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Abstract Background Preeclampsia, especially early-onset preeclampsia (EO-PE), is a pregnancy complication that has serious consequences for the health of both the mother and the fetus. Although abnormal placentation due to mitochondrial dysfunction is speculated to contribute to the development of EO-PE, the underlying mechanisms have yet to be fully elucidated. Methods The expression and localization of Siglec-6 in the placenta from normal pregnancies, preterm birth and EO-PE patients were examined by RT-qPCR, Western blot and IHC. Transwell assays were performed to evaluate the effect of Siglec-6 on trophoblast cell migration and invasion. Seahorse experiments were conducted to assess the impact of disrupting Siglec-6 expression on mitochondrial function. Co-IP assay was used to examine the interaction of Siglec-6 with SHP1/SHP2. RNA-seq was employed to investigate the mechanism by which Siglec-6 inhibits mitochondrial function in trophoblast cells. Results The expression of Siglec-6 in extravillous trophoblasts is increased in placental tissues from EO-PE patients. Siglec-6 inhibits trophoblast cell migration and invasion and impairs mitochondrial function. Mechanismly, Siglec-6 inhibits the activation of NF-κB by recruiting SHP1/SHP2, leading to increased expression of GPR20. Notably, the importance of GPR20 function downstream of Siglec-6 in trophoblasts is supported by the observation that GPR20 downregulation rescues defects caused by Siglec-6 overexpression. Finally, overexpression of Siglec-6 in the placenta induces a preeclampsia-like phenotype in a pregnant mouse model. Conclusions This study indicates that the regulatory pathway Siglec-6/GPR20 has a crucial role in regulating trophoblast mitochondrial function, and we suggest that Siglec-6 and GPR20 could serve as potential markers and targets for the clinical diagnosis and therapy of EO-PE.

ABSTRACT The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an ex vivo model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4+ cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our in vivo findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an ex vivo model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our in vivo study indicates that in contrast to in vitro observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency.

Fruits and vegetables are an important part of the human diet, but during transportation and storage, microbial pathogens attack and spoil fruits and vegetables, causing huge economic losses to agriculture. Traditionally used chemical fungicides leave chemical residues, leading to environmental pollution and health risks. With the emphasis on food safety, biocontrol agents are attracting more and more attention due to their environmental friendliness. Endophytic fungi are present in plant tissues and do not cause host disease. The volatile organic compounds (VOCs) they produce are used to control postharvest diseases due to their significant antifungal activity, as well as their volatility, safety and environmental protection characteristics. This review provides the concept and characterization of endophytic fungal VOCs, concludes the types of endophytic fungi that release antifungal VOCs and their biological control mechanisms, as well as focuses on the practical applications and the challenges of applying VOCs as fumigants. Endophytic fungal VOCs can be used as emerging biocontrol resources to control postharvest diseases that affect fruits and vegetables.

Abstract Introduction Locoregional recurrent breast cancers have a poor prognosis. Little is known about the prognostic impact of immune microenvironment, and tertiary lymphoid structures (TLSs) in particular have not been reported. Thus, we aimed to characterize the immune microenvironment in locoregional recurrent breast tumors and to investigate its relationship with prognosis. Methods We retrospectively included 112 patients with locoregional recurrent breast cancer, and hematoxylin–eosin staining and immunohistochemical staining (CD3, CD4, CD8, CD19, CD38, and CD68) were performed on locoregional recurrent tumor samples. The association of immune cells and TLSs with progression‐free survival (PFS) were analyzed by survival analysis. Results We found more immune cells in the peritumor than stroma. After grouping according to estrogen receptor (ER) status, a low level of peritumoral CD3+ cells in ER+ subgroup (p = 0.015) and a low level of stromal CD68+ cells in ER− subgroup (p = 0.047) were both associated with longer PFS. TLSs were present in 68% of recurrent tumors, and CD68+ cells within TLSs were significantly associated with PFS as an independent prognostic factor (p = 0.035). TLSs and immune cells (CD3, CD38, and CD68) within TLSs were associated with longer PFS in ER− recurrent tumors (p = 0.044, p = 0.012, p = 0.050, p

