Transforming Lipoxygenases: PE-Specific Enzymes in Disguise.

In this issue of Cell, Wenzel et al. solve a long-standing mystery regarding how damage to cell membranes occurs during ferroptosis, an iron-dependent form of regulated cell death. They found that lipoxygenases are like Transformer toys, being converted from one enzyme type to another in the presence of the protein PEBP1.

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation.

Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

STIL is upregulated in nasopharyngeal carcinoma tissues and promotes nasopharyngeal carcinoma proliferation, migration and invasion.

Nasopharyngeal carcinoma (NPC) is the most common primary malignancy that originates from the nasopharynx. Some regulatory networks involved in nasopharyngeal carcinoma have been reported, but the relevant genes have not been fully identified. We have used mRNA microarray to identify differential expression genes between NPC tissues and adjacent normal tissues. Then high-content shRNA screening was carried out to screen the genes that may control proliferation in nasopharyngeal carcinoma. Cell proliferation was monitored by MTT assays and Celigo image cytometry in vitro and subcutaneous transplantation model in vivo. Flow cytometric analysis was carried out to detect the distribution of cell cycle stages and apoptosis. Transwell assay was performed to measure the migratory and invasive capacities of NPC cells. We identified 20 genes that potentially play an important role in the proliferation of nasopharyngeal carcinoma by mRNA microarray and functional analysis. The result of high-content shRNA screening indicated that STIL had the greatest effect on reducing the proliferation rate of NPC cells. The analysis of The Cancer Genome Atlas (TCGA) data showed that STIL was upregulated in several human cancer tissues, and higher STIL expression level was correlated with shorter survival time. STIL knockdown also inhibited NPC cell migration and invasion, promoted G1/S phase transition and apoptosis. Three genes including ITGA2, SMAD2, JAK1, associated with molecular mechanisms of cancer were influenced by downregulating STIL. Our study confirmed STIL as a key regulator that promotes the proliferation of NPC, providing insight into the molecular mechanisms of nasopharyngeal carcinoma and suggesting a novel therapeutic strategy.

Successful interruption of seasonal influenza transmission under the COVID-19 rapid response in Zhejiang Province, China.

OBJECTIVES: The objective of this study was to evaluate whether the non-pharmaceutical interventions (NPIs) introduced to curb the spread of coronavirus disease 2019 (COVID-19) also interrupted the transmission of influenza. STUDY DESIGN: This is a descriptive epidemiological study. METHODS: Data on changes in the number of reported influenza cases, number of influenza-like illness (ILI) visits, ILI percentage and influenza virus positivity were compared between the first 18 weeks of 2020 and the same period of 2019. RESULTS: The changes in the weekly average number of influenza cases were statistically significant between 2020 and 2019 (-4319 vs -525 per week; P < 0.05). The slopes of regression lines for the number of ILI visits were also statistically significant between 2020 and 2019 (-911 vs -98 per week; P < 0.05). CONCLUSIONS: This study found that the prevalence of influenza was substantially decreased when NPIs were implemented for the containment of COVID-19.

[Epidemiological characteristics of COVID-19 family clustering in Zhejiang Province].

Objective: To investigate the epidemiological characteristics for family clusters of COVID-19 in Zhejiang Province. Methods: The data including cases information of asymptomatic infected cases of family clusters of COVID-19 in Zhejiang Province were collected from Public Health Emergencies Reporting System of China Center for Disease Control and Prevention. Calculate the case number of subsequent cases, index cases, asymptomatic infected cases, exposure cases, and then, compute family secondary attack rate (SIR) and serial interval. Results: A total of 389 cases comprised 149 family index cases and 240 subsequent cases. The clinical symptoms between family index cases and subsequent cases (exclude asymptomatic infected cases ) were similar, fever was the most common symptoms in the two groups 115 (77.18%) and 110（48.67%）respectively, the cases with diarrhea symptoms accounted for the least proportion, which were 7 (4.70%) and 6 (2.65%) respectively. The serial interval between the family index cases and the subsequent cases [M (P25, P75)] was 4.00 (2.00, 6.00) days. Family secondary attack rate for subsequent cases was 34.43%, subsequent cases aged between 14 and 60 have the highest SIR (43.42%) compared with other two age groups, the difference was statistically (P<0.001); the family SIR of the spouses of the family index cases is 68.57%, and are higher than that of parents (29.03%), children (25.00%) and other family members (24.21%), the difference was also statistically (P<0.001). Conclusion: 2019 novel coronavirus has shorter serial interval and higher family SIR, the SIR of spouses is higher than other family members.

