Construction and evaluation of a Salmonella Paratyphi A vaccine candidate based on a poxA gene mutation.

Salmonella Paratyphi A, the pathogen of paratyphoid A accounts for an obviously growing proportion of cases in many areas. Therefore, development of specific paratyphoid A vaccines is needed. In the present study, the poxA gene of Salmonella Paratyphi A, encoding the aminoacyl-tRNA synthetase, was deleted successfully by the method of lambda Red recombination system, the resulting strain, ΔpoxA was characterized in respect of growth, adhesion and invasion, virulence, immunogenicity and protective efficacy. It was found that the growth of the ΔpoxA strain was significantly delayed compared with the wild type strain, the mutant ΔpoxA was less invasive to Caco-2 BBE epithelioid cells and THP-1 macrophages than the wild type strain, strain ΔpoxA was attenuated at least 1000-fold in mice, significant immune response and efficient protection were provided by the mutant ΔpoxA after oral immunization. It is concluded that the Salmonella Paratyphi A poxA deletion mutant ΔpoxA can be used as a live oral vaccine candidate against paratyphoid A.

Ovarian cancer: Diagnosis and treatment strategies (Review).

Ovarian cancer is a malignant tumor that seriously endangers health. Early ovarian cancer symptoms are frequently challenging to detect, resulting in a large proportion of patients reaching an advanced stage when diagnosed. Conventional diagnosis relies heavily on serum biomarkers and pathological examination, but their sensitivity and specificity require improvement. Targeted therapy inhibits tumor growth by targeting certain characteristics of tumor cells, such as signaling pathways and gene mutations. However, the effectiveness of targeted therapy varies among individuals due to differences in their unique biological characteristics and requires individualized strategies. Immunotherapy is a promising treatment for ovarian cancer due to its long-lasting antitumor effect. Nevertheless, issues such as variable efficacy, immune-associated adverse effects and drug resistance remain to be resolved. The present review discusses the diagnostic strategies, rationale, treatment strategies and prospects of targeted therapy and immunotherapy for ovarian cancer.

Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.

Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.

HPS6 Deficiency Leads to Reduced V-ATPase and Impaired Biogenesis of Lamellar Bodies in Alveolar Type II Cells.

Lamellar body (LB) is a tissue-specific lysosome-related organelle in type II alveolar cells, which is the main site for the synthesis, storage and secretion of pulmonary surfactants. Defects in pulmonary surfactants lead to a variety of respiratory and immune-related disorders. LB biogenesis is closely related to its function, but the underlying regulatory mechanism is largely unclear. Here, we found that deficiency of HPS6, a subunit of BLOC-2 (biogenesis of lysosome-related organelles complex-2), led to the reduction of the steady-state level of V-ATPase and the increase of luminal pH of LB. Furthermore, we observed increased LB size, accumulated surfactant proteins, and altered lipid profiling of lung tissue and bronchoalveolar lavage fluid due to HPS6 deficiency. These findings suggest that HPS6 regulates the distribution of V-ATPase on LBs to maintain its luminal acidity and LB homeostasis. This may provide new insights into the LB pathology.

Spatial prioritization for widespread invasive species control: Trade-offs between current impact and future spread.

Spatially explicit prioritization of invasive species control is a complex issue, requiring consideration of trade-offs between immediate and future benefits. This study aimed to prioritize management efforts to account for current and future threats from widespread invasions and examine the strength of the trade-off between these different management goals. As a case study, we identified spatially explicit management priorities for the widespread invasion of introduced willow into riparian and wetland habitats across a 102,145-km2 region in eastern Australia. In addition to targeting places where willow threatens biodiversity now, a second set of management goals was to limit reinfestation and further spread that could occur via two different mechanisms (downstream and by wind). A model of likely willow distribution across the region was combined with spatial data for biodiversity (native vegetation, threatened species and communities), ecological conditions, management costs, and two potential dispersal layers. We used systematic conservation planning software (Zonation) to prioritize where willow management should be focussed across more than 100,000 catchments for a range of different scenarios that reflected different weights between management goals. For willow invasion, we found that we could prioritize willow management to reduce the future threat of dispersal downstream with little reduction in the protection of biodiversity. However, accounting for future threats from wind dispersal resulted in a stronger trade-off with protection of threatened biodiversity. The strongest trade-off was observed when both dispersal mechanisms were considered together. This study shows that considering current and future goals together offers the potential to substantially improve conservation outcomes for invasive species management. Our approach also informs land managers about the relative trade-offs among different management goals under different control scenarios, helping to make management decisions more transparent. This approach can be used for other widespread invasive species to help improve invasive species management decisions.

