Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2.

COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.

A rare case of bladder cancer that metastasized to brain, heart, and lung lymph nodes benefited from immunotherapy.

Bladder cancer is a common malignant tumor of the genitourinary system, with the primary cause of death being metastasis. The most common metastatic sites are the lymph nodes, liver, lung, bone, peritoneum, pleura, kidney, adrenal gland, and the intestine. Brain and heart metastases are rare. In this report, we describe a patient who had pulmonary lymph node metastases more than a year after being diagnosed with bladder cancer, followed by brain and cardiac metastases more than two years later. Following the failure of standard first-line chemotherapy, the patient accepted 6 cycles of tislelizumab immunotherapy. The re-examination revealed that the bilateral frontal brain metastases had vanished, the right temporal lobe metastases had been greatly decreased, the neurological symptoms had been alleviated, and the cardiac metastases had disappeared. This is a rare clinical case with encouraging effects of tislelizumab and can serve as a model for the treatment of similar patients.

Oceanic non-Kolmogorov optical turbulence and spherical wave propagation.

Light propagation in turbulent media is conventionally studied with the help of the spatio-temporal power spectra of the refractive index fluctuations. In particular, for natural water turbulence several models for the spatial power spectra have been developed based on the classic, Kolmogorov postulates. However, as currently widely accepted, non-Kolmogorov turbulent regime is also common in the stratified flow fields, as suggested by recent developments in atmospheric optics. Until now all the models developed for the non-Kolmogorov optical turbulence were pertinent to atmospheric research and, hence, involved only one advected scalar, e.g., temperature. We generalize the oceanic spatial power spectrum, based on two advected scalars, temperature and salinity concentration, to the non-Kolmogorov turbulence regime, with the help of the so-called "Upper-Bound Limitation" and by adopting the concept of spectral correlation of two advected scalars. The proposed power spectrum can handle general non-Kolmogorov, anisotropic turbulence but reduces to Kolmogorov, isotropic case if the power law exponents of temperature and salinity are set to 11/3 and anisotropy coefficient is set to unity. To show the application of the new spectrum, we derive the expression for the second-order mutual coherence function of a spherical wave and examine its coherence radius (in both scalar and vector forms) to characterize the turbulent disturbance. Our numerical calculations show that the statistics of the spherical wave vary substantially with temperature and salinity non-Kolmogorov power law exponents and temperature-salinity spectral correlation coefficient. The introduced spectrum is envisioned to become of significance for theoretical analysis and experimental measurements of non-classic natural water double-diffusion turbulent regimes.

Wide-range Prandtl/Schmidt number power spectrum of optical turbulence and its application to oceanic light propagation.

Light influenced by the turbulent ocean can be fully characterized with the help of the power spectrum of the water's refractive index fluctuations, resulting from the combined effect of two scalars, temperature and salinity concentration advected by the velocity field. The Nikishovs' model [ Fluid Mech. Res.27, 8298 (2000)] frequently used in the analysis of light evolution through the turbulent ocean channels is the linear combination of the temperature spectrum, the salinity spectrum and their co-spectrum, each being described by an approximate expression developed by Hill [ J. Fluid Mech.88, 541562 (1978)] in the first of his four suggested models. The fourth of the Hill's models provides much more precise power spectrum than the first one expressed via a non-linear differential equation that does not have a closed-form solution. We develop an accurate analytic approximation to the fourth Hill's model valid for Prandtl/Schmidt numbers in the interval [3, 3000] and use it for the development of a more precise oceanic power spectrum. To illustrate the advantage of our model, we include numerical examples relating to the spherical wave scintillation index evolving in the underwater turbulent channels with different average temperatures, and, hence, different Prandtl numbers for temperature and different Schmidt numbers for salinity. Since our model is valid for a large range of Prandtl number (or/and Schmidt number), it can be readily adjusted to oceanic waters with seasonal or extreme average temperature and/or salinity or any other turbulent fluid with one or several advected quantities.

An optimized band-target entropy minimization for mass spectral reconstruction of severely co-eluting and trace-level components.

