Hypoxia inducible factor 2α promotes tolerogenic macrophage development during cardiac transplantation through transcriptional regulation of colony stimulating factor 1 receptor.

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.

Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche.

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts1. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types2,3. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E2 (PGE2). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion οf a population of Sca-1+ reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1+ cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1+ cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE2-Ptger4. Analyses of patient-derived organoids established that PGE2-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE2-Ptger4-Yap signalling axis.

Altered distribution and loss of ACE2 into the urine in acute kidney injury.

There are diverse pathophysiological mechanisms involved in acute kidney injury (AKI). Among them, overactivity of the renin angiotensin system (RAS) has been described. Angiotensin converting enzyme 2 (ACE2) is a tissue RAS enzyme expressed in the apical border of proximal tubules. Given the important role of ACE2 in the metabolism of Angiotensin II this study was aimed to characterize kidney and urinary ACE2 in amouse model of AKI. Ischemia reperfusion injury (IRI) was induced in C57BL/6 mice by clamping of the left renal artery followed by removal of the right kidney. In kidneys harvested 48 hours after IRI, immunostaining revealed a striking maldistribution of ACE2 including spillage into the tubular lumen and presence of ACE2 positive luminal casts in the medulla. In cortical membranes ACE2 protein and enzymatic activity were both markedly reduced (37±4 vs. 100±6 ACE2/ß-Actin, P=0.0004 and 96±14 vs. 152±6 RFU/µg protein/h P=0.006). In urine, the full-length membrane bound ACE2 protein (100kD) was markedly increased (1120±405 vs. 100±46 ACE2/µg Crea, P=0.04) and casts stained for ACE2 were recovered in the urine sediment. In AKI caused by IRI there is a marked loss of ACE2 from the apical tubular border with deposition of ACE2 positive material in the medulla and increased urinary excretion of the full length-membrane bound ACE2 protein. The deficiency of tubular ACE2 in AKI suggests that provision of this enzyme could have therapeutic applications and that its excretion in the urine may also serve as a diagnostic marker of severe proximal tubular injury.

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy.

Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies-MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)-has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model.

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). Using this model, we evaluated tumor burden, T-cell activation, and cytokine release in response to bispecific T-cell-engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD-scid Il2rgnull mice lacking expression of mouse MHC class I and II (NSG-MHC-DKO mice) and implanted with a tumor xenograft predict both efficacy for tumor control by CD19xCD3 BiTE and stimulated cytokine release. Moreover, our findings indicate that this PBMC-engrafted model captures variability among donors for tumor control and cytokine release following treatment. Tumor control and cytokine release were reproducible for the same PBMC donor in separate experiments. The PBMC humanized mouse model described here is a sensitive and reproducible platform that identifies specific patient/cancer/therapy combinations for treatment efficacy and development of complications.

Fuzzy Entropy-Assisted Deconvolution Method and Its Application for Bearing Fault Diagnosis.

Vibration signal analysis is an important means for bearing fault diagnosis. Affected by the vibration of other machine parts, external noise and the vibration transmission path, the impulses induced by a bearing defect in the measured vibrations are very weak. Blind deconvolution (BD) methods can counteract the effect of the transmission path and enhance the fault impulses. Most BD methods highlight fault features of the filtered signals by impulse-featured objective functions (OFs). However, residual noise in the filtered signals has not been well tackled. To overcome this problem, a fuzzy entropy-assisted deconvolution (FEAD) method is proposed. First, FEAD takes advantage of the high noise sensitivity of fuzzy entropy (FuzzyEn) and constructs a weighted FuzzyEn-kurtosis OF to enhance the fault impulses while suppressing noise interference. Then, the PSO algorithm is used to iteratively solve the optimal inverse deconvolution filter. Finally, envelope spectrum analysis is performed on the filtered signal to realize bearing fault diagnosis. The feasibility of FEAD was first verified by the bearing fault simulation signals at constant and variable speeds. The bearing test signals from Case Western Reserve University (CWRU), the railway wheelset and the test bench validated the good performance of FEAD in fault feature enhancement. A comparison with and quantitative results for the other state-of-the-art BD methods indicated the superiority of the proposed method.

Fault Diagnosis Method for Rolling Bearings Based on Grey Relation Degree.