Monitoring insect numbers and biodiversity with a vertical-beam entomological radar.

Concerns about perceived widespread declines in insect numbers have led to recognition of a requirement for long-term monitoring of insect biodiversity. Here we examine whether an existing, radar-based, insect monitoring system developed for research on insect migration could be adapted to this role. The radar detects individual larger (greater than 10 mg) insects flying at heights of 150-2550 m and estimates their size and mass. It operates automatically and almost continuously through both day and night. Accumulation of data over a 'half-month' (approx. 15 days) averages out weather effects and broadens the source area of the wind-borne observation sample. Insect counts are scaled or interpolated to compensate for missed observations; adjustment for variation of detectability with range and insect size is also possible. Size distributions for individual days and nights exhibit distinct peaks, representing different insect types, and Simpson and Shannon-Wiener indices of biodiversity are calculated from these. Half-month count, biomass and index statistics exhibit variations associated with the annual cycle and year to year changes that can be attributed to drought and periods of high rainfall. While species-based biodiversity measures cannot be provided, the radar's capacity to estimate insect biomass over a wide area indicates utility for tracking insect population sizes. This article is part of the theme issue 'Towards a toolkit for global insect biodiversity monitoring'.

Study on Spectrum Shifting and Pulse Splitting of Mode-Locked Fiber Lasers Based on NPR Technology.

We conducted a systematic investigation into the spectral and pulse characteristics of C and L-band Nonlinear Polarization Rotation (NPR) mode-locked fiber lasers effectively employing nonlinear polarization rotation technology. In our experimental setup, we achieved a stable mode-locked state at 1560.076 nm, exhibiting a 3 dB spectral bandwidth of 9.1 nm. As the pump power increased, we observed spectral shifts accompanied by shifts in the first Kelly sideband and the generation of new Kelly sidebands. In this paper, the phenomenon of spectral deviation is elucidated through the interplay of self-phase modulation, group velocity drift, and polarization-dependent isolator (PD-ISO) filter effect, with an analysis of the formation and deviation of Kelly sidebands. Notably, spectral shift persisted even when the pump power exceeded 200 mW. However, continuous pump power escalation led to soliton splitting, resulting in the formation of new soliton beams. Based on the simultaneous generation of spectral shift and pulse splitting, our study contributes to an enhanced understanding of soliton dynamics in ultrafast fiber lasers and lays a foundation for the application of high-repetition-frequency harmonic mode-locked lasers with tunable wavelengths.

Physical Contacts Between Mitochondria and WPBs Participate in WPB Maturation.

BACKGROUND: Weibel-Palade bodies (WPBs) are endothelial cell-specific cigar-shaped secretory organelles containing various biologically active molecules. WPBs play crucial roles in thrombosis, hemostasis, angiogenesis, and inflammation. The main content of WPBs is the procoagulant protein vWF (von Willebrand factor). Physical contacts and functional cross talk between mitochondria and other organelles have been demonstrated. Whether an interorganellar connection exists between mitochondria and WPBs is unknown. METHODS: We observed physical contacts between mitochondria and WPBs in human umbilical vein endothelial cells by electron microscopy and living cell confocal microscopy. We developed an artificial intelligence-assisted method to quantify the duration and length of organelle contact sites in live cells. RESULTS: We found there existed physical contacts between mitochondria and WPBs. Disruption of mitochondrial function affected the morphology of WPBs. Furthermore, we found that Rab3b, a small GTPase on the WPBs, was enriched at the mitochondrion-WPB contact sites. Rab3b deficiency reduced interaction between the two organelles and impaired the maturation of WPBs and vWF multimer secretion. CONCLUSIONS: Our results reveal that Rab3b plays a crucial role in mediating the mitochondrion-WPB contacts, and that mitochondrion-WPB coupling is critical for the maturation of WPBs in vascular endothelial cells.