Gas chromatography-mass spectrometry (GC-MS) is a versatile analytical method but its data is usually complicated by the presence of severely co-eluting and trace-level components. In this work, we introduce an optimized band-target entropy minimization approach for the analysis of complex mass spectral data. This new approach enables an automated mass spectral analysis which does not require any user-dependent inputs. Moreover, the approach provides improved sensitivity and accuracy for mass spectral reconstruction of severely co-eluting and trace-level components. The accuracy of our approach is compared to the automatic mass spectral deconvolution and identification system (AMDIS) with two controlled mixtures and a sample of Eucalyptus essential oil. Our approach was able to putatively identify 130 compounds in Eucalyptus essential oil, which was 46% in excess of that identified by AMDIS. This new approach is expected to benefit GC-MS analysis of complex mixtures such as biological samples and essential oils, in which the data are often complicated by co-eluting and trace-level components. Graphical abstract ᅟ.

[Yangjing capsule plus low-dose tadalafil for functional anejaculation].

OBJECTIVE: To search for an effective therapy for functional anejaculation (AE). METHODS: Fifty-five AE patients were randomized into a treatment group (n = 30) and a control group (n = 25), the former treated with Yangjing Capsule (once 5 pills, tid) and low-dose tadalafil (5 mg, qd alt, 1 h before bedtime), while the latter with oral ephedrine (25 mg before bedtime). Meanwhile, the patients were advised to expose themselves to sexual stimulation, reduce the frequency of sexual intercourses and quit masturbation. The medication lasted 1-3 months, followed by observation of the therapeutic effects. RESULTS: The total effectiveness rate was 83.34% in the treatment group, 11 cases cured, 8 obviously improved, 6 improved and 5 unimproved, significantly higher than 40.00% in the control group, 4 cases cured, 3 obviously improved, 3 improved and 15 unimproved (P < 0.05). CONCLUSION: Yangiing Capsule plus low-dose tadalafil is safe and effective for the treatment of functional anejaculation.

Effect of diabetes mellitus on long-term outcomes of surgical revascularization in patients with ischemic heart failure: a propensity score-matching study.

BACKGROUND: Diabetes mellitus (DM) is an important risk factor in the long-term outcomes of surgical revascularization. However, few studies have focused on patients with ischemic heart failure (IHF) and DM, and the results are controversial. This study aimed to evaluate the effect of DM on the long-term outcomes of IHF patients undergoing coronary artery bypass grafting (CABG). METHODS: In this propensity-matched study, data of IHF patients who underwent CABG in our hospital from January 2007 to December 2017 were analyzed. With a mean 73-month follow-up time, the patients were divided into two groups according to whether they had DM. The primary endpoint was all-cause death, and the secondary endpoint was a composite of all-cause death, stroke, recurrent myocardial infarction, and revascularization. RESULTS: There was no significant difference in all-cause mortality between the two groups (5.8% vs. 4.1%, P = 0.216). The incidence of main adverse cardiovascular and cerebrovascular events (MACCE) in the secondary endpoint was significantly higher in the DM group than that in the non-DM group (10.4% vs. 8.1%, P = 0.023). CONCLUSIONS: DM can negatively affect the long-term outcomes of IHF patients undergoing CABG by significantly increasing the overall incidence of MACCE, though the long-term survival does not show a significant difference between the DM and non-DM patients.

Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.

[Azoospermia factor and male infertility].

Azoospermia factor (AZF) microdeletions of the Y chromosome, which occur in 1 - 55% of infertile men, are closely associated with severe spermatogenic failure and represent the most frequent molecular genetic causes of azoospermia and severe oligozoospermia. Researches on AZF and its related genes, approaching the mechanisms of spermatogenic failure at the molecular level, are of great significance for the diagnosis, treatment and prognosis of male infertility. The detection of AZF microdeletions can provide scientific basis for correct diagnosis and reasonable therapy. This article outlines the structure and functional characteristics of AZF, as well as its relationship with male infertility, cryptorchidism, varicocele, Klinefelter syndrome, seminoma, and recurrent abortion.