Aiming at the difficult problem of extracting fault characteristics and the low accuracy of fault diagnosis throughout the full life cycle of rolling bearings, a fault diagnosis method for rolling bearings based on grey relation degree is proposed in this paper. Firstly, the subtraction-average-based optimizer is used to optimize the parameters of the variational mode decomposition algorithm. Secondly, the vibration signals of bearings are decomposed by using the optimized results, and the feature vector of the intrinsic mode function component corresponding to the minimum envelope entropy is extracted. Finally, the grey proximity and similarity relation degree based on standard distance entropy are weighted to calculate the grey comprehensive relation degree between the feature vector of vibration signals and each standard state. By comparing the results, the diagnosis of different fault states and degrees of rolling bearings is realized. The XJTU-SY dataset was used for experimentation, and the results show that the proposed method achieves a diagnostic accuracy of 95.24% and has better diagnosis performance compared to various algorithms. It provides a reference for the fault diagnosis of rolling bearings throughout the full life cycle.

[Research on Locating Device for the Entry Point of Intramedullary Nail Based on Inertial Navigation].

Objective: To introduce a locating device for the entry point of intramedullary nail based on the inertial navigation technology, which utilizes multi-dimensional angle information to assist in rapid and accurate positioning of the ideal direction of femoral anterograde intramedullary nails' entry point, and to verify its clinical value through clinical tests. Methods: After matching the locating module with the developing board, which are the two components of the locating device, they were placed on the skin surface of the proximal femur of the affected side. Anteroposterior fluoroscopy was performed. The developing angle corresponding to the ideal direction of entry point was selected based on the X-ray image, and then the yaw angle of the locating module was reset to zero. After resetting, the locating module was combined with the surgical instrument to guide the insertion angle of the guide wire. The ideal direction of entry point was accurately located based on the angle guidance. By setting up an experimental group and a control group for clinical surgical operations, the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss with or without the locating device was recorded. Results: Compared to the control group, the experimental group showed significant improvement in the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss, with a statistically significant difference (P<0.01). Conclusion: The locating device can assist doctors in quickly locating the entry point of intramedullary nail, effectively reducing the fluoroscopy frequency and surgical time by improving the success rate of the guide wire insertion with one shot, improving surgical efficiency, and possessing certain clinical value.

Clay-Originated Two-Dimensional Holey Silica Separator for Dendrite-Free Lithium Metal Anode.

Lithium metal anode is the ultimate choice to obtain next-generation high-energy-density lithium batteries, while the dendritic lithium growth owing to the unstable lithium anode/electrolyte interface largely limits its practical application. Separator is an important component in batteries and separator engineering is believed to be a tractable and effective way to address the above issue. Separators can play the role of ion redistributors to guide the transport of lithium ions and regulate the uniform electrodeposition of Li. The electrolyte wettability, thermal shrinkage resistance, and mechanical strength are of importance for separators. Here, clay-originated two-dimensional (2D) holey amorphous silica nanosheets (ASN) to develop a low-cost and eco-friendly inorganic separator is directly adopted. The ASN-based separator has higher porosity, better electrolyte wettability, much higher thermal resistance, larger lithium transference number, and ionic conductivity compared with commercial separator. The large amounts of holes and rich surface oxygen groups on the ASN guide the uniform distribution of lithium-ion flux. Consequently, the Li//Li cell with this separator shows stable lithium plating/stripping, and the corresponding Li//LiFePO4 , Li//LiCoO2, and Li//NCM523 full cells also show high capacity, excellent rate performance, and outstanding cycling stability, which is much superior to that using the commercial separator.

Fractional carbon dioxide laser combined with subcision for the treatment of three subtypes of atrophic acne scars: a retrospective analysis.

Fractional carbon dioxide (CO2) laser combined with subcision has been widely used for the clinical treatment, but the efficacy of the combined therapy on three types of atrophic acne scars remains unreported. This retrospective study analyzed the clinical data of 413 patients with atrophic acne scars, treated with fractional CO2 laser combined with subcision in the combined group and with fractional CO2 laser in the control group. The treatment efficacy was evaluated by the Investigator's Global Assessment (IGA) and the Échelle d'évaluation clinique des cicatrices d'acné (ECCA). We reported adverse reactions such as erythema, lump, skin sensitivity, acne recurrence, and hyperpigmentation that occurred in both treatment groups. The treatment efficiency of the combined group was significantly higher than that of the control group (P < 0.001). Among the three subtypes of atrophic acne scars, the ECCA scores in the combined group of boxcar-type and rolling-type scars after treatment were lower than those in the control group (P = 0.041, P < 0.001, respectively), and no statistical difference in scores between the two groups for icepick-type scars was seen (P = 0.062). There was no statistical difference in adverse reactions between the two groups (P = 0.361). Fractional CO2 laser combined with subcision is more effective than fractional CO2 laser in the treatment of boxcar-type and rolling-type scars, but there is no significant difference in the treatment of icepick-type scars.