Electric field tuned MoS2/metal interface for hydrogen evolution catalyst from first-principles investigations.

Understanding the interfacial properties of catalyst/substrate is crucial for the design of high-performance catalyst for important chemical reactions. Recent years have witnessed a surge of research in utilizing MoS2 as a promising electro-catalyst for hydrogen production, and field effect has been employed to enhance the activity (Wang et al 2017 Adv. Mater. 29, 1604464; Yan et al 2017 Nano Lett. 17, 4109-15). However, the underlying atomic mechanism remains unclear. In this paper, by using the prototype MoS2/Au system as a probe, we investigate effects of external electric field on the interfacial electronic structures via density functional theory (DFT) based first-principles calculations. Our results reveal that although there is no covalent interaction between MoS2 overlayer and Au substrate, an applied electric field efficiently adjusts the charge transfer between MoS2 and Au, leading to tunable Schottky barrier type (n-type to p-type) and decrease of barrier height to facilitate charge injection. Furthermore, we predict that the adsorption energy of atomic hydrogen on MoS2/Au to be readily controlled by electric field to a broad range within a modest magnitude of field, which may benefit the performance enhancement of hydrogen evolution reaction. Our DFT results provide valuable insight into the experimental observations and pave the way for future understanding and control of catalysts in practice, such as those with vacancies, defects, edge states or synthesized nanostructures.

Sensory trait variation contributes to biased dispersal of threespine stickleback in flowing water.

Gene flow is widely thought to homogenize spatially separate populations, eroding effects of divergent selection. The resulting theory of 'migration-selection balance' is predicated on a common assumption that all genotypes are equally prone to dispersal. If instead certain genotypes are disproportionately likely to disperse, then migration can actually promote population divergence. For example, previous work has shown that threespine stickleback (Gasterosteus aculeatus) differ in their propensity to move up- or downstream ('rheotactic response'), which may facilitate genetic divergence between adjoining lake and stream populations of stickleback. Here, we demonstrate that intraspecific variation in a sensory system (superficial neuromast lines) contributes to this variation in swimming behaviour in stickleback. First, we show that intact neuromasts are necessary for a typical rheotactic response. Next, we showed that there is heritable variation in the number of neuromasts and that stickleback with more neuromasts are more likely to move downstream. Variation in pectoral fin shape contributes to additional variation in rheotactic response. These results illustrate how within-population quantitative variation in sensory and locomotor traits can influence dispersal behaviour, thereby biasing dispersal between habitats and favouring population divergence.

Will integrated surveillance systems for vectors and vector-borne diseases be the future of controlling vector-borne diseases? A practical example from China.

Vector-borne diseases are one of the world's major public health threats and annually responsible for 30-50% of deaths reported to the national notifiable disease system in China. To control vector-borne diseases, a unified, effective and economic surveillance system is urgently needed; all of the current surveillance systems in China waste resources and/or information. Here, we review some current surveillance systems and present a concept for an integrated surveillance system combining existing vector and vector-borne disease monitoring systems. The integrated surveillance system has been tested in pilot programmes in China and led to a 21·6% cost saving in rodent-borne disease surveillance. We share some experiences gained from these programmes.

Antibacterial efficacy and pharmacokinetic evaluation of sanguinarine in common carp (Cyprinus carpio) following a single intraperitoneal administration.