Lifelong treatment is required for people living with HIV as current antiretroviral therapy (ART) does not eradicate HIV infection. Latently infected cells are essentially indistinguishable from uninfected cells and cannot be depleted by currently available approaches. This study evaluated antibody mediated transient CD4+ T cell depletion as a strategy to reduce the latent HIV reservoir. Anti-CD4 antibodies effectively depleted CD4+ T cells in the peripheral blood and tissues of humanized mice. We then demonstrate that antibody-mediated CD4+ T cell depletion of HIV infected ART-suppressed animals results in substantial reductions in cell-associated viral RNA and DNA levels in peripheral blood cells over the course of anti-CD4 antibody treatment. Recovery of CD4+ T cells was observed in all tissues analyzed except for the lung 26 days after cessation of antibody treatment. After CD4+ T cell recovery, significantly lower levels of cell-associated viral RNA and DNA were detected in the tissues of anti-CD4 antibody-treated animals. Further, an 8.5-fold reduction in the levels of intact HIV proviral DNA and a 3.1-fold reduction in the number of latently infected cells were observed in anti-CD4-antibody-treated animals compared with controls. However, there was no delay in viral rebound when ART was discontinued in anti-CD4 antibody-treated animals following CD4+ T cell recovery compared with controls. Our results suggest that transient CD4+ T cell depletion, a long-standing clinical intervention that might have an acceptable safety profile, during suppressive ART can reduce the size of the HIV reservoir in humanized mice.

AbstractObjective This nonrandomized prospective clinical trial aimed to assess the efficacy, safety and follow-up outcomes of ultrasound-guided high-intensity focused ultrasound (USgHIFU) surgery in patients with breast fibroadenoma.Methods With the approval of the institutional ethics committee and written informed consent, a total of 113 patients diagnosed with breast fibroadenoma by core-needle biopsy in our hospital were recruited. USgHIFU surgery was performed under local anesthesia. Contrast-enhanced ultrasound (CEUS) or contrast-enhanced MRI (CEMRI) was performed to evaluate the nonperfused volume (NPV). The patients were followed up with physical examination and ultrasound imaging.Results The clinical outcome of 85 patients with 147 fibroadenomas with a follow-up time of more than 3 months was analyzed in this study. Fifty-two patients had one lesion, twenty-one patients had two lesions and twelve patients had more than two lesions. During USgHIFU, the median localization time for all fibroadenomas was 3 (interquartile range: 1, 5) min, and the median treatment time was 9 (interquartile range: 5, 15) min. Under local anesthesia, all the patients tolerated the treatment well. No serious epidermal burns were observed in any of the patients. Based on CEUS or CEMRI imaging evaluation, the median NPV ratio was 100% (interquartile range: 79.2%, 116.8%). The VRR were 26.77 ± 50.05%, 50.22 ± 42.01% and 72.74 ± 35.39% at 3–6 months, 6–12 months and >12 months, respectively, which showed significant statistical difference (p

Fungal pathogen contamination is one of the most important factors affecting the postharvest quality and shelf life of wolfberry fruits. Therefore, the prevention and control of fungal pathogens that cause fruit rot has become particularly important. Volatile antifungal agents of biological origin have broad application prospects. They may be safer and more efficient than traditional physical and chemical methods. Four pathogenic fungi were isolated and purified from rotting wolfberry. These pathogenic fungi were determined to be Mucor circinelloides LB1, Fusarium arcuatisporum LB5, Alternaria iridiaustralis LB7, and Colletotrichum fioriniae LB8. In vitro fumigation experiments showed that 2,3-butanedione can effectively inhibit the mycelial growth, spore germination, and sporulation ability of pathogenic fungi. The scanning electron microscope (SEM) showed morphological changes in hyphae. Propidium iodide (PI) Staining and leakage of 260 and 280 nm-absorbing increased, suggesting damage to cell membranes. Furthermore, 2,3-butanedione was found to significantly improve fruit firmness, soluble solid, total phenol, flavonoid, and soluble sugar content, as well as higher SOD enzyme activity and lower PPO and POD enzyme activity in the treated fruit, indicating that 2,3-butanedione can effectively reduce the adverse effects of pathogenic fungi in wolfberry. Based on these results, we conclude that 2,3-butanedione is effective against infection by pathogenic fungi in post-harvest wolfberry. 2,3-butanedione should be considered a viable substitute for conventional fungicides that are currently used to control rot in wolfberry.

