Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal CA1 hippocampus (dCA1). Local field-potential recording combined with selective optogenetic inhibition first revealed an increase of dCA1 synaptic responses to the conditioned stimulus (CS) induced during conditioning at both Schaffer collaterals to the stratum radiatum (Rad) and temporoammonic input to the lacunosum moleculare (LMol). At these dCA1 inputs, synaptic potentiation of CS-responding excitatory synapses was further demonstrated by locally blocking NMDA receptors during conditioning and whole-cell recording sensory-evoked synaptic responses in dCA1 neurons from naive animals. An overall similar time course of the induction of synaptic potentiation was found in the Rad and LMol by multiple-site recording; this emerged later and saturated earlier than conditioned behavioral responses. Our experiments demonstrate a cued memory-associated dCA1 synaptic plasticity induced at both Schaffer collaterals and temporoammonic pathways.
Animals ; CA1 Region, Hippocampal/physiology* ; Male ; Association Learning/physiology* ; Neuronal Plasticity/physiology* ; Cues ; Memory/physiology* ; Synapses/physiology* ; Conditioning, Classical/physiology* ; Excitatory Postsynaptic Potentials/physiology* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Rats ; Optogenetics

Genetic counseling for hearing loss today originated from decoding the genetic code of hereditary hearing loss, which serves as an effective strategy for preventing hearing loss and constitutes a crucial component of the diagnostic and therapeutic framework. This paper described the main principles and contents of genetic counseling for hearing loss, the key points of counseling across various genetic models and its application in tertiary prevention strategies targeting hearing impairment. The prospects of an AI-assisted genetic counseling decision system and the envisions of genetic counseling in preventing hereditary hearing loss were introduced. Genetic counseling for hearing loss today embodies the hallmark of a new era, which is inseparable from the advancements in science and technology, and will undoubtedly contribute to precise gene intervention!
Humans ; Genetic Counseling ; Deafness/genetics* ; Hearing Loss/diagnosis* ; Hearing Loss, Sensorineural/genetics*

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG^@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

OBJECTIVE: To analyze the density, distribution and insecticide resistance of Aedes albopictus in Ningbo City in 2021, so as to provide insights into formulation of dengue fever control strategies. METHODS: Four administrative villages were randomly selected from each county (district) in Ningbo City from April to November, 2021, to investigate the indoor population density of Aedes larvae, and the Breteau index (BI) was calculated. The population density of adult mosquitoes was investigated in residential areas, parks/bamboo forests, waste tire stacking sites/waste stations/construction sites in each county (district). On June 2021, larvae of the natural strain A. albopictus were collected from epidemic sites of dengue fever in Ningbo City in 2018, and raised in laboratory. Then, larvae and female mosquitoes without blood feeding were selected for insecticide resistance bioassays, while insecticide-sensitive strains of A. albopictus served as controls. The resistance of A. albopictus larvae to deltamethrin, beta-cypermethrin, propoxur, temephos and dichlorvos using the impregnation method, and the medium lethal concentration (LC₅₀) and resistance ratio (RR) were calculated. The resistance of adult A. albopictus to beta-cypermethrin, permethrin, deltamethrin, propoxur and malathion was determined using the tube bioassay, and the mosquito mortality was calculated. RESULTS: A total of 10 072 small water containers from 9 935 households were investigated in Ningbo City in 2021, and there were 1 276 containers with Aedes larvae detected, with an average BI of 12.89. Totally 1 422 mosquito nets were allocated and 954 female A. albopictus were captured, with an average net trapping index of 1.34 mosquitoes/(net·hour). Both larval and adult A. albopictus mosquitoes were found from April to November, and the density of larval A. albopictus peaked in September (BI = 21.21), while the density of adult A. albopictus peaked in August, with a net trapping index of 2.38 mosquitoes/(net·hour). The LC₅₀ values of delta-methrin, beta-cypermethrin, propoxur, temephos and dichlorvos were 0.017 4, 0.000 9, 0.364 1, 0.038 1 mg/L and 0.001 6 mg/L against larvae of natural strains of A. albopicchus, with RRs of 49.66, 25.53, 9.65, 2.24 and 6.06, and the mortality rates of adult mosquitoes were 66.00% (66/100), 69.39% (68/98), 25.00% (25/100), 98.97% (96/97) and 100.00% (98/98) 24 hours post-treatment with 0.08% beta-cypermethrin, 0.03% deltamethrin, 0.4% permethrin, 0.05% propoxur, and 0.5% malathion for 24 h, respectively. CONCLUSIONS A. albopictus is widely distributed in Ningbo City, with a high population density and presents high-level resistance to common pyrethroid insecticides. The population density and insecticide resistance of A. albopictus requires to be reinforced.
Animals ; Female ; Malathion ; Temefos ; Aedes ; Propoxur ; Permethrin ; Dichlorvos ; Mosquito Vectors ; Larva ; Dengue/prevention & control*