Sanguinarine (SA), with antimicrobial and antiparasitic activities against fish pathogens, exhibits great potential commercial use in aquaculture. However, little information on pharmacokinetics of SA restricts further application in aquaculture. In this study, pharmacokinetics of SA in common carp (Cyprinus carpio) following a single intraperitoneal administration [10 mg kg(-1) BW (body weight)] was evaluated by high-performance liquid chromatography (HPLC). The peak concentration (Cmax ) of SA in kidney was 11.8 µg g(-1) , which was higher than in other tissues and plasma. The terminal half-life in fish tissue and plasma was as follows: 42.3 h (kidney) > 37.2 h (liver) > 20.1 h (gill) > 18.8 h (muscle) > 10.9 h (spleen) > 10.0 h (plasma). Additionally, we determined the bacterial loads in tissues of common carp infected with Aeromonas hydrophila after i.p. administration of SA at 0, 5, 10 and 20 mg kg(-1) BW. The results showed that i.p. administration of SA at 10 mg kg(-1) BW significantly enhanced antibacterial efficacy against A. hydrophila, where the antibacterial ratio in the gill, kidney, spleen and liver on day 5 was 95.13%, 93.33%, 90.09% and 92.82%, respectively. Overall, these results suggested the potential of SA to treat A. hydrophila infection in common carp farming industry.

Investigation on the role of XPG gene polymorphisms in breast cancer risk in a Chinese population.

We conducted a case-control study to investigate the role of XPG gene polymorphisms (rs2094258, rs751402, and rs17655) in the development of breast cancer. Patients with breast cancer (320) and control subjects (294) were consecutively selected from the Zhongshan Hospital between April 2013 and January 2015. The genotyping of XPG rs2094258, rs751402, and rs17655 was performed using polymerase chain reaction-restriction fragment length polymorphism. Using the chi-square test, we did not find any significant differences in the genotype distributions of XPG rs2094258 (χ(2) = 1.48, P = 0.48), rs751402 (χ(2) = 0.65, P = 0.72), and rs17655 (χ(2) = 0.01, P = 0.92) genes between breast cancer patients and control subjects. The genotype distributions of XPG rs2094258, rs751402, and rs17655 did not deviate from the Hardy-Weinberg equilibrium in control subjects, and the P values were 0.58, 0.97, and 0.26, respectively. Using unconditional logistic regression analysis, we found that XPG rs2094258, rs751402 and rs17655 gene polymorphisms are not associated with the development of breast cancer after adjusting for potential confounding factors. In conclusion, we found that XPG rs2094258, rs751402, and rs17655 do not influence the development of breast cancer in a Chinese population.

Seroprevalence of severe fever with thrombocytopenia syndrome virus in southeastern China and analysis of risk factors.

Severe fever with thrombocytopenia syndrome virus (SFTSV) has been prevalent for some time in China and it was first identified in 2010. However, the seroprevalence of SFTSV in the general population in southeastern China and risk factors associated with the infection are currently unclear. Blood samples were collected from seven counties across Zhejiang province and tested for the presence of SFTSV-specific IgG antibodies by ELISA. A total of 1380 blood samples were collected of which 5·51% were seropositive for SFTSV with seroprevalence varying significantly between sites. Seroprevalence of SFTSV in people who were family members of the patient, lived in the same village as the patient, or lived in a different village than the patient varied significantly. There was significant difference in seroprevalence between participants who bred domestic animals and participants who did not. Domestic animals are probably potential reservoir hosts and contact with domestic animals may be a transmission route of SFTSV.

Impedance analysis of secondary phases in a Co-implanted ZnO single crystal.

