Photonic time-delayed reservoir computing based on series-coupled microring resonators with high memory capacity.

On-chip microring resonators (MRRs) have been proposed to construct time-delayed reservoir computing (RC) systems, which offer promising configurations available for computation with high scalability, high-density computing, and easy fabrication. A single MRR, however, is inadequate to provide enough memory for the computation task with diverse memory requirements. Large memory requirements are satisfied by the RC system based on the MRR with optical feedback, but at the expense of its ultralong feedback waveguide. In this paper, a time-delayed RC is proposed by utilizing a silicon-based nonlinear MRR in conjunction with an array of linear MRRs. These linear MRRs possess a high quality factor, providing enough memory capacity for the RC system. We quantitatively analyze and assess the proposed RC structure's performance on three classical tasks with diverse memory requirements, i.e., the Narma 10, Mackey-Glass, and Santa Fe chaotic timeseries prediction tasks. The proposed system exhibits comparable performance to the system based on the MRR with optical feedback, when it comes to handling the Narma 10 task, which requires a significant memory capacity. Nevertheless, the dimension of the former is at least 350 times smaller than the latter. The proposed system lays a good foundation for the scalability and seamless integration of photonic RC.

Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer.

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment. METHODS: By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG's catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition. RESULTS: Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors. CONCLUSIONS: We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.

Star Formation Shut Down by Multiphase Gas Outflow in a Galaxy at a Redshift of 2.45.

Large-scale outflows driven by supermassive black holes are thought to play a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star formation quenching is remarkably rapid1-3, thus requiring effective removal of gas4 as opposed to slow gas heating5,6. While outflows of ionized gas are commonly detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at redshift z = 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray or radio activity are detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.

IncX3 plasmid-mediated spread of blaNDM gene in Enterobacteriaceae among children in China.

OBJECTIVES: The blaNDM gene was prevalent among children and became the predominant cause of severe infection in infants and children. This study aimed to investigate the epidemiology and molecular characteristics of blaNDM in Enterobacteriaceae among children in China. METHODS: Carbapenem-resistant Enterobacteriaceae (CRE) were collected in the Children's Hospital of Fudan University from January 2016 to December 2022. Five carbapenemase genes (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48) were screened by PCR method. Multilocus sequence typing (MLST) was conducted for phylogenetic analyses. blaNDM-carrying plasmids were typed by PCR-based Incompatibility (Inc) typing method. Moreover, plasmid comparison was performed with 213 publicly available IncX3 plasmids. RESULTS: A total of 330 CRE strains were enrolled, 96.4% of which carried carbapenemase genes. blaNDM gene accounted for 64.8% (214 strains) and included four variants, including blaNDM-1 (59.8%), blaNDM-5 (39.3%), blaNDM-7 (0.5%), and blaNDM-9 (0.5%). There were no predominant MLST lineages of blaNDM carrying strains. IncX3 was the major plasmid carrying blaNDM-1 (68.0%) and blaNDM-5 (72.6%) and was dominant in blaNDM-Klebsiella penumoniae (79.8%), blaNDM-Escherichia coli (58.2%), and blaNDM-Enterobacter cloacae (61.0%), respectively. Most (79.0%) clinical IncX3 plasmids in the world carried blaNDM, and the prevalence of blaNDM in IncX3 plasmids was more common in China (95.8%) than other countries (58.1%, P <0.01). CONCLUSION: blaNDM is highly prevalent in CRE among children in China. The spread of blaNDM was mainly mediated by IncX3 plasmids. Surveillance and infection control on the spread of blaNDM among children are important.

All-Trans-Retinoic Acid-Adjuvanted mRNA Vaccine Induces Mucosal Anti-Tumor Immune Responses for Treating Colorectal Cancer.