OBJECTIVE: To examine the impact of COVID-19 pandemic on the epidemic status of imported malaria and national malaria control program in China, so as to provide insights into post-elimination malaria surveillance. METHODS: All data pertaining to imported malaria cases were collected from Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region during the period from January 1, 2018 through December 31, 2021. The number of malaria cases, species of malaria parasites, country where malaria parasite were infected, diagnosis and treatment after returning to China, and response were compared before (from January 1, 2018 to January 22, 2020) and after the COVID-19 pandemic (from January 23, 2020 to December 31, 2021). RESULTS: A total of 2 054 imported malaria cases were reported in Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region during the period from January 1, 2018 to December 31, 2021, and there were 1 722 cases and 332 cases reported before and after the COVID-19 pandemic, respectively. All cases were reported within one day after definitive diagnosis. The annual mean number of reported malaria cases reduced by 79.30% in Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region after the COVID-19 pandemic (171 cases) than before the pandemic (826 cases), and the number of monthly reported malaria cases significantly reduced in Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region since February 2020. There was a significant difference in the constituent ratio of species of malaria parasites among the imported malaria cases in Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region before and after the COVID-19 pandemic (χ² = 146.70, P < 0.05), and P. falciparum malaria was predominant before the COVID-19 pandemic (72.30%), while P. ovale malaria (44.28%) was predominant after the COVID-19 pandemic, followed by P. falciparum malaria (37.65%). There was a significant difference in the constituent ratio of country where malaria parasites were infected among imported malaria cases in Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region before and after the COVID-19 pandemic (χ² = 13.83, P < 0.05), and the proportion of malaria cases that acquired Plasmodium infections in western Africa reduced after the COVID-19 pandemic that before the pandemic (44.13% vs. 37.95%; χ² = 4.34, P < 0.05), while the proportion of malaria cases that acquired Plasmodium infections in eastern Africa increased after the COVID-19 pandemic that before the pandemic (9.58% vs. 15.36%; χ² = 9.88, P = 0.02). The proportion of completing case investigation within 3 days was significantly lower after the COVID-19 pandemic than before the pandemic (96.69% vs. 98.32%; χ²= 3.87, P < 0.05), while the proportion of finishing foci investigation and response within 7 days was significantly higher after the COVID-19 pandemic than before the pandemic (100.00% vs. 98.43%; χ² = 3.95, P < 0.05). CONCLUSIONS The number of imported malaria cases remarkably reduced in Anhui Province, Hubei Province, Henan Province, Zhejiang Province and Guangxi Zhuang Autonomous Region of China during the COVID-19 pandemic, with a decreased proportion of completing case investigations within 3 days. The sensitivity of the malaria surveillance-response system requires to be improved to prevent the risk of secondary transmission of malaria due to the sharp increase in the number of imported malaria cases following the change of the COVID-19 containment policy.
Humans ; Pandemics ; China/epidemiology* ; Incidence ; COVID-19/epidemiology* ; Malaria/prevention & control* ; Malaria, Falciparum/epidemiology*