Co ions with 100 keV energy with a fluence of 1 × 10(15) cm(-2) are implanted into ZnO(0001) single crystals at 300 °C under vacuum. The resulting Co-implanted ZnO single crystals and the subsequent 750 °C and 900 °C annealed samples are analysed with respect to their structural, optical, electronic, magnetic and ac electrical properties. Photoluminescence and X-ray photoelectron spectroscopy results indicate the signatures of the Co(2+) state and its substitution at the tetrahedrally coordinated Zn-sites. X-ray diffraction and X-ray photoelectron spectroscopy identify the presence of the ZnCo2O4 and Co3O4 phases in the 900 °C annealed sample. By comparing the resistance response of the identified phases towards different magnetic environments, the impedance spectroscopy results successfully identify two magnetic phases (ZnCo2O4 and Co3O4) and a paramagnetic (CoZn) phase for the 750 °C and 900 °C annealed samples, implying the extrinsic nature of room temperature ferromagnetism. The observed ferromagnetism in each sample is not of single origin, instead the mutual effects of the secondary phases embedded in the paramagnetic host matrix are in competition with each other.

Vortex domain structures of an epitaxial ferroelectric nanodot and its temperature-misfit strain phase diagram.

Phase field simulations were conducted to investigate the effect of misfit strain on the vortex domain structure (VDS) in a BaTiO3 nanodot. Taking into account the effect of inhomogeneous eletromechanical fields, ambient temperature and surface effects, our calculations demonstrate a strong effect of misfit strain on the orientation and magnitude of the polarization dipoles. As a consequence, fruitful equilibrium vortex domain patterns can be obtained by adjusting the epitaxial misfit strain between the substrate and the nanodot. While the nanodot exhibits a single transition from a paraelectric to a near-rhombohedral vortex state at zero misfit strain with the decrease of temperature, complicated transformations of vortex domain patterns are found under nonzero misfit strain. Typically, orthorhombic, tetragonal and several unreported vortex domain patterns (e.g., with zero toroidal moment) are found. Moreover, misfit strain-induced transformations into these domain patterns are also predicted for a ferroelectric nanodot with initial near-rhombohedral vortex state. Combining effects of the ambient temperature and misfit strain, a "temperature-misfit strain" phase-diagram depicting the fruitful vortex domain patterns of the nanodot was obtained. Our simulations indicate promising application of strain engineering in controlling the VDS in ferroelectric nanostructures.

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

Characterization of the major histocompatibility complex class I A alleles in cynomolgus macaques of Vietnamese origin.

Cynomolgus macaques (Macaca fascicularis, Mafa) have emerged as an important animal model for infectious disease and transplantation research. Extensive characterization of their major histocompatibility complex (MHC) polymorphism regions therefore becomes urgently required. In this study, we identified 41 MHC class I A nucleotide sequences in 34 unrelated cynomolgus macaques of Vietnamese origin farmed in Southern China, including eight novel Mafa-A sequences. We found two sequences with perfect identity and six sequences with close similarity to previously defined MHC class I alleles from other populations, especially from Indonesian-origin macaques. We also found three Vietnamese-origin cynomolgus macaque MHC class I sequences for which the predicted protein sequences identical throughout their B and F binding pockets to Mamu-A1*001:01 and Mamu-A3*13:03, respectively. This is important because Mamu-A1*001:01 and Mamu-A3*13:03 are associated with longer survival and lower set-point viral load in simian immunodeficiency virus (SIV)-infected rhesus monkeys. These findings have implications for the evolutionary history of Vietnamese-origin cynomolgus macaque as well as for the use of this model in SIV/SHIV (a virus combining parts of the HIV and SIV genomes) research.

[Epidemiological characteristics of COVID-19 caused by 2019-nCoV Delta variant in Shangyu district, Shaoxing of Zhejiang province].

