration, photogenerated electrons over metal NCs can directionally flow to the TMC substrate with the aid of PAH, which functions as an interfacial charge transfer mediator, and simultaneously holes migrate in the opposite direction, thereby collaboratively contributing to substantially boosted charge separation and prolonged charge lifetime. Benefiting from these merits, the thus self-assembled TMCs/PAH/metal NC heterostructure unfolds conspicuously enhanced photoactivity toward anaerobic selective photocatalytic reduction of nitroaromatics to amino derivatives under visible light irradiation. This work would significantly reinforce our fundamental understanding of the charge transfer characteristic of atomically precise metal NCs and the charge-withdrawing capability of solid insulating polymers for solar energy conversion.

Alloy Metal Nanocluster: A Robust and Stable Photosensitizer for Steering Solar Water Oxidation.

Metal nanoclusters (NCs) have been unleashed as an emerging category of metal materials by virtue of integrated merits including the unusual atom-stacking mode, quantum confinement effect, and fruitful catalytically active sites. Nonetheless, development of metal NCs as photosensitizers is blocked by light-induced instability and ultrashort carrier lifespan, which remarkably retards the design of metal NC-involved photosystems, hence resulting in the decreased photoactivities. To solve these obstacles, herein, we conceptually probed the charge transfer characteristics of the BiVO4 photoanode photosensitized by atomically precise alloy metal NCs, wherein tailor-made l-glutathione-capped gold-silver bimetallic (AuAg) NCs were controllably self-assembled on the BiVO4 substrate. It was uncovered that alien Ag atom doping is able to effectively stabilize the alloy AuAg NCs and simultaneously photosensitize the BiVO4 photoanode, significantly boosting the photoelectrochemical (PEC) water oxidation performances. The reasons for the robust and stable PEC water oxidation activities of the AuAg NCs/BiVO4 composite photoanode were unambiguously unleashed. We ascertain that Ag atom doping in the staple motif of Aux NCs efficaciously protects the NCs from rapid oxidation, enhancing the photostability, boosting the photosensitization efficiency, and thus leading to the considerably improved PEC water splitting activities compared with the homometallic counterpart. This work could afford a new strategy to judiciously tackle the inherent detrimental instability of metal NCs for solar energy conversion.

Assessment of Color Reproducibility and Mitigation of Color Variation in Whole Slide Image Scanners for Toxicologic Pathology.

Digital pathology workflows in toxicologic pathology rely on whole slide images (WSIs) from histopathology slides. Inconsistent color reproduction by WSI scanners of different models and from different manufacturers can result in different color representations and inter-scanner color variation in the WSIs. Although pathologists can accommodate a range of color variation during their evaluation of WSIs, color variability can degrade the performance of computational applications in digital pathology. In particular, color variability can compromise the generalization of artificial intelligence applications to large volumes of data from diverse sources. To address these challenges, we developed a process that includes two modules: (1) assessing the color reproducibility of our scanners and the color variation among them and (2) applying color correction to WSIs to minimize the color deviation and variation. Our process ensures consistent color reproduction across WSI scanners and enhances color homogeneity in WSIs, and its flexibility enables easy integration as a post-processing step following scanning by WSI scanners of different models and from different manufacturers.

Steering Photocatalytic CO2 Conversion over CsPbBr3 Perovskite Nanocrystals by Coupling with Transition-Metal Chalcogenides.

Transition-metal chalcogenides (TMCs) have received enormous attention by virtue of their large light absorption coefficient, abundant catalytically active sites, and markedly reduced spatially vectorial charge-transfer distance originating from generic structural merits. However, the controllable construction of TMC-based heterostructured photosystems for photocatalytic carbon dioxide (CO2) reduction is retarded by the ultrashort charge lifetime, sluggish charge-transfer kinetics, and low target product selectivity. Herein, we present the rational design of two-dimensional (2D)/zero-dimensional (0D) heterostructured CO2 reduction photosystems by an electrostatic self-assembly strategy, which is enabled by precisely anchoring CsPbBr3 quantum dots (QDs) on the 2D TMC (CdIn2S4, ZnIn2S4, In2S3) frameworks. The peculiar 2D/0D integration mode and suitable energy-level alignment between these two assembly units afford maximal interfacial contact and applicable potential for CO2 photoreduction, thus endowing the self-assembled TMCs/CsPbBr3 nanocomposites with considerably improved visible-light-driven photocatalytic performances toward CO2 reduction to carbon monoxide with high selectivity. The enhanced photocatalytic performances of TMCs/CsPbBr3 heterostructures are attributed to the abundant active sites on the TMC frameworks, excellent light absorption of CsPbBr3 QDs, and well-defined 2D/0D heterostructures of TMCs/CsPbBr3 QDs photosystems, which synergistically boosts the directional charge transport from CsPbBr3 QDs to TMCs, enhancing the interfacial charge migration/separation. Our work would inspire the construction of novel TMCs-involved photosystems for solar-to-fuel conversion.

Atomically Precise Metal Nanoclusters versus Metal Nanocrystals: Maneuvering Tunable Charge Transfer in an Integrated Photosystem.