Heparin anticoagulation versus regional citrate anticoagulation for membrane therapeutic plasma exchange in patients with increased bleeding risk.

Background Heparin anticoagulation (HA) is commonly employed for membrane therapeutic plasma exchange (mTPE). However, for patients with increased bleeding risk, there were controversial opinions on the use of HA versus regional citrate anticoagulation (RCA) for mTPE. Our present study aimed to evaluate the efficacy and safety of HA vs. RCA for mTPE in patients with increased bleeding risk.Methods Patients with increased bleeding risk who underwent mTPE between 2014 and 2021 in our center were screened. Observations of anticoagulation efficacy and safety were used as the study endpoints.Results A total of 108 patients with 368 mTPE sessions were included. Of the included patients, 38 and 70 received HA and RCA mTPE, respectively. There was no significant difference in the clotting of extracorporeal circuits between the HA and RCA groups (4.1% vs. 4.4%, p = 0.605). More bleeding episodes were observed in the HA group compared to the RCA group (16.4% vs. 4.4% mTPE sessions, p < 0.001). The frequency of postoperative transfusion within 24 h (11% vs. 3.4%, p = 0.007) was significantly different in the HA and RCA group. Anticoagulation strategy (HA vs. RCA; OR 5.659, 95%CI 2.266-14.129; p < 0.001), and mean arterial pressure (prior treatment, OR 1.052, 95%CI 1.019-1.086; p = 0.002) were independent risk factors of bleeding episodes. At the end of mTPE treatment, the incidence of metabolic alkalosis (16.7% vs. 54.1%, p = 0.027) and hypocalcemia (41.7% vs. 89.2%, p = 0.001) was significantly different in the HA (n = 5, 12 sessions) and RCA (n = 22, 74 sessions) groups, respectively.Conclusion RCA is as effective as HA for mTPE. However, for patients with increased bleeding risk, RCA is associated with a lower risk of bleeding, compared with HA. With careful monitoring and timely adjustment, RCA most likely is a safe and effective anticoagulation option for mTPE in patients with increased bleeding risk.

A Novel Method for Bearing Fault Diagnosis under Variable Speed Based on Envelope Spectrum Fault Characteristic Frequency Band Identification.

Rolling element bearing (REB) vibration signals under variable speed (VS) have non-stationary characteristics. Order tracking (OT) and time-frequency analysis (TFA) are two widely used methods for REB fault diagnosis under VS. However, the effect of OT methods is affected by resampling errors and close-order harmonic interference, while the accuracy of TFA methods is mainly limited by time-frequency resolution and ridge extraction algorithms. To address this issue, a novel method based on envelope spectrum fault characteristic frequency band identification (FCFBI) is proposed. Firstly, the characteristics of the bearing fault vibration signal's envelope spectrum under VS are analyzed in detail and the fault characteristic frequency band (FCFB) is introduced as a new and effective representation of faults. Then, fault templates based on FCFB are constructed as reference for fault identification. Finally, based on the calculation of the correlation coefficients between the envelope spectrum and fault templates in the extended FCFB, the bearing fault can be diagnosed automatically according to the preset correlation coefficient criterion. Two bearing VS experiments indicate that the proposed method can achieve satisfactory diagnostic accuracy. The comparison of OT and TFA methods further demonstrates the comprehensive superiority of the proposed method in the overall consideration of accuracy, diagnostic time, tachometer dependency, and automatic degree.

Cross-Domain Echocardiography Segmentation with Multi-Space Joint Adaptation.

The segmentation of the left ventricle endocardium (LVendo) and the left ventricle epicardium (LVepi) in echocardiography plays an important role in clinical diagnosis. Recently, deep neural networks have been the most commonly used approach for echocardiography segmentation. However, the performance of a well-trained segmentation network may degrade in unseen domain datasets due to the distribution shift of the data. Adaptation algorithms can improve the generalization of deep neural networks to different domains. In this paper, we present a multi-space adaptation-segmentation-joint framework, named MACS, for cross-domain echocardiography segmentation. It adopts a generative adversarial architecture; the generator fulfills the segmentation task and the multi-space discriminators align the two domains on both the feature space and output space. We evaluated the MACS method on two echocardiography datasets from different medical centers and vendors, the publicly available CAMUS dataset and our self-acquired dataset. The experimental results indicated that the MACS could handle unseen domain datasets well, without requirements for manual annotations, and improve the generalization performance by 2.2% in the Dice metric.