Messenger RNA (mRNA) cancer vaccines are a new class of immunotherapies that can activate the immune system to recognize and destroy cancer cells. However, their effectiveness in treating colorectal cancer located on the mucosal surface of the gut is limited due to the insufficient activation of mucosal immune response and inadequate infiltration of cytotoxic T cells into tumors. To address this issue, a new mRNA cancer vaccine is developed that can stimulate mucosal immune responses in the gut by co-delivering all-trans-retinoic acid (ATRA) and mRNA using lipid nanoparticle (LNP). The incorporation of ATRA has not only improved the mRNA transfection efficiency of LNP but also induced high expression of gut-homing receptors on vaccine-activated T cells. Additionally, the use of LNP improves the aqueous solubility of ATRA, eliminating the need for toxic solvents to administer ATRA. Upon intramuscular injections, ATRA-adjuvanted mRNA-LNP significantly increase the infiltration of antigen-specific, cytotoxic T cells in the lamina propria of the intestine, mesenteric lymph nodes, and orthotopic colorectal tumors, resulting in significantly improved tumor inhibition and prolonged animal survival compared to conventional mRNA-LNP without ATRA. Overall, this study provides a promising approach for improving the therapeutic efficacy of mRNA cancer vaccines against colorectal cancer.

Impact Of Low-Frequency HIV-1 Drug Resistance Mutations On Antiretroviral Therapy Outcomes.

BACKGROUND: The association between low-frequency HIV-1 drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using NGS methods that accurately sample low-frequency DRMs. METHODS: We enrolled women with HIV-1 in Malawi who were either ART naïve (A), had ART failure (B), or had discontinued ART (C). At entry, A and C began an NNRTI-based regimen and B started a PI-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤ 20%. RESULTS: We sequenced 360 participants. Cohort B and C participants were more likely to have TF than Cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HR of 3.12 [1.58-6.18, 95% CI] and 2.38 [1.00-5.67, 95% CI] respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART. CONCLUSIONS: Using accurate NGS for DRM detection may benefit an additional 10% of the patients by identifying low-frequency K103N mutations.

Predictors of HIV rebound differ by timing of antiretroviral therapy initiation.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Hidden Flaws Behind Expert-Level Accuracy of Multimodal GPT-4 Vision in Medicine.

Recent studies indicate that Generative Pre-trained Transformer 4 with Vision (GPT-4V) outperforms human physicians in medical challenge tasks. However, these evaluations primarily focused on the accuracy of multi-choice questions alone. Our study extends the current scope by conducting a comprehensive analysis of GPT-4V's rationales of image comprehension, recall of medical knowledge, and step-by-step multimodal reasoning when solving New England Journal of Medicine (NEJM) Image Challenges - an imaging quiz designed to test the knowledge and diagnostic capabilities of medical professionals. Evaluation results confirmed that GPT-4V performs comparatively to human physicians regarding multi-choice accuracy (81.6% vs. 77.8%). GPT-4V also performs well in cases where physicians incorrectly answer, with over 78% accuracy. However, we discovered that GPT-4V frequently presents flawed rationales in cases where it makes the correct final choices (35.5%), most prominent in image comprehension (27.2%). Regardless of GPT-4V's high accuracy in multi-choice questions, our findings emphasize the necessity for further in-depth evaluations of its rationales before integrating such multimodal AI models into clinical workflows.

Coexistence of a novel SRBD1-ALK, ALK-CACNA1D double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report.

A Chinese male patient with advanced lung adenocarcinoma experienced disease progression one and a half years after receiving first-line immunochemotherapy. The second biopsy was performed and tissue immunohistochemistry revealed Anaplastic lymphoma kinase (ALK) expression in the cytoplasm of tumor cells, so he began to receive Alectinib treatment. Then the next generation sequencing found double fusion variants of S1 RNA binding domain 1 (SRBD1)- ALK and ALK- Calcium voltage-gated channel subunit alpha1 D (CACNA1D). After continuous Alectinib treatment for 7 months, almost complete response (CR) was achieved. The patient is currently taking Alectinib for 13 months, the condition is stable, and is waiting for the next cycle of efficacy evaluation.

A Novel Bacillus Velezensis for Efficient Degradation of Zearalenone.