Research on Spheroidization of Tungsten Powder from Three Different Raw Materials.

In this work, three kinds of tungsten powders with different particle sizes were spheroidized by radio-frequency (RF) inductively coupled plasma spheroidization. The spheroidization behavior of these tungsten powders was investigated and compared. The spheroidization effects of irregular tungsten powder improves with the decrease in degree of agglomeration and increases with primary particle size. Spherical tungsten powder from irregular powder with a primary particle size of 19.9 µm and an agglomeration coefficient of 1.59 had the best spheroidization effect; its apparent density, hall flow time, and spheroidization ratio are 9.36 g/cm3, 6.28 s/50 g, and 98%, respectively. The results show that irregular feedstock tungsten powder with a smaller primary particle size and higher agglomeration degree has a poor spheroidization effect because it is easily affected by the gas flow and deviates from the high temperature zone. On the contrary, irregular feedstock tungsten powder with larger primary particle sizes and lower agglomeration degrees has better spheroidization effects.

New insights into the pathogenesis of Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is characterized by defects of multiple tissue-specific lysosome-related organelles (LROs), typically manifesting with oculocutaneous albinism or ocular albinism, bleeding tendency, and in some cases with pulmonary fibrosis, inflammatory bowel disease or immunodeficiency, neuropsychological disorders. Eleven HPS subtypes in humans and at least 15 subtypes in mice have been molecularly identified. Current understanding of the underlying mechanisms of HPS is focusing on the defective biogenesis of LROs. Compelling evidences have shown that HPS protein-associated complexes (HPACs) function in cargo transport, cargo recycling, and cargo removal to maintain LRO homeostasis. Further investigation on the molecular and cellular mechanism of LRO biogenesis and secretion will be helpful for better understanding of its pathogenesis and for the precise intervention of HPS.

HPS6 Regulates the Biogenesis of Weibel-Palade Body in Endothelial Cells Through Trafficking v-ATPase to Its Limiting Membrane.

The Weibel-Palade body (WPB) is one of the lysosome-related organelles (LROs) in endothelial cells, whose main content is von Willebrand factor (vWF). The biogenesis of LROs is regulated by the Hermansky-Pudlak syndrome (HPS) protein-associated complexes through transporting cargo proteins to WPBs. Our previous studies have shown that HPS6, a subunit of BLOC-2 complex, is likely involved in the maturation of WPBs. However, the underlying mechanism remains unknown. In this study, we found that the knockdown of HPS6 in human umbilical vein endothelial cells (HUVECs) resulted in misshaped WPBs, decreased WPB number, and impaired vWF tubulation, which are similar to the characteristics of HPS6-deficient mouse endothelial cells. We observed similar morphological changes of WPBs in HUVECs after the knockdown of ATP6V0D1 (a subunit of v-ATPase). Furthermore, we found that HPS6 interacted with ATP6V0D1, suggesting that HPS6 transports ATP6V0D1 to the WPB limiting membrane for the assembly of the v-ATPase complex to maintain its acidic luminal pH, which is critical for the formation of vWF tubules during WPB maturation. In conclusion, HPS6 likely regulates the biogenesis of WPBs by participating in the trafficking of v-ATPase to the WPB membrane.

Bacteroides thetaiotaomicron relieves colon inflammation by activating aryl hydrocarbon receptor and modulating CD4+T cell homeostasis.