Integrated Transcriptomic and Metabolomic Analysis Reveals the Mechanism of Gibberellic acid Regulates the Growth and Flavonoid Synthesis in Phellodendron chinense Schneid Seedlings.

The phytohormone gibberellic acids (GAs) play a crucial role in the processes of growth, organ development, and secondary metabolism. However, the mechanism of exogenous GA3 regulating the growth and flavonoid synthesis in Phellodendron chinense Schneid (P. chinense Schneid) seedlings remains unclear. In this study, the physicochemical properties, gene expression level, and secondary metabolite of P. chinense Schneid seedlings under GA3 treatment were investigated. The results showed that GA3 significantly improved the plant height, ground diameter, fresh weight, chlorophyll content, soluble substance content, superoxide dismutase, and peroxidase activities. This was accompanied by elevated relative expression levels of Pc(S)-GA2ox, Pc(S)-DELLA, Pc(S)-SAUR50, Pc(S)-PsaD, Pc(S)-Psb 27, Pc(S)-PGK, Pc(S)-CER3, and Pc(S)-FBA unigenes. Conversely, a notable reduction was observed in the carotenoid content, catalase activity and the relative expression abundances of Pc(S)-KAO, Pc(S)-GID1/2, and Pc(S)-GH 3.6 unigenes in leaves of P. chinense Schneid seedlings (p < 0.05). Furthermore, GA3 evidently decreased the contents of pinocembrin, pinobanksin, isosakuranetin, naringin, naringenin, (-)-epicatechin, tricetin, luteolin, and vitexin belonged to flavonoid in stem bark of P. chinense Schneid seedlings (p < 0.05). These results indicated that exogenous GA3 promoted growth through improving chlorophyll content and gene expression in photosynthesis and phytohormone signal pathway and inhibited flavonoid synthesis in P. chinense Schneid seedlings.

[The correlation between sperm DNA damage and IVF-ET clinical pregnancy outcomes in different BMI population with normal routine semen examination].

OBJECTIVE: To analyze the correlation between sperm DFI, HDS and IVF-ET pregnancy outcomes in different BMI populations with normal routine semen examination. METHODS: The clinical data of 199 cycles of IVF-ET were retrospectively analyzed. Sperm chromatin structure analysis based on flow cytometry was used to detect sperm DFI and HDS. The correlation between sperm DFI, HDS and pregnancy outcome of IVF-ET were analyzed. RESULTS: The sperm DFI was negatively correlated with IVF-ET pregnancy in overweight (24.0 kg/m2≤BMI<28.0 kg/m2) population (OR=0.935, P=0.043). In the normal BMI group (18.5 kg/m2≤BMI < 24.0 kg/m2), the clinical pregnancy outcome of IVF-ET was not significantly correlated with sperm DFI, and was negatively correlated with male age (OR=0.744, P=0.020). In the obese population (BMI ≥ 28.0 kg/m2) , there was no significant correlation between the clinical pregnancy outcome of IVF-ET and sperm DNA fragmentation index (DFI) , but a negative correlation with male BMI (OR = 0.779, P = 0.043). CONCLUSION: The male BMI affected the correlation between sperm DFI and IVF-ET pregnancy outcomes: ①Sperm DFI was only associated with IVF-ET clinical pregnancy outcome in the overweight population; ② In normal BMI and obese populations, male age and male BMI were important factors affecting IVF-ET clinical pregnancy outcome respectively; ③No correlation was found between sperm HDS and IVF-ET pregnancy outcomes.

Antibody-suppressor CXCR5+ CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice.

CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.

Exploring How a Generalist Pathogen and Within-Host Priority Effects Alter the Risk of Being Infected by a Specialist Pathogen.

