Molecular insights into the adaptive evolution of SARS-CoV-2 spike protein.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially damaged the global economy and human health. The spike (S) protein of coronaviruses plays a pivotal role in viral entry by binding to host cell receptors. Additionally, it acts as the primary target for neutralizing antibodies in those infected and is the central focus for currently utilized or researched vaccines. During the virus's adaptation to the human host, the S protein of SARS-CoV-2 has undergone significant evolution. As the COVID-19 pandemic has unfolded, new mutations have arisen and vanished, giving rise to distinctive amino acid profiles within variant of concern strains of SARS-CoV-2. Notably, many of these changes in the S protein have been positively selected, leading to substantial alterations in viral characteristics, such as heightened transmissibility and immune evasion capabilities. This review aims to provide an overview of our current understanding of the structural implications associated with key amino acid changes in the S protein of SARS-CoV-2. These research findings shed light on the intricate and dynamic nature of viral evolution, underscoring the importance of continuous monitoring and analysis of viral genomes. Through these molecular-level investigations, we can attain deeper insights into the virus's adaptive evolution, offering valuable guidance for designing vaccines and developing antiviral drugs to combat the ever-evolving viral threats.

Dihydroartemisinin abolishes cisplatin-induced nephrotoxicity in vivo.

Dihydroartemisinin (DHA), a derivative of artemisinin which is primarily used to treat malaria in clinic, also confers protective effect on lipopolysaccharide-induced nephrotoxicity. While, the activities of DHA in cisplatin (CDDP)-caused nephrotoxicity are elusive. To investigate the role and underlying mechanism of DHA in CDDP-induced nephrotoxicity. Mice were randomly separated into four groups: normal, CDDP, and DHA (25 and 50 mg/kg were orally injected 1 h before CDDP for consecutive 10 days). All mice except the normal were single injected intraperitoneally with CDDP (22 mg/kg) for once on the 7th day. Combined with quantitative proteomics and bioinformatics analysis, the impact of DHA on renal cell apoptosis, oxidative stress, biochemical indexes, and inflammation in mice were investigated. Moreover, a human hepatocellular carcinoma cells xenograft model was established to elucidate the impact of DHA on tumor-related effects of CDDP. DHA reduced the levels of creatinine (CREA) (p < 0.01) and blood urea nitrogen (BUN) (p < 0.01), reversed CDDP-induced oxidative, inflammatory, and apoptosis indexes (p < 0.01). Mechanistically, DHA attenuated CDDP-induced inflammation by inhibiting nuclear factor κB p65 (NFκB p65) expression, and suppressed CDDP-induced renal cell apoptosis by inhibiting p63-mediated endogenous and exogenous apoptosis pathways. Additionally, DHA alone significantly decreased the tumor weight and did not destroy the antitumor effect of CDDP, and did not impact AST and ALT. In conclusion, DHA prevents CDDP-triggered nephrotoxicity via reducing inflammation, oxidative stress, and apoptosis. The mechanisms refer to inhibiting NFκB p65-regulated inflammation and alleviating p63-mediated mitochondrial endogenous and Fas death receptor exogenous apoptosis pathway.

Heterogeneity of mesencephalic dopaminergic neurons: From molecular classifications, electrophysiological properties to functional connectivity.

The mesencephalic dopamine (DA) system is composed of neuronal subtypes that are molecularly and functionally distinct, are responsible for specific behaviors, and are closely associated with numerous brain disorders. Existing research has made significant advances in identifying the heterogeneity of mesencephalic DA neurons, which is necessary for understanding their diverse physiological functions and disease susceptibility. Moreover, there is a conflict regarding the electrophysiological properties of the distinct subsets of midbrain DA neurons. This review aimed to elucidate recent developments in the heterogeneity of midbrain DA neurons, including subpopulation categorization, electrophysiological characteristics, and functional connectivity to provide new strategies for accurately identifying distinct subtypes of midbrain DA neurons and investigating the underlying mechanisms of these neurons in various diseases.

Performance optimization for Pb(II) -containing wastewater treatment in constructed wetland-microbial fuel cell triggered by biomass dosage and Pb(II) level.