[46, XX testicular disorder of sex development: report of 2 cases and review of the literature].

OBJECTIVE: To investigate the phenotype, pathogenesis and molecular biological features of 46, XX testicular disorder of sex development. METHODS: We obtained the history of 2 patients with 46, XX testicular disorder of sex development, examined the cavitas pelvis by type-B ultrasonography, analyzed the karyotype of the chromosome, and detected the genes SRY, YRRM1, DYS240 and DAZ by PCR amplification. RESULTS: Microrchidia, azoospermia and maldevelopment of secondary sex characteristics were observed in both of the patients, but ultrasonography revealed no female internal genitals. Their chromosome gender was karyotyped as 46, XX, with the SRY gene positive in both, but the YRRM1 gene positive in only one of the cases. CONCLUSION: Chromosome karyotyping and detection of the SRY gene for patients with abnormal sex development can give us an insight into the genetic pathogenesis and provide us with scientific evidence for the diagnosis and treatment of the condition.

Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques.

The 2019 novel coronavirus (SARS-CoV-2) outbreak is a major challenge for public health. SARS-CoV-2 infection in human has a broad clinical spectrum ranging from mild to severe cases, with a mortality rate of ~6.4% worldwide (based on World Health Organization daily situation report). However, the dynamics of viral infection, replication and shedding are poorly understood. Here, we show that Rhesus macaques are susceptible to the infection by SARS-CoV-2. After intratracheal inoculation, the first peak of viral RNA was observed in oropharyngeal swabs one day post infection (1 d.p.i.), mainly from the input of the inoculation, while the second peak occurred at 5 d.p.i., which reflected on-site replication in the respiratory tract. Histopathological observation shows that SARS-CoV-2 infection can cause interstitial pneumonia in animals, characterized by hyperemia and edema, and infiltration of monocytes and lymphocytes in alveoli. We also identified SARS-CoV-2 RNA in respiratory tract tissues, including trachea, bronchus and lung; and viruses were also re-isolated from oropharyngeal swabs, bronchus and lung, respectively. Furthermore, we demonstrated that neutralizing antibodies generated from the primary infection could protect the Rhesus macaques from a second-round challenge by SARS-CoV-2. The non-human primate model that we established here provides a valuable platform to study SARS-CoV-2 pathogenesis and to evaluate candidate vaccines and therapeutics.

Low toxicity and high immunogenicity of an inactivated vaccine candidate against COVID-19 in different animal models.

The ongoing COVID-19 pandemic is causing huge impact on health, life, and global economy, which is characterized by rapid spreading of SARS-CoV-2, high number of confirmed cases and a fatality/case rate worldwide reported by WHO. The most effective intervention measure will be to develop safe and effective vaccines to protect the population from the disease and limit the spread of the virus. An inactivated, whole virus vaccine candidate of SARS-CoV-2 has been developed by Wuhan Institute of Biological Products and Wuhan Institute of Virology. The low toxicity, immunogenicity, and immune persistence were investigated in preclinical studies using seven different species of animals. The results showed that the vaccine candidate was well tolerated and stimulated high levels of specific IgG and neutralizing antibodies. Low or no toxicity in three species of animals was also demonstrated in preclinical study of the vaccine candidate. Biochemical analysis of structural proteins and purity analysis were performed. The inactivated, whole virion vaccine was characterized with safe double-inactivation, no use of DNases and high purity. Dosages, boosting times, adjuvants, and immunization schedules were shown to be important for stimulating a strong humoral immune response in animals tested. Preliminary observation in ongoing phase I and II clinical trials of the vaccine candidate in Wuzhi County, Henan Province, showed that the vaccine is well tolerant. The results were characterized by very low proportion and low degree of side effects, high levels of neutralizing antibodies, and seroconversion. These results consistent with the results obtained from preclinical data on the safety.

[Qianlie Beixi capsule for unliquefiable semen: a clinical study of 180 cases].