Zearalenone (ZEN) is considered one of the most serious mycotoxins contaminating grains and their by-products, causing significant economic losses in the feed and food industries. Biodegradation pathways are currently considered the most efficient solution to remove ZEN contamination from foods. However, low degradation rates and vulnerability to environmental impacts limit the application of biodegradation pathways. Therefore, the main research objective of this article was to screen strains that can efficiently degrade ZEN and survive under harsh conditions. This study successfully isolated a new strain L9 which can efficiently degrade ZEN from 108 food ingredients. The results of sequence alignment showed that L9 is Bacillus velezensis. Meanwhile, we found that the L9 degradation rate reached 91.14% at 24 h and confirmed that the primary degradation mechanism of this strain is biodegradation. The strain exhibits resistance to high temperature, acid, and 0.3% bile salts. The results of whole-genome sequencing analysis showed that, it is possible that the strain encodes the key enzyme, such as chitinase, carboxylesterases, and lactone hydrolase, that work together to degrade ZEN. In addition, 227 unique genes in this strain are primarily involved in its replication, recombination, repair, and protective mechanisms. In summary, we successfully excavated a ZEN-degrading, genetically distinct strain of Bacillus velezensis that provides a solid foundation for the detoxification of feed and food contamination in the natural environment.

SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency.

Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent coronavirus disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median times to nasal viral RNA and culture clearance in individuals with severe immunosuppression due to hematologic malignancy or transplant (S-HT) were 72 and 40 days, respectively, both of which were significantly longer than clearance rates in individuals with severe immunosuppression due to autoimmunity or B cell deficiency (S-A), individuals with nonsevere immunodeficiency, and nonimmunocompromised groups (P < 0.01). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing resistance against therapeutic monoclonal antibodies. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral responses, whereas only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across distinct immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.

Review: The Landscape of Antiviral Therapy for COVID-19 in the Era of Widespread Population Immunity and Omicron-Lineage Viruses.

The goals of coronavirus disease 2019 (COVID-19) antiviral therapy early in the pandemic were to prevent severe disease, hospitalization, and death. As these outcomes have become infrequent in the age of widespread population immunity, the objectives have shifted. For the general population, COVID-19-directed antiviral therapy should decrease symptom severity and duration and minimize infectiousness, and for immunocompromised individuals, antiviral therapy should reduce severe outcomes and persistent infection. The increased recognition of virologic rebound following ritonavir-boosted nirmatrelvir (NMV/r) and the lack of randomized controlled trial data showing benefit of antiviral therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for standard-risk, vaccinated individuals remain major knowledge gaps. Here, we review data for selected antiviral agents and immunomodulators currently available or in late-stage clinical trials for use in outpatients. We do not review antibody products, convalescent plasma, systemic corticosteroids, IL-6 inhibitors, Janus kinase inhibitors, or agents that lack Food and Drug Administration approval or emergency use authorization or are not appropriate for outpatients.

Charge Dispersion Strategy for High-Performance and Rain-Proof Triboelectric Nanogenerator.

Triboelectric nanogenerator (TENG) is becoming a sustainable and renewable way of energy harvesting and self-powered sensing because of low cost, simple structure, and high efficiency. However, the output current of existing TENGs is still low. It is proposed that the output current of TENGs can be dramatically improved if the triboelectric charges can distribute inside the triboelectric layers. Herein, a novel single-electrode conductive network-based TENG (CN-TENG) is developed by introducing a conductive network of multiwalled carbon nanotubes in dielectric triboelectric layer of thermoplastic polyurethane (TPU). In this CN-TENG, the contact electrification-induced charges distribute on both the surface and interior of the dielectric TPU layer. Thus, the short-circuit current of CN-TENG improves for 100-fold, compared with that of traditional dielectric TENG. In addition, this CN-TENG, even without packing, can work stably in high-humidity environments and even in the rain, which is another main challenge for conventional TENGs due to charge leakage. Further, this CN-TENG is applied for the first time, to successfully distinguish conductive and dielectric materials. This work provides a new and effective strategy to fabricate TENGs with high output current and humidity-resistivity, greatly expanding their practical applications in energy harvesting, movement sensing, human-machine interaction, and so on.