Inflammatory bowel disease (IBD) is a form of nonspecific chronic intestinal inflammation associated with gut microbiome dysbiosis. Modulating the composition of the intestinal flora may be a viable means of alleviating such inflammatory pathology. Bacteroides thetaiotaomicron (B. thetaiotaomicron) is a symbiotic intestinal microbe that has been associated with IBD, although the mechanistic basis for this association remains to be clarified. In this present study, we determined that B. thetaiotaomicron can alleviate colonic inflammation through mechanisms associated with the modulation of tryptophan metabolism and T cell subsets within inflamed intestinal tissues. Specifically, we found that B. thetaiotaomicron promotes the preferential differentiation of anti-inflammatory Treg/Th2 cells while suppressing the relative differentiation of pro-inflammatory Th1/Th17 cells, thereby decreasing inflammation within the colon. At a molecular level, B. thetaiotaomicron treatment was linked to altered CpG methylation within the Foxp3 promoter that was associated with enhanced Treg cell functionality. In a murine dextran sulfate sodium (DSS) colitis model system, B. thetaiotaomicron increased the levels of the aryl hydrocarbon receptor (AHR) ligands indole metabolites-indole acetic acid (IAA) and indole propionic acid (IPA), thereby increasing AHR activation that is related to changes of transcription factor expression profiles within T cells. In summary, our data suggest that B. thetaiotaomicron can activate AHR and modulate CD4+ T cell differentiation profiles in a murine DSS colitis model system, suggesting that this bacterium may be of therapeutic relevance for the treatment of IBD.

HPS1 Regulates the Maturation of Large Dense Core Vesicles and Lysozyme Secretion in Paneth Cells.

HPS1, a BLOC-3 subunit that acts as a guanine nucleotide exchange factor of Rab32/38, may play a role in the removal of VAMP7 during the maturation of large dense core vesicles of Paneth cells. Loss of HPS1 impairs lysozyme secretion and alters the composition of intestinal microbiota, which may explain the susceptibility of HPS-associated inflammatory bowel disease. Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding tendency, and other chronic organ lesions due to defects in tissue-specific lysosome-related organelles (LROs). For some HPS subtypes, such as HPS-1, it is common to have symptoms of HPS-associated inflammatory bowel disease (IBD). However, its underlying mechanism is largely unknown. HPS1 is a subunit of the BLOC-3 complex which functions in the biogenesis of LROs. Large dense core vesicles (LDCVs) in Paneth cells of the intestine are a type of LROs. We here first report the abnormal LDCV morphology (increased number and enlarged size) in HPS1-deficient pale ear (ep) mice. Similar to its role in melanosome maturation, HPS1 plays an important function in the removal of VAMP7 from LDCVs to promote the maturation of LDCVs. The immature LDCVs in ep mice are defective in regulated secretion of lysozyme, a key anti-microbial peptide in the intestine. We observed changes in the composition of intestinal microbiota in both HPS-1 patients and ep mice. These findings provide insights into the underlying mechanism of HPS-associated IBD development, which may be implicated in possible therapeutic intervention of this devastating condition.

Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway.

Alternative complement pathway (AP) plays an important role in the development of sepsis, which is life threatening. Deficiency of factor H-related protein 1 (FHR-1), which is a regulator of AP, has been considered as a susceptible factor for atypical hemolytic uremic syndrome (aHUS) and other types of nephropathy when an inducer such as infection exists. However, the underlying mechanism of the disease development is largely unknown. There is no report on CFHR1 gene knockout in any animal infection model and its function in vivo is still unclear. Here, a Cfhr1 knockout mouse was generated for investigating AP in sepsis and sepsis-induced acute kidney injury (AKI). We found that murine FHR-1 homolog (FHR-E) deficiency enhanced lipopolysaccharide (LPS)-induced AP activation both in vitro and in vivo and that Cfhr1 knockout mice exhibited more severe sepsis and AKI in response to LPS challenge. These results indicated that FHR-E deficiency promoted LPS-induced sepsis and AKI through AP over-activation, providing a mouse model for studying AP regulation and sepsis. This study revealed the function of FHR-E in vivo, which may further provide hints to the pathogenesis of FHR-1 deficiency-related diseases by enhancing LPS-induced AP activation.