Three identical sets of constructed wetland-microbial fuel cells (CW-MFCs) fabricated with biomass carbon source addition were constructed and underwent the short- and long-term experiments. For this, the efficacy of biomass dosage and Pb(II) concentration towards Pb(II) removal and concurrent bioelectricity production of CW-MFCs were systematically explored. From the perspective of integrated capabilities and economic benefits, the solid biomass carbon sources equivalent to 500 mg/L COD was regarded as the optimal dosage, and the corresponding device was labeled as CW-MFC-2. For the short-term experiment, the closed-circuit CW-MFC-2 produced maximum output voltages and power densities in a range of 386-657 mV and 1.55 × 103-6.31 × 103 mW/m2 with the increasing Pb(II) level, respectively. Also, Pb(II) removal up to 94.4-99.6% was obtained in CW-MFC-2. With respect to long-term experiment, Pb(II) removal, the maximum output voltage, and power density of CW-MFC-2 ranged from 98.7 to 99.2%, 322 to 387 mV, and 3.28 × 102 to 2.26 × 103 mW/m2 upon 200 mg/L Pb(II) level, respectively. The migration results confirmed the potential of substrate and biomass for Pb(II) adsorption and fixation. For the cathode, Pb(II) was fixed and removed via binding to O. This study enlarges our knowledge of effective modulation of CW-MFCs for the treatment of high-level Pb(II)-containing wastewater and bioelectricity generation via adopting desirable biomass dosage.

Convergent and divergent evolution of microRNA-mediated regulation in metazoans.

The evolution of microRNAs (miRNAs) has been studied extensively to understand their roles in gene regulation and evolutionary processes. This review focuses on how miRNA-mediated regulation has evolved in bilaterian animals, highlighting both convergent and divergent evolution. Since animals and plants display significant differences in miRNA biogenesis and target recognition, the 'independent origin' hypothesis proposes that miRNA pathways in these groups independently evolved from the RNA interference (RNAi) pathway, leading to modern miRNA repertoires through convergent evolution. However, recent evidence raises the alternative possibility that the miRNA pathway might have already existed in the last common ancestor of eukaryotes, and that the differences in miRNA pathway and miRNA repertoires among animal and plant lineages arise from lineage-specific innovations and losses of miRNA pathways, miRNA acquisition, and loss of miRNAs after eukaryotic divergence. The repertoire of miRNAs has considerably expanded during bilaterian evolution, primarily through de novo creation and duplication processes, generating new miRNAs. Although ancient functionally established miRNAs are rarely lost, many newly emerged miRNAs are transient and lineage specific, following a birth-death evolutionary pattern aligning with the 'out-of-the-testis' and 'transcriptional control' hypotheses. Our focus then shifts to the convergent molecular evolution of miRNAs. We summarize how miRNA clustering and seed mimicry contribute to this phenomenon, and we review how miRNAs from different sources converge to degrade maternal messenger RNAs (mRNAs) during animal development. Additionally, we describe how miRNAs evolve across species due to changes in sequence, seed shifting, arm switching, and spatiotemporal expression patterns, which can result in variations in target sites among orthologous miRNAs across distant strains or species. We also provide a summary of the current understanding regarding how the target sites of orthologous miRNAs can vary across strains or distantly related species. Although many paralogous miRNAs retain their seed or mature sequences after duplication, alterations can occur in the seed or mature sequences or expression patterns of paralogous miRNAs, leading to functional diversification. We discuss our current understanding of the functional divergence between duplicated miRNAs, and illustrate how the functional diversification of duplicated miRNAs impacts target site evolution. By investigating these topics, we aim to enhance our current understanding of the functions and evolutionary dynamics of miRNAs. Additionally, we shed light on the existing challenges in miRNA evolutionary studies, particularly the complexity of deciphering the role of miRNA-mediated regulatory network evolution in shaping gene expression divergence and phenotypic differences among species.

Serum alpha-fetoprotein level is correlated with the level of inflammatory markers in the immune-clearance phase of chronic hepatitis B in Eastern China.

PURPOSE: To clarify the association of serum alpha-fetoprotein (AFP) with inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α in patients with chronic hepatitis B (CHB) during the immune-clearance phase in Eastern China. METHODS: This research selected 60 CHB patients during the immune clearance phase who tested positive for AFP, including 32 cases treated by non-antiviral therapy (experimental group) and 28 cases treated by antiviral therapy (positive control group). Another 30 cases tested negative for AFP were set as a negative control group. The correlations of serum AFP with IL-6 and TNF-α in patients were analyzed. RESULTS: HBV DNA clearance in patients receiving antiviral therapy, in both the positive or negative control groups, was not significantly related to other clinical data. In the experimental group, a positive correlation of HBV DNA clearance with serum AFP level (r=0.5126, P=0.0027), alanine aminotransferase (r=0.3924, P=0.0263), and total bilirubin (r=0.5126, P=0.0027) was found. The experimental and positive control groups exhibited elevated serum IL-6 and TNF-α contents versus the negative control group (P<0.05). A positive association of AFP with IL-6 and TNF-α was also identified. CONCLUSION: Serum AFP level is positively related to IL-6 and TNF-α levels in CHB patients during the immune-clearance phase.