Volatile organic compounds (VOCs) produced by antagonistic microorganisms have good biocontrol prospects against postharvest diseases. Infection caused by Alternaria iridiaustralis and 10 other significant fungal diseases can be successfully inhibited by VOCs produced by an identified and screened endophytic strain L1 (Bacillus velezensis). This study revealed the in vivo and in vitro biocontrol effects of VOCs released by B. velezensis L1 on A. iridiaustralis, a pathogenic fungus responsible for rot of wolfberry fruit. The inhibition rates of VOCs of B. velezensis L1 on the mycelial growth of A. iridiaustralis in vitro were 92.86 and 90.30%, respectively, when the initial inoculum concentration on the plate was 1 × 109 colony forming unit (CFU)/ml. Spore germination and sporulation were 66.89 and 87.96%, respectively. VOCs considerably decreased the wolfberry’s disease index and decay incidence in vivo. Scanning electron microscopy revealed that the morphological and structural characteristics of A. iridiaustralis could be altered by VOCs. Ten VOCs were identified through headspace-gas chromatography-ion mobility spectrometry. Pure chemical tests revealed that 2.3-butanedione had the strongest antifungal effects, totally inhibiting A. iridiaustralis in wolfberry fruit at a 60 μl/L concentration. The theory underpinning the potential application of VOCs from B. velezensis is provided herein. This is also the first study to document the antifungal capabilities of the B. velezensis strain on postharvest wolfberry fruit.GRAPHICAL ABSTRACT

Abstract Minimally invasive thermal therapies have been attempted in the treatment of breast cancer, and the immune response induced by these therapies has not been fully reported. A clinical trial is performed to determine the effect of microwave ablation (MWA) in the treatment of early‐stage breast cancer. The authors perform single‐cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from six patients before and after ablation. NK and CD8+T cells are activated by MWA of breast cancer, with the increased inhibitory signature of CD8+T cells but not dysfunctional. Enhanced co‐stimulatory signature of CD4+ T cells is observed and increased frequency of ICOS+CD4+ T cells after MWA is confirmed by flow cytometric analysis. After ablation, T‐cell clones expand with increased T‐cell receptor diversities. Activated antigen receptor‐mediated signaling pathways are found in B cells. Enhanced interactions between B cells and CD4+ T cells are found, indicating that B cells are important antigen‐presenting cells that initiate CD4+T cells in MWA‐induced immune response. Blockade of CTLA‐4 or PD‐1 of post‐MWA PBMCs show higher T‐cell activity than that of pre‐MWA PBMCs. This study provide global characteristics of MWA‐induced systemic immune response and pave a way for the identification of potential targets to improve the immune response.

HIV resistance to the Tat inhibitor didehydro-cortistatin A (dCA) in vitro correlates with higher levels of Tat-independent viral transcription and a seeming inability to enter latency, which rendered resistant isolates more susceptible to CTL-mediated immune clearance. Here, we investigated the ability of dCA-resistant viruses to replicate in vivo using a humanized mouse model of HIV infection. Animals were infected with WT or two dCA-resistant HIV-1 isolates in the absence of dCA and followed for 5 weeks. dCA-resistant viruses exhibited lower replication rates compared to WT. Viral replication was suppressed early after infection, with viral emergence at later time points. Multiplex analysis of cytokine and chemokines from plasma samples early after infection revealed no differences in expression levels between groups, suggesting that dCA-resistance viruses did not elicit potent innate immune responses capable of blocking the establishment of infection. Viral single genome sequencing results from plasma samples collected at euthanasia revealed that at least half of the total number of mutations in the LTR region of the HIV genome considered essential for dCA evasion reverted to WT. These results suggest that dCA-resistant viruses identified in vitro suffer a fitness cost in vivo, with mutations in LTR and Nef pressured to revert to wild type.