AbstractIn multihost-multipathogen communities, a focal host's risk of being infected by a particular pathogen can be influenced by the presence of other host and pathogen species. We explore how indirect interactions between pathogens at the within-host level (through coinfecting the same individual) and the between-host level (through altered susceptible host densities) affect the focal host's risk of infection. We use an SI-type epidemiological model of two host species and two environmentally transmitted pathogens where one pathogen is a specialist on the focal host and the other pathogen is a generalist. We show that monotonic, unimodal, and U-shaped relationships between the specialist and generalist infectious propagule densities (proxies of the focal host's risk of infection) are driven by the way within-host priority effects alter the production of specialist infectious propagules by infected focal host individuals. Interestingly, within-host priority effects can also lead to overcompensation in density wherein increased infected host mortality results in greater specialist infectious propagule density. We interpret these results in terms of how the focal host's risk of being infected by a specialist pathogen is affected by the presence of a generalist pathogen, its alternative host, and within-host priority effects.

Optimization strategies for expression of a novel bifunctional anti-PD-L1/TGFBR2-ECD fusion protein.

The novel anti-PD-L1/TGFBR2-ECD fusion protein (BR102) comprises an anti-PD-L1 antibody (HS636) which is fused at the C terminus of the heavy chain to a TGF-ß1 receptor Ⅱ ectodomain (TGFBR2-ECD), and which can sequester the PD-1/PD-L1 pathway and TGF-ß bioactivity in the immunosuppressive tumor microenvironment. In the expression of TGFBR2-ECD wild-type fused protein (BR102-WT), a 50 kDa clipped species was confirmed to be induced by proteolytic cleavage at a "QKS" site located in the N-terminus of the ectodomain, which resulted in the formation of IgG-like clipping. The matrix metalloproteinase-9 was determined to be associated with BR102-WT digestion. In addition, it was observed that the N-glycosylation modifications of the fusion protein were tightly involved in regulating proteolytic activity and the levels of cleavage could be significantly suppressed by MMP-inhibitors. To avoid proteolytic degradation, eliminating protease-sensitive amino acid motifs and introducing potential glycosylation were performed. Three sensitive motifs were mutated, and the levels of clipping were strongly restrained. The mutant candidates exhibited similar binding affinities to hPD-L1 and hTGF-ß1 as well as highly purified BR102-WT2. Furthermore, the mutants displayed more significant proteolytic resistance than that of BR102-WT2 in the lysate incubation reaction and the plasma stability test. Moreover, the bifunctional candidate Mu3 showed an additive antitumor effect in MC38/hPD-L1 bearing models as compared to that of with anti-PD-L1 antibody alone. In conclusion, in this study, the protease-sensitive features of BR102-WT were well characterized and efficient optimization was performed. The candidate BR102-Mutants exhibited advanced druggability in drug stability and displayed desirable antitumor activity.

How public reaction to disease information across scales and the impacts of vector control methods influence disease prevalence and control efficacy.

With the development of social media, the information about vector-borne disease incidence over broad spatial scales can cause demand for local vector control before local risk exists. Anticipatory intervention may still benefit local disease control efforts; however, infection risks are not the only focal concerns governing public demand for vector control. Concern for environmental contamination from pesticides and economic limitations on the frequency and magnitude of control measures also play key roles. Further, public concern may be focused more on ecological factors (i.e., controlling mosquito populations) or on epidemiological factors (i.e., controlling infection-carrying mosquitoes), which may lead to very different control outcomes. Here we introduced a generic Ross-MacDonald model, incorporating these factors under three spatial scales of disease information: local, regional, and global. We tailored and parameterized the model for Zika virus transmitted by Aedes aegypti mosquito. We found that sensitive reactivity caused by larger-scale incidence information could decrease average human infections per patch breeding capacity, however, the associated increase in total control effort plays a larger role, which leads to an overall decrease in control efficacy. The shift of focal concerns from epidemiological to ecological risk could relax the negative effect of the sensitive reactivity on control efficacy when mosquito breeding capacity populations are expected to be large. This work demonstrates that, depending on expected total mosquito breeding capacity population size, and weights of different focal concerns, large-scale disease information can reduce disease infections without lowering control efficacy. Our findings provide guidance for vector-control strategies by considering public reaction through social media.

Iodine-Promoted Metal-Free Cyclization and O/S Exchange of Acrylamides with Thiuram: One-Step Synthesis of Quinolino-2-thiones.

A one-step cyclization and O/S exchange reaction of readily available acrylamides in the presence of iodine and thiuram has been developed. The reaction provides an efficient approach for the synthesis of highly important heterocycle quinolino-2-thiones with diverse substitution patterns.