SARS-CoV-2 mRNA Vaccines Induce Greater Complement Activation and Decreased Viremia and Nef Antibodies in Men With HIV-1.

BACKGROUND: Immune dysregulation in people with human immunodeficiency virus-1 (PWH) persists despite potent antiretroviral therapy and, consequently, PWH tend to have lower immune responses to licensed vaccines. However, limited information is available about the impact of mRNA vaccines in PWH. This study details the immunologic responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in PWH and their impact on HIV-1. METHODS: We quantified anti-S immunoglobulin G (IgG) binding and neutralization of 3 SARS-CoV-2 variants of concern and complement activation in blood from virally suppressed men with HIV-1 (MWH) and men without HIV-1 (MWOH), and the characteristics that may impact the vaccine immune responses. We also studied antibody levels against HIV-1 proteins and HIV-1 plasma RNA. RESULTS: MWH had lower anti-S IgG binding and neutralizing antibodies against the 3 variants compared to MWOH. MWH also produced anti-S1 antibodies with a 10-fold greater ability to activate complement and exhibited higher C3a blood levels than MWOH. MWH had decreased residual HIV-1 plasma viremia and anti-Nef IgG approximately 100 days after immunization. CONCLUSIONS: MWH respond to SARS-CoV-2 mRNA vaccines with lower antibody titers and with greater activation of complement, while exhibiting a decrease in HIV-1 viremia and anti-Nef antibodies. These results suggest an important role of complement activation mediating protection in MWH.

SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study.

BACKGROUND: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR). OBJECTIVE: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. DESIGN: Observational cohort study. SETTING: Multicenter health care system in Boston, Massachusetts. PARTICIPANTS: Ambulatory adults with acute COVID-19 with and without use of N-R. INTERVENTION: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. MEASUREMENTS: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL. RESULTS: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected. LIMITATIONS: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission. CONCLUSION: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus. PRIMARY FUNDING SOURCE: National Institutes of Health.

Viral and host mediators of non-suppressible HIV-1 viremia.

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

Current Advances of Atomically Dispersed Metal-Centered Nanozymes for Tumor Diagnosis and Therapy.

Nanozymes, which combine enzyme-like catalytic activity and the biological properties of nanomaterials, have been widely used in biomedical fields. Single-atom nanozymes (SANs) with atomically dispersed metal centers exhibit excellent biological catalytic activity due to the maximization of atomic utilization efficiency, unique metal coordination structures, and metal-support interaction, and their structure-activity relationship can also be clearly investigated. Therefore, they have become an emerging alternative to natural enzymes. This review summarizes the examples of nanocatalytic therapy based on SANs in tumor diagnosis and treatment in recent years, providing an overview of material classification, activity modulation, and therapeutic means. Next, we will delve into the therapeutic mechanism of SNAs in the tumor microenvironment and the advantages of synergistic multiple therapeutic modalities (e.g., chemodynamic therapy, sonodynamic therapy, photothermal therapy, chemotherapy, photodynamic therapy, sonothermal therapy, and gas therapy). Finally, this review proposes the main challenges and prospects for the future development of SANs in cancer diagnosis and therapy.

Defective Uterine Spiral Artery Remodeling and Placental Senescence in a Pregnant Rat Model of Polycystic Ovary Syndrome.

Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.

SARS-CoV-2 Viral Clearance and Evolution Varies by Extent of Immunodeficiency.

Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged SARS-CoV-2 infection, but the immune defects that predispose to persistent COVID-19 remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median time to nasal viral RNA and culture clearance in the severe hematologic malignancy/transplant group (S-HT) were 72 and 40 days, respectively, which were significantly longer than clearance rates in the severe autoimmune/B-cell deficient (S-A), non-severe, and non-immunocompromised groups (P<0.001). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing antiviral treatment resistance. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral, while only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.

Effects of maternal hypothyroidism on postnatal cardiomyocyte proliferation and cardiac disease responses of the progeny.

Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.