Spatial database of planted forests in East Asia.

Planted forests are critical to climate change mitigation and constitute a major supplier of timber/non-timber products and other ecosystem services. Globally, approximately 36% of planted forest area is located in East Asia. However, reliable records of the geographic distribution and tree species composition of these planted forests remain very limited. Here, based on extensive in situ and remote sensing data, as well as an ensemble modeling approach, we present the first spatial database of planted forests for East Asia, which consists of maps of the geographic distribution of planted forests and associated dominant tree genera. Of the predicted planted forest areas in East Asia (948,863 km2), China contributed 87%, most of which is located in the lowland tropical/subtropical regions, and Sichuan Basin. With 95% accuracy and an F1 score of 0.77, our spatially-continuous maps of planted forests enable accurate quantification of the role of planted forests in climate change mitigation. Our findings inform effective decision-making in forest conservation, management, and global restoration projects.

Optimization and Deoptimization of Codons in SARS-CoV-2 and Related Implications for Vaccine Development.

The spread of coronavirus disease 2019 (COVID-19), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), has progressed into a global pandemic. To date, thousands of genetic variants have been identified among SARS-CoV-2 isolates collected from patients. Sequence analysis reveals that the codon adaptation index (CAI) values of viral sequences have decreased over time but with occasional fluctuations. Through evolution modeling, it is found that this phenomenon may result from the virus's mutation preference during transmission. Using dual-luciferase assays, it is further discovered that the deoptimization of codons in the viral sequence may weaken protein expression during virus evolution, indicating that codon usage may play an important role in virus fitness. Finally, given the importance of codon usage in protein expression and particularly for mRNA vaccines, it is designed several codon-optimized Omicron BA.2.12.1, BA.4/5, and XBB.1.5 spike mRNA vaccine candidates and experimentally validated their high levels of expression. This study highlights the importance of codon usage in virus evolution and provides guidelines for codon optimization in mRNA and DNA vaccine development.

Reducing spatial resolution increased net primary productivity prediction of terrestrial ecosystems: A Random Forest approach.

Net primary production (NPP) is a pivotal component of the terrestrial carbon dynamic, as it directly contributes to the sequestration of atmospheric carbon by vegetation. However, significant variations and uncertainties persist in both the total amount and spatiotemporal patterns of terrestrial NPP, primarily stemming from discrepancies among datasets, modeling approaches, and spatial resolutions. In order to assess the influence of different spatial resolutions on global NPP, we employed a random forest (RF) model using a global observational dataset to predict NPP at 0.05°, 0.25°, and 0.5° resolutions. Our results showed that (1) the RF model performed satisfactorily with modeling efficiencies of 0.53-0.55 for the three respective resolutions; (2) NPP exhibited similar spatial patterns and interannual variation trends at different resolutions; (3) intriguingly, total global NPP varied greatly across different spatial resolutions, amounting 57.3 ± 3.07 for 0.05°, 61.46 ± 3.27 for 0.25°, and 66.5 ± 3.42 Pg C yr-1 for 0.5°. Such differences may be associated with the resolution transformation of the input variables when resampling from finer to coarser resolution, which significantly increased the spatial and temporal variation characteristics, particularly in regions within the southern hemisphere such as Africa, South America, and Australia. Therefore, our study introduces a new concept emphasizing the importance of selecting an appropriate spatial resolution when modeling carbon fluxes, with potential applications in establishing benchmarks for global biogeochemical models.