OBJECTIVE: To establish a snail control approach for spraying chemicals with drones against Oncomelania hupensis in complex snail habitats in hilly regions, and to evaluate its molluscicidal effect. METHODS: The protocol for evaluating the activity of spraying chemical molluscicides with drones against O. hupensis snails was formulated based on expert consultation and literature review. In August 2022, a pretest was conducted in a hillside field environment (12 000 m²) north of Dafengji Village, Dacang Township, Weishan County, Yunnan Province, which was assigned into four groups, of no less than 3 000 m² in each group. In Group A, environmental cleaning was not conducted and 5% niclosamide ethanolamine salt granules were sprayed with drones at a dose of 40 g/m², and in Group B, environmental cleaning was performed, followed by 5% niclosamide ethanolamine salt granules sprayed with drones at a dose of 40 g/m², while in Group C, environmental cleaning was not conducted and 5% niclosamide ethanolamine salt granules were sprayed with knapsack sprayers at a dose of 40 g/m², and in Group D, environmental cleaning was performed, followed by 5% niclosamide ethanolamine salt granules sprayed with knapsack sprayers at a dose of 40 g/m². Then, each group was equally divided into six sections according to land area, with Section 1 for baseline surveys and sections 2 to 6 for snail surveys after chemical treatment. Snail surveys were conducted prior to chemical treatment and 1, 3, 5, 7 days post-treatment, and the mortality and corrected mortality of snails, density of living snails and costs of molluscicidal treatment were calculated in each group. RESULTS: The mortality and corrected mortality of snails were 69.49%, 69.09%, 53.57% and 83.48%, and 68.58%, 68.17%, 52.19% and 82.99% in groups A, B, C and D 14 days post-treatment, and the density of living snails reduced by 58.40%, 63.94%, 68.91% and 83.25% 14 days post-treatment relative to pre-treatment in four groups, respectively. The median concentrations of chemical molluscicides were 37.08, 35.42, 42.50 g/m² and 56.25 g/m² in groups A, B, C and D, and the gross costs of chemical treatment were 0.93, 1.50, 0.46 Yuan per m² and 1.03 Yuan per m² in groups A, B, C and D, respectively. CONCLUSIONS The molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones against O. hupensis snails is superior to manual chemical treatment without environmental cleaning, and chemical treatment with drones and manual chemical treatment show comparable molluscicidal effects following environmental cleaning in hilly regions. The cost of chemical treatment with drones is slightly higher than manual chemical treatment regardless of environmental cleaning. Spraying 5% niclosamide ethanolamine salt granules with drones is recommended in complex settings with difficulty in environmental cleaning to improve the molluscicidal activity and efficiency against O. hupensis snails.
Niclosamide/pharmacology* ; Ethanolamine/pharmacology* ; Unmanned Aerial Devices ; China ; Molluscacides/pharmacology* ; Ethanolamines

Objective: To investigate the clinicopathological characteristics of esophageal carcinoma with gland duct differentiation. Methods: The clinical, morphologic and immunohistochemical (IHC) features of eight cases of esophageal carcinoma with gland duct differentiation diagnosed from 2012 to 2022 at the First Affiliated Hospital of Soochow University were summarized. Results: There were four males and four females, with a mean age of 68.5 (range 59-82) years. Two tumors were located in middle esophagus, five in the lower esophagus, and one in the cardia. The mean diameter was 2.4 cm (range 0.6-4.5 cm). The tumor had a bilayer epithelial structure, including the inner luminal epithelium and the outer basal epithelium. Immunohistochemistry showed that CK7 (8/8) and CK18 (8/8) were positive in the inner epithelium. p40 (8/8), p63 (8/8) and CK5/6 (8/8) were positive in the outer epithelium. SMA, calponin and CD117 were all negative. p53 mutants were found in all eight cases (strong and diffuse positivity in 6/8; complete loss of expression in 2/8). No columnar metaplasia, intestinal metaplasia and ectopic gastric mucosa were observed in the surface squamous epithelium in the cases. The mean follow-up time was 21.5 months (range 5-51 months). Seven patients survived and one patient died 31 months after surgery due to recurrence and liver metastasis. Conclusion: Esophageal carcinoma with esophageal gland duct differentiation is a rare tumor with unique histologic and IHC characteristics.
Male ; Female ; Humans ; Middle Aged ; Aged ; Aged, 80 and over ; Esophageal Neoplasms/pathology* ; Epithelium/pathology* ; Metaplasia/metabolism* ; Carcinoma/pathology*

Adult ; Humans ; Stomach ; Histiocytosis, Langerhans-Cell/diagnosis*