OBJECTIVE: To investigate the efficacy and possible action mechanism of Qianlie Beixi Capsule in the treatment of unliquefiable semen. METHODS: A total of 240 patients with unliquefiable semen were randomly divided into a treatment group (n = 180), treated with Qianlie Beixi Capsule, and a control group (n = 60), given compound tablets of zinc and protein. The treatment lasted two courses of 45 days each, and the seminal changes were observed and recorded. RESULTS: Of the patients in the treatment group, 144 were cured, 12 responded and 24 failed to respond to the medication after the first course; and 158 were cured, 7 responded and 15 failed to after the second course, with the effectiveness rate of 91.67%. Meanwhile, sperm motility was obviously improved, with statistically significant difference from that of the controls (P < 0.01). CONCLUSION: Qianlie Beixi Capsule is effective for unliquefiable semen by improving the function of the prostate and shortening the time of seminal liquefaction.

Intranasally delivered TGF-beta1 enters brain and regulates gene expressions of its receptors in rats.

This study is aimed to evaluate the brain distribution of transforming growth factor-beta1 (TGF-beta1) following intranasal administration and the subsequent biological effects of TGF-beta1. Adult rats were given recombinant human TGF-beta1 (rhTGF-beta1) or vehicle solution intranasally. TGF-beta1 concentrations were significantly raised in several brain regions and the trigeminal nerve following intranasal delivery. The elevation appeared within 30 min and was sustained for at least 6 h, reaching its greatest level at 60 min. A concentration gradient in the central nervous system (CNS) regions was produced during the first 2 h after intranasal administration, with the OB presenting a significantly higher concentration than any other CNS regions. The nasally administered TGF-beta1 subsequently regulated gene expressions of its two receptors (TGF-beta receptor types I and II) in vivo, but did not affect mRNA level of TGF-beta1 itself. Our results suggest that TGF-beta1 can be transported into the CNS via the olfactory and trigeminal pathways, and may consequently exert its biological effects by regulating gene expressions of its receptors. Intranasal administration of neurotrophic factors may offer a potential strategy for treating some CNS disorders.

[Long-term outcomes of off-pump coronary artery bypass grafting in patients aged over 75 years].

OBJECTIVE: To investigate the long-term outcomes of off-pump coronary artery bypass grafting (OPCAB) in patients aged over 75 years and analyze the risk factors affecting the outcomes of the procedure. METHODS: Clinical data were reviewed for 97 consecutive patients aged 75 years or above receiving OPCAB at our center between November, 2000 and November, 2013. The perioperative data including length of ICU stay, duration of mechanical ventilation, incidence of postoperative complications and mortality rate of the patients were analyzed. The follow-up data of the patients were also analyzed including all-cause mortality rate and major adverse cardiac and cerebral events (MACCE, including myocardial infarction, cerebrovascular event, and repeated revascularization). RESULTS: The perioperative mortality rate was 3.09% (3/97) in these patients. Of the 97 patients analyzed, 91 (93%) were available for follow-up for 29-192 months (with a median of 95.61∓34.07 months). The 10-year survival rate of the patients was 62% with a 10-year MACCE-free survival rate of 47.4%. During the follow-up, 6 (6.8%) patients underwent repeated revascularization procedures, 12 (12.37%) had cerebrovascular accidents and 5 (5.15%) had myocardial infarction. Logistic regression analysis showed that hypertension (OR=1.388, P=0.043) and diabetes (OR=1.692, P=0.017) were independent predictors of MACCE, and incomplete revascularization did not increase the risk of postoperative MACCE. CONCLUSION: OPCAB is safe and effective in elderly patients with good long-term outcomes. Hypertension and diabetes are independent risk factors of MACCE, and adequate control of blood pressure and blood glucose can reduce the incidence of postoperative MACCE. Incomplete revascularization is not detrimental to the long-term outcomes of OPCAB in elderly patients.

[Characteristics of sediment heavy metal pollution in three water supply reservoirs in Huizhou, Guangdong Province of South China].