Clinical and Radiologic Features Among Children With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Myelitis.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) often manifests as optic neuritis, transverse myelitis(TM), and acute disseminated encephalomyelitis. Patients with a TM phenotype are at high risk for neurological sequelae, so recognizing the characteristics of MOG-IgG myelitis is essential for early, accurate diagnosis and treatment. METHODS: This was a single-center retrospective study. Pediatric MOG antibody-associated disease patients who had clinical myelitis were recruited for this study. Data on clinical and radiologic features and outcomes were retrospectively collected. RESULTS: Thirty-four patients (age range: 6 months to 13 years; median age, 7 years; female, 16) were enrolled in this study. As one patient had two clinical episodes of myelitis, 35 episodes were included. Isolated transverse myelitis was the initial manifestation in 28 (82%) patients. The most frequent clinical features of MOG-IgG myelitis were weakness and neurogenic bladder, and 80% were better than wheelchair-dependent at the nadir. There was a high presentation of weakness (91%), bowel/bladder dysfunction (63%), and sensory dysfunction (46%), and 80% were better than wheelchair-dependent at the nadir. In addition, seven patients (20%) had radicular pain, and six had flaccid areflexia. Magnetic resonance imaging features were often longitudinally extensive (63%) and prominently involved gray matter (H-sign) (63%), accompanied by leptomeningeal enhancement (4/14.29%) and spinal root enhancement (6/14.43%). At the final follow-up (median, 28 months; range, 8-109 months), 10 patients (29%) had developed one or more relapses, spinal cord lesions resolved entirely in 11 of 22 children (50%), and none had appreciable spinal cord atrophy. At the final follow-up, most patients had favorable outcomes, with median (interquartile range) Expanded Disability Status Scale scores of 0 (range, 0-2), four patients (12%) had sphincter dysfunction, and one patient had gait problems. CONCLUSIONS: Pediatric MOG-IgG myelitis clinically presents with weakness and bowel and bladder dysfunctions. Prominent involvement of the gray matter, leptomeningeal enhancement, and spinal root enhancement are common in pediatric MOG-IgG myelitis.

CT and MRI Features of Hairy Polyps in Neonates and Infants: A Retrospective Study of 14 Patients.

BACKGROUND: The typical imaging findings of hairy polyps have been described mostly in case reports. This study was conducted to describe the CT and MRI features of hairy polyps and their common associated abnormalities. METHODS: Medical records of 14 patients with pathological diagnosis of hairy polyps were collected for this study. For each patient, the medical records, including demographics, clinical manifestations, and imaging findings were reviewed. RESULTS: The female-to-male ratio was 3.7:1. The age at first episode varied from birth to 2.7 years. The masses were derived from the back side of the soft palate in seven (50.0%) cases, from the lateral pharyngeal wall in four (28.6%) cases, from the soft palate in one (7.1%) case, from the nasal vestibule in one (7.1%) case, and from the parapharyngeal space in one (7.1%) case. A total of 11 (78.6%) cases presented with pedicled masses containing fat and a central core of soft tissue, there were 3 (21.4%) cases whose imaging findings were atypical, and there were 6 (42.9%) patients who had other pathologies. CONCLUSIONS: Hairy polyps typically presented as pedicled masses containing fat and a central core of soft tissue, but sometimes their imaging findings can be atypical and they can be associated with other congenital abnormalities. CT and MRI are reliable methods for the diagnosis of hairy polyps and their associated abnormalities.

Adaptive Evolution of the Spike Protein in Coronaviruses.

Coronaviruses are single-stranded, positive-sense RNA viruses that can infect many mammal and avian species. The Spike (S) protein of coronaviruses binds to a receptor on the host cell surface to promote viral entry. The interactions between the S proteins of coronaviruses and receptors of host cells are extraordinarily complex, with coronaviruses from different genera being able to recognize the same receptor and coronaviruses from the same genus able to bind distinct receptors. As the coronavirus disease 2019 pandemic has developed, many changes in the S protein have been under positive selection by altering the receptor-binding affinity, reducing antibody neutralization activities, or affecting T-cell responses. It is intriguing to determine whether the selection pressure on the S gene differs between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses due to the host shift from nonhuman animals to humans. Here, we show that the S gene, particularly the S1 region, has experienced positive selection in both SARS-CoV-2 and other coronaviruses. Although the S1 N-terminal domain exhibits signals of positive selection in the pairwise comparisons in all four coronavirus genera, positive selection is primarily detected in the S1 C-terminal domain (the receptor-binding domain) in the ongoing evolution of SARS-CoV-2, possibly owing to the change in host settings and the widespread natural infection and SARS-CoV-2 vaccination in humans.