Atomically precise metal nanoclusters (NCs) have recently emerged as a promising sector of metal nanomaterials in terms of peculiar atomic stacking fashion, quantum confinement effect, and enriched catalytically active sites, which are wholly distinct from conventional metal nanocrystals (NYs) in all respects. However, atomically precise metal NCs inevitably suffer from intrinsic poor instability either under light irradiation or thermal treatment owing to the ultrahigh surface energy, thereby resulting in substantial loss of photosensitization efficiency and retarding their emerging utilization in photoredox catalysis. Here, we first conceptually reveal the charge transfer characteristic difference between atomically precise metal NCs and metal NYs attained by self-transformation in boosting interfacial charge migration and separation. The results signify that the interfacial charge transfer impetus of atomically precise metal NCs as a photosensitizer versus metal NYs as a Schottky-type electron-withdrawing mediator is closely associated with the loading amount on the semiconductor substrate. The photosensitization effect of atomically precise metal NCs is superior to the electron trapping capability of metal NYs when the loading amount of the metal ingredient is relatively high and vice versa. Our work would significantly bridge the gap between atomically precise metal NCs and metal NYs in fine tuning of the charge transfer pathway in photocatalysis toward solar energy conversion.

Cholinergic modulation of persistent inward currents is mediated by activating muscarinic receptors of serotonergic neurons in the brainstem of ePet-EYFP mice.

Persistent inward currents (PICs) play important roles in regulating neural excitability. Results from our previous studies showed that serotonergic (5-HT) neurons of the brainstem expressed PICs. However, little is known about cholinergic (ACh) modulation of PICs in the 5-HT neurons. The whole-cell patch-clamp recordings were performed in the brainstem slices of ePet-EYFP mice to investigate the electrophysiological properties of PICs with cholinergic modulation. PICs in 5-HT neurons were activated at - 51.4 ± 3.7 mV with the amplitude of - 171.6 ± 48.9 pA (n = 71). Bath application of 20-25 µM ACh increased the amplitude by 79.1 ± 42.5 pA (n = 23, p < 0.001) and hyperpolarized the onset voltage by 2.2 ± 2.7 mV (n = 23, p < 0.01) and half-maximal activation by 3.6 ± 2.7 mV (n = 6, p < 0.01). Muscarine mimicked the effects of ACh on PICs, while bath application of nicotine (15-20 µM) did not induce substantial change in the PICs (n = 9). Muscarine enhanced the amplitude of PICs by 100.0 ± 27.4 pA (n = 28, p < 0.001) and lowered the onset voltage by 2.8 ± 1.2 mV (n = 28, p < 0.001) and the half-maximal activation by 2.9 ± 1.4 mV. ACh-induced increase of amplitude and hyperpolarization of onset voltage were blocked by 3-5 µM atropine. Furthermore, the muscarine-induced enhancement of the PICs was antagonized by 5 µM 4-DAMP, the antagonist of M3 receptor, while the antagonists of M1 (Telenzepine, 5 µM) and M5 (VU6008667, 5 µM) receptors did not significantly affect the PIC enhancement. This study suggested that ACh potentiated PICs in 5-HT neurons of the brainstem by activating muscarinic M3 receptor.

Toxicologic Pathology Forum: A Roadmap for Building State-of-the-Art Digital Image Data Resources for Toxicologic Pathology in the Pharmaceutical Industry.

Digitization of histologic slides brings with it the promise of enhanced toxicologic pathology practice through the increased application of computational methods. However, the development of these advanced methods requires access to substrate image data, that is, whole slide images (WSIs). Deep learning methods, in particular, rely on extensive training data to develop robust algorithms. As a result, pharmaceutical companies interested in leveraging computational methods in their digital pathology workflows must first invest in data infrastructure to enable data access for both data scientists and pathologists. The process of building robust image data resources is challenging and includes considerations of generation, curation, and storage of WSI files, and WSI access including via linked metadata. This opinion piece describes the collective experience of building resources for WSI data in the Roche group. We elaborate on the challenges encountered and solutions developed with the goal of providing examples of how to build a data resource for digital pathology analytics in the pharmaceutical industry.

ß-Glucan from Lentinula edodes prevents cognitive impairments in high-fat diet-induced obese mice: involvement of colon-brain axis.

BACKGROUND: Long-term high fat (HF) diet intake can cause neuroinflammation and cognitive decline through the gut-brain axis. (1, 3)/(1, 6)-ß-glucan, an edible polysaccharide isolated from medical mushroom, Lentinula edodes (L. edodes), has the potential to remodel gut microbiota. However, the effects of L. edodes derived ß-glucan against HF diet-induced neuroinflammation and cognitive decline remain unknown. This study aimed to evaluate the neuroprotective effect and mechanism of dietary L edodes ß-glucan supplementation against the obesity-associated cognitive decline in mice fed by a HF diet. METHODS: C57BL/6J male mice were fed with either a lab chow (LC), HF or HF with L. edodes ß-glucan supplementation diets for 7 days (short-term) or 15 weeks (long-term). Cognitive behavior was examined; blood, cecum content, colon and brain were collected to evaluate metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. RESULTS: We reported that short-term and long-term L. edodes ß-glucan supplementation prevented the gut microbial composition shift induced by the HF diet. Long-term L. edodes ß-glucan supplementation prevented the HF diet-induced recognition memory impairment assessed by behavioral tests (the temporal order memory, novel object recognition and Y-maze tests). In the prefrontal cortex and hippocampus, the ß-glucan supplementation ameliorated the alteration of synaptic ultrastructure, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits induced by HF diet. Furthermore, the ß-glucan supplementation increased the mucosal thickness, upregulated the expression of tight junction protein occludin, decreased the plasma LPS level, and inhibited the proinflammatory macrophage accumulation in the colon of mice fed by HF diet. CONCLUSIONS: This study revealed that L. edodes ß-glucan prevents cognitive impairments induced by the HF diet, which may occur via colon-brain axis improvement. The finding suggested that dietary L. edodes ß-glucan supplementation may be an effective nutritional strategy to prevent obesity-associated cognitive decline.

Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1.

Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.