SARS-CoV-2 infection-induced immune responses: Friends or foes?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that belongs to the ß-genus, causing the outbreak of coronavirus disease 19 (COVID-19). SARS-CoV-2 infection can stimulate a pronounced immune response in the host, which embodies in the decrease of lymphocytes and aberrant increase of cytokines in COVID-19 patients. SARS-CoV-2 RNA and proteins interact with various pattern recognition receptors that switch on antiviral immune responses to regulate viral replication and spreading within the host in vivo. However, overactive and impaired immune responses also cause immune damage and subsequent tissue inflammation. This article focuses on the dual roles of immune system during SARS-CoV-2 infection, providing a theoretical basic for identifying therapeutic targets in a situation with an unfavourable immune reaction.

Resolving the heading-direction ambiguity in vertical-beam radar observations of migrating insects.

Each year, massive numbers of insects fly across the continents at heights of hundreds of meters, carried by the wind, bringing both environmental benefits and serious economic and social costs. To investigate the insects' flight behavior and their response to winds, entomological radar has proved to be a particularly valuable tool; however, its observations of insect orientation are ambiguous with regard to the head/tail direction, and this greatly hinders interpretation of the migrants' flight behavior.We have developed two related methods of using wind data to resolve the head/tail ambiguity, and we have compared their outputs with those from simply assigning the heading direction to be that which is closer to the track direction. We applied all three methods to observations of Australian plague locust migrations made with an insect monitoring radar.For the study dataset, some of the headings selected by the simpler method are shown to be clearly incorrect. The two new methods generally agree and reveal a significantly different, and presumably more accurate, relationship of heading direction to track direction. However, use of these methods leads to quite a large proportion of the sample being lost because the wind values, which derive from a regional-scale numerical model, are shown to be incompatible with the radar observations. This exploratory study has moreover demonstrated that locusts are frequently oriented at a large angle to their track and that quite often their movement is at least slightly tailfirst.Both new methods appear to be a significant improvement on the simpler method. As well as providing an accurate representation of migratory flight behavior, they allow occasions when the model wind values are unreliable to be eliminated from the data sample.

Amplitude demodulation for electrical capacitance tomography based on singular value decomposition.

Amplitude demodulation is essential in image reconstruction for electrical capacitance tomography (ECT). In this paper, an amplitude demodulation method is proposed based on singular value decomposition (SVD), which can substitute the role of phase-sensitive demodulation in ECT. First, an M × N Hankel matrix is constructed based on a set of discrete samples. Then, SVD operation is performed on the matrix. Finally, the mathematical expression between the sinusoid amplitude and effective singular values is given; i.e., the first two singular values are used to estimate the amplitude information of the acquired signal. The proposed method has the following advantages: (1) since no reference signals are needed, the synchronization between the acquired and reference signals is not necessary; (2) this method can obtain the amplitude information of the acquired signal with a high signal-to-noise ratio (SNR), even in the case of non-integrity period sampling; and (3) SVD itself can also implement the filtering function; thus, no additional low-pass filters are required in the signal conditioning module. The demodulation accuracy and feasibility of the proposed method were verified by numerical simulations and experiments, indicating that it can provide amplitude demodulation with excellent SNR and robust performances.

A general method for evaluating the effects of air pollutants on lung cancer prevalence.