Whether the Subacute MPTP-Treated Mouse is as Suitable as a Classic Model of Parkinsonism.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model is one of the most common animal models for Parkinson's disease (PD). It is classified into three types: acute, subacute, and chronic intoxication models. The subacute model has attracted much attention for its short period and similarity to PD. However, whether subacute MPTP intoxication in mouse mimics the movement and cognitive disorders of PD still remains highly controversial. Therefore, the present study reassessed the behavioral performances of subacute MPTP intoxication in mice using open field, rotarod, Y maze,  and gait analysis at different time points (1, 7, 14, and 21 days) after modeling. Results of the current study showed that although MPTP-treated mice using subacute regimen showed severe dopaminergic neuronal loss and evident astrogliosis, they failed to display significant motor and cognitive deficits. Besides, expression of mixed lineage kinase domain-like (MLKL), a marker of necroptosis, was also significantly increased in the ventral midbrain and striatum of MPTP-intoxicated mice. This evidently implies that necroptosis may play an important role in MPTP-induced neurodegeneration. In conclusion, the findings of the present study suggest that subacute MPTP-intoxicated mice may not be a suitable model for studying parkinsonism. However, it can help in revealing the early pathophysiology of PD and studying the compensatory mechanisms which occur in early PD that prevent the emergence of behavioral deficits.

Controls and variability of soil respiration temperature sensitivity across China.

Understanding the temperature sensitivity (Q10) of soil respiration is critical for benchmarking the potential intensity of regional and global terrestrial soil carbon fluxes-climate feedbacks. Although field observations have demonstrated the strong spatial heterogeneity of Q10, a significant knowledge gap still exists regarding to the factors driving spatial and temporal variabilities of Q10 at regional scales. Therefore, we used a machine learning approach to predict Q10 from 1994 to 2016 with a spatial resolution of 1 km across China from 515 field observations at 5 cm soil depth using climate, soil and vegetation variables. Predicted Q10 varied from 1.54 to 4.17, with an area-weighted average of 2.52. There was no significant temporal trend for Q10 (p = 0.32), but annual vegetation production (indicated by normalized difference vegetation index, NDVI) was positively correlated to it (p < 0.01). Spatially, soil organic carbon (SOC) was the most important driving factor in 62 % of the land area across China, and varied greatly, demonstrating soil controls on the spatial pattern of Q10. These findings highlighted different environmental controls on the spatial and temporal pattern of soil respiration Q10, which should be considered to improve global biogeochemical models used to predict the spatial and temporal patterns of soil carbon fluxes to ongoing climate change.

Enhanced nickel removal and synchronous bioelectricity generation based on substrate types in microbial fuel cell coupled with constructed wetland: performance and microbial response.

In this study, an attempt was made to clarify the impact of substrates on the microbial fuel cell coupled with constructed wetland (CW-MFC) towards the treatment of nickel-containing wastewater. Herein, zeolite (ZEO), coal cinder (COA), ceramsite (CER), and granular activated carbon (GAC) were respectively introduced into lab-scaled CW-MFCs to systematically investigate the operational performances and microbial community response. GAC was deemed as the most effective substrate, and the corresponding device yielded favorable nickel removal efficiencies over 99% at different initial concentrations of nickel. GAC-CW-MFC likewise produced a maximum output voltage of 573 mV, power density of 8.95 mW/m2, and internal resistance of 177.9 Ω, respectively. The strong adsorptive capacity of nickel by GAC, accounting for 54.5% of total contaminant content, was mainly responsible for the favorable nickel removal performances of device GAC-CW-MFC. The high-valence Ni2+ was partially reduced to elemental Ni0 on the cathode, which provided evidence for the removal of heavy metals via the cathodic reduction of CW-MFC. The microbial community structure varied considerably as a result of substrates addition. For an introduction of GAC into the CW-MFC, a remarkably enriched population of genera Thermincola, norank_f__Geobacteraceae, Anaerovorax, Bacillus, etc. was noted. This study was dedicated to providing a theoretical guidance for an effective regulation of CW-MFC treatment on nickel-containing wastewater and accompanied by bioelectricity generation via the introduction of optimal substrate.

Cannabinoids inhibit ethanol-induced activation of liver toxicity in rats through JNK/ERK/MAPK signaling pathways.

Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT-alanine transferase, AST-aspartate aminotransferase, ALP-alanine peroxidase, MDA-malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.

Hypofractionated versus conventional intensity-modulated radiation irradiation (HARVEST-adjuvant): study protocol for a randomised non-inferior multicentre phase III trial.