To understand the present status of the heavy metal (Cr, Cu, Zn, Cd, Pb and Hg) pollution of the sediments in water supply reservoirs in Huizhou, sediment cores were sampled from three representative reservoirs. The heavy metal concentrations were analyzed by ICP-MS, and the pollution status was assessed by geo-accumulation index (Igeo) and potential ecological risk index (RI). In the meantime, the possible sources of the heavy metals were analyzed by the principal component analysis (PCA). In the sediments of the three reservoirs, the test heavy metals had different vertical distribution, some had less change, the others decreased or increased with depth, and the distribution patterns differed with the reservoirs. According to the Igeo, the sediments in the reservoirs were seriously polluted by Zn and Pb (Zn: 49.98-640.29 mg x kg(-1); Pb: 21.94-300.66 mg x kg(-1)), reaching slight to high pollution, and the middle or bottom part of the sediments was slightly polluted by Cu (16.85-45.46 mg x kg(-1)). On the whole, the sediments were not polluted by Cr, Cd and Hg. According to the RI and the potential ecological risk coefficient [Er(i)], the sediments in the three reservoirs were under low potential ecological risk. Based on the PCA and relevant information, the human activities such as mining and smelting, urbanization, and agriculture and forestry had great contribution to the heavy metal pollution. The Zn and Pb pollution mainly originated from mining and smelting, Pb pollution also came from motor vehicle exhaust emission and domestic wastes, and Cu pollution mainly derived from agriculture and forestry.

[Distribution and pollution characteristics of nutrients and heavy metals in sediments of Hedi Reservoir].

Core sediments were collected from the riverine, transition and lacustrine zones of Hedi Reservoir in southern China to investigate the spatial distributions of nutrients and heavy metals and assess the potential ecological risk of heavy metals. The total nitrogen (TN) contents of the sediments at three sampling sites are between 2.314-2.427 mg x g(-1), while total phosphorus (TP) contents range from 0.591 mg x g(-1) to 0.760 mg x g(-1), TN contents of the surface sediments increase from the riverine zone to the lacustrine zone, but the TP content in the transition zone is higher than that in the other two sites (riverine zone and lacustrine zone). The mean contents of heavy metals are: 31.094, 46.85, 75.615, 385.739, 0.624 and 0.171 mg x kg(-1) respectively, except Cr, the contents of heavy metals in sediment of lacustrine zone are higher than the sediment of transition zone. In all core sediments, the contents of nutrients and heavy metals decrease from the surface to the bottom of core sediments. Inorganic phosphorus (IP) is the dominant fraction of phosphorus in the sediment and the NaOH-P is the main forms of inorganic phosphorus. The potential ecological risk assessed by using of the highest environmental background values before industrialization as the reference indicates that each single heavy metal only causes slightly pollution, but two heavy metals (Cd and Hg) cause heavy pollution based on the soil environmental background values of Guangdong province. In spite of the slight difference between two kinds of risk assessment, all demonstrated that Cd and Hg resulted in more serious pollution than the other metals and these two metals contributed most to the RI values.

[Analysis of therapeutic effects of external fixator for the treatment of comminuted fracture of distal radius].

OBJECTIVE: To evaluate the clinical effects of external fixator in treating comminuted fracture of distal radius. METHODS: From Mar.2008 to Dec.2009, 37 patients with comminuted fracture of distal radius were treated with external fixator or assisted with Kirschner wire and T-shape locking compression plate (T-LCP) fixation. There were 14 males and 23 females, ranging in age from 30 to 79 years, with an average of 59.1 years. According to AO typing, type C1 was in 3 cases, type C2 was in 11 cases and type C3 was in 23 cases. Function of wrist joint and X-ray films were observed according to Gratland-Werley system at different months. RESULTS: All patients were followed up from 8 to 24 months with an average of 12 months. All fractures had healing with an average time of 8 weeks. According to Gratland-Werley system, 16 cases obtained excellent result, 17 good, 4 fair, the rate of excellent and good was 89.0%. CONCLUSION: External fixator can obtained satisfactory clinical effect in treating comminuted fracture of distal radius.