It is widely accepted that some air pollutants are related to lung cancer prevalence. An effective method is proposed to quantitatively evaluate the effects of air pollutants and the interactions between them. The method consisted of three parts: data decomposition, comparable data generation and relationship inference. Firstly, very limited monitoring data published by Geographic Information System were applied to calculate the inhalable air pollution of relatively massive patient samples. Then the investigated area was partitioned into a number of districts, and the comparable data containing air pollutant concentrations and lung cancer prevalence in all districts were generated. Finally, the relationships between pollutants and lung cancer prevalence were concluded by an information fusion tool: Choquet integral. As an example, the proposed method was applied in the investigation of air pollution in Tianjin, China. Overall, SO2, O3 and PM2.5 were the top three factors for lung cancer. And there was obvious positive interaction between O3 and PM2.5 and negative interaction among SO2, O3 and PM10. The effect of SO2 on men was larger than on women. O3 and SO2 were the most important factors for the adenocarcinoma and squamous cell carcinoma, respectively. The effect of SO2 or NO2 on squamous cell carcinoma is obviously larger than that on adenocarcinoma, while the effect of O3 or PM2.5 on adenocarcinoma is obviously larger than that on squamous cell carcinoma. The results provide important suggestions for management of pollutants and improvement of environmental quality. The proposed method without any parameter is general and easily realized, and it sets the foundation for further researches in other cities/countries. Implications: For total lung cancer prevalence, male and female lung cancer prevalence, and adenocarcinoma and squamous cell carcinoma prevalence, the proposed method not only quantify the effect of single pollutant (SO2, NO2, CO, O3, PM2.5, and PM10) but also reveals the correlations between different pollutants such as positive interaction or negative interaction. The proposed method without any geographic predictor and parameter is much easier to realize, and it sets the foundation for further research in other cities/countries. The study results provide important suggestions for the targeted management of different pollutants and the improvement of human lung health.

Singular value decomposition based impulsive noise reduction in multi-frequency phase-sensitive demodulation of electrical impedance tomography.

As an important means in electrical impedance tomography (EIT), multi-frequency phase-sensitive demodulation (PSD) can be viewed as a matched filter for measurement signals and as an optimal linear filter in the case of Gaussian-type noise. However, the additive noise usually possesses impulsive noise characteristics, so it is a challenging task to reduce the impulsive noise in multi-frequency PSD effectively. In this paper, an approach for impulsive noise reduction in multi-frequency PSD of EIT is presented. Instead of linear filters, a singular value decomposition filter is employed as the pre-stage filtering module prior to PSD, which has advantages of zero phase shift, little distortion, and a high signal-to-noise ratio (SNR) in digital signal processing. Simulation and experimental results demonstrated that the proposed method can effectively eliminate the influence of impulsive noise in multi-frequency PSD, and it was capable of achieving a higher SNR and smaller demodulation error.

Optimal distance of multi-plane sensor in three-dimensional electrical impedance tomography.

Electrical impedance tomography (EIT) is a visual imaging technique for obtaining the conductivity and permittivity distributions in the domain of interest. As an advanced technique, EIT has the potential to be a valuable tool for continuously bedside monitoring of pulmonary function. The EIT applications in any three-dimensional (3 D) field are very limited to the 3 D effects, i.e. the distribution of electric field spreads far beyond the electrode plane. The 3 D effects can result in measurement errors and image distortion. An important way to overcome the 3 D effect is to use the multiple groups of sensors. The aim of this paper is to find the best space resolution of EIT image over various electrode planes and select an optimal plane spacing in a 3 D EIT sensor, and provide guidance for 3 D EIT electrodes placement in monitoring lung function. In simulation and experiment, several typical conductivity distribution models, such as one rod (central, midway and edge), two rods and three rods, are set at different plane spacings between the two electrode planes. A Tikhonov regularization algorithm is utilized for reconstructing the images; the relative error and the correlation coefficient are utilized for evaluating the image quality. Based on numerical simulation and experimental results, the image performance at different spacing conditions is evaluated. The results demonstrate that there exists an optimal plane spacing between the two electrode planes for 3 D EIT sensor. And then the selection of the optimal plane spacing between the electrode planes is suggested for the electrodes placement of multi-plane EIT sensor.