Objective: To investigate the epidemiological characteristics of COVID-19 caused by 2019-nCoV Delta variant in Shangyu district, Shaoxing of Zhejiang province in 2021, and provide evidence for the improvement of COVID-19 control and prevention measures. Methods: The incidence data of COVID-19 in Shangyu from December 7 to 21, 2021 was obtained from Shangyu District Center for Disease Control and Prevention. The epidemiological characteristics of the cases, i.e. the population, time and space distributions, were analyzed, and the incubation period and time-varying reproduction numbers (Rt) were calculated. Results: From December 7 to 21, 2021, a total of 380 COVID-19 cases caused by 2019-nCoV Delta variant were detected in Shangyu, the median age of the cases was 52 years, M (Q1，Q3: 38, 61). The male to female ratio of the cases was 1∶1.25, and the cases were mainly workers (36.58%) and farmers (27.63%). The epidemic affected 9 townships (or community) of Shangyu, especially Caoe and Baiguan communities with the cases accounting for 57.10% and 31.53% respectively. The median incubation period of cases was 4.00 days, M (Q1，Q3: 3.00, 5.75). The basic reproduction number (R0) was 4.06, and the Rt was 5.62 in early phase of the outbreak (the highest) and continuously decreased to less than 1.00 within 10 days after the detection of the outbreak. The number of COVID-19 cases decreased to 0 within 14 days after the outbreak (December 7-21), and the main detection methods were screening in centralized isolation (55.53%) and home isolation (40.00%). The infection rates of close contacts and secondary close contacts were 2.06% and 0.46% respectively. Conclusion: The epidemic of COVID-19 in Shangyu characterized by short incubation period, large number of infected people, and case clustering, suggesting the strong transmission of Delta variant (B.1.617.2). Comprehensive prevention and control measures, such as management of close contacts and secondary close contacts, and high-risk area, are essential for the rapid control of the epidemic.

Eighteen novel MHC class I A alleles identified in Vietnamese-origin cynomolgus macaques.

We report herein the identification of 18 novel Mafa-A alleles in cynomolgus macaques of Vietnamese origin.

Twenty-three novel major histocompatibility complex class I B alleles identified in cynomolgus macaques of Vietnamese origin.

We report herein the identification of 23 novel Mafa-B alleles in cynomolgus macaques of Vietnamese origin.

[Study on epidemic trend of hemorrhagic fever with renal syndrome in Zhejiang province, 2005-2020].

Objective: To analyze the epidemiological characteristics and spatiotemporal distribution of hemorrhagic fever with renal syndrome (HFRS) in Zhejiang province from 2005 to 2020, and provide scientific information for the precise prevention and control of HFRS. Methods: Data on HFRS cases in Zhejiang province during 2005-2020 were collected from the China National Notifiable Infectious Disease Reporting Information System (NNDS) for a descriptive analysis, and software ArcGIS 10.2 was used for global autocorrelation and local autocorrelation analyses. Spatiotemporal clusters were scanned with SaTScan 9.4.4 and visualized with ArcGIS 10.2. Results: A total of 7 724 HFRS cases were reported in Zhejiang province from 2005 to 2020, including 25 deaths. There were two incidence peaks each year, in late spring and early summer (May-June) and in winter (November-January). The top three areas with high cumulative cases were Ningbo (1 875, 24.27%), Taizhou (1 642, 21.25%), and Shaoxing (1 123, 14.54%). Among the reported cases, with a male to female ratio of 2.73∶1(5 656∶2 068). The majority of HFRS cases were middle-aged and elderly people, with cases aged 41-70 years accounting for 60.95%. Most HFRS cases were farmers, accounting for 69.89% (5 398/7 724). The spatial distribution of HFRS in most years was correlated. SaTScan was used for retrospective spatiotemporal scanning and three clusters were detected: the first type clusters were in 21 counties in eastern Zhejiang province and central Zhejiang province, among which 4 were in Ningbo, Shaoxing and Jinhua, 8 were in Taizhou, and 1 was in Lishui (RR=13.69, LLR=5 522.60, P<0.001); the second type clusters were in Longquan and Qingyuan counties (RR=31.20, LLR=1 232.46, P<0.001); the third types of clusters were in Changxing and Anji counties of Huzhou in northern Zhejiang province (RR=3.42, LLR=23.93, P<0.001). Conclusions: HFRS mainly occurred in middle-aged,elderly and male farmers in Zhejiang province. The incidence was high in late spring, early summer and winter in eastern Zhejiang province. Precise prevention and control measures are needed for populations at high risk before the epidemic season.