INTRODUCTION: Short course regimen has become the major trend in the field of adjuvant radiotherapy for patients with breast cancer. Hypofractionated radiotherapy (HF-RT) regimen of 40-42.5 Gy in 15-16 fractions has been established as a preferred option for whole breast irradiation. However, few evidences of hypofractionated regional nodal irradiation (RNI), especially involving internal mammary nodes (IMNs), could be available during the era of intensity-modulated radiation therapy (IMRT). Against this background, we design this trial to explore the hypothesis that HF-RT regimen involving RNI (including infraclavicular, supraclavicular nodes and IMNs) will be non-inferior to a standard schedule by using IMRT technique. METHODS AND ANALYSIS: This is an open-label randomised, non-inferior, multicentre phase III trial. Patients with breast cancer with an indication for RNI after breast conserving surgery or mastectomy are randomised at a ratio of 1:1 into the following two groups: hypofractionated regimen of 2.67 Gy for 16 fractions or conventional regimen of 2 Gy for 25 fractions. The dose was prescribed to ipsilateral chest wall or whole breast and RNI (including infraclavicular, supraclavicular nodes and IMNs, lower axilla if indicated). The trial plans to enrol a total of 801 patients and all patients will be treated using IMRT technique. The primary endpoint is 5-year locoregional recurrence. The secondary endpoints include 5-year distant metastasis free survival, invasive recurrence-free survival, overall survival, accumulative acute radiation-induced toxicity and accumulative late radiation-induced toxicity, cosmetic outcomes and quality of life. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (version 2018-95-3) and approvals from ethical committee of each participating centre have also been obtained. Research findings will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03829553.

Expression profiles of microRNAs in midbrain of MPTP-treated mice determined by microRNA sequencing.

MPTP models have been developed to mimic human Parkinson's disease and serve as an indispensable tool for studying PD. Among them, subacute MPTP PD models are popular due to their short modeling period and similarity to PD pathology. However, the early pathophysiological mechanism of the model remains to be further clarified. More and more studies have shown that dysregulation of miRNAs plays an important role in the occurrence and development of neurodegenerative diseases, including PD. In this study, we identified 43 differentially expressed microRNAs (miRNAs) in the ventral midbrain of MPTP-induced subacute PD mouse by RNA sequencing. Further bioinformatics analysis revealed that these miRNAs were significantly enriched in axon guidance/neuron projection, metabolic pathways/cellular macromolecule metabolic process and PI3K/AKT signaling pathways, which were involved in the occurrence and development of early PD. Thus, targeted regulation of these miRNAs may reverse the neurodegeneration of early PD.

Exogenous Otx2 protects midbrain dopaminergic neurons from MPP+ by interacting with ATP5a1 and promoting ATP synthesis.

Mitochondrial dysfunction is the main pathological mechanism responsible for the death of midbrain dopaminergic (mDA) neurons. Thus, mitochondria-targeting therapy is a potential therapeutic strategy for Parkinson's disease (PD). Homeodomain transcription factors such as Otx2 can translocate between cells and exert non-cellular autonomous functions in recipient cells to stimulate neuronal survival. In this study, we investigated if exogenous Otx2 acts as a survival factor for mDA neurons by protecting them against MPP+-induced neurotoxicity in vitro. We show that subacute MPTP dosing regimen induces significant reduction in the levels of Otx2 homeoprotein in the ventral midbrain of PD mice. We also show that exogenous Otx2-myc recombinant protein protected primary mDA neurons against MPP+ by interacting with ATP5a1and promoting ATP synthesis.

Evolutionary dynamics of the severe acute respiratory syndrome coronavirus 2 genomes.

The coronavirus disease 2019 (COVID-19) pandemic has caused immense losses in human lives and the global economy and posed significant challenges for global public health. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has evolved, thousands of single nucleotide variants (SNVs) have been identified across the viral genome. The roles of individual SNVs in the zoonotic origin, evolution, and transmission of SARS-CoV-2 have become the focus of many studies. This review summarizes recent comparative genomic analyses of SARS-CoV-2 and related coronaviruses (SC2r-CoVs) found in non-human animals, including delineation of SARS-CoV-2 lineages based on characteristic SNVs. We also discuss the current understanding of receptor-binding domain (RBD) evolution and characteristic mutations in variants of concern (VOCs) of SARS-CoV-2, as well as possible co-evolution between RBD and its receptor, angiotensin-converting enzyme 2 (ACE2). We propose that the interplay between SARS-CoV-2 and host RNA editing mechanisms might have partially resulted in the bias in nucleotide changes during SARS-CoV-2 evolution. Finally, we outline some current challenges, including difficulty in deciphering the complicated relationship between viral pathogenicity and infectivity of different variants, and monitoring transmission of SARS-CoV-2 between humans and animals as the pandemic progresses.