Perinatal Licensing of Thermogenesis by IL-33 and ST2.

For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the "alarmin" IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period. PAPERCLIP.

Activated type 2 innate lymphoid cells regulate beige fat biogenesis.

Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα(+) APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PAPERCLIP:

Secular Trends in Outcomes and Impact of Novel Oral Anticoagulants in Atrial Fibrillation-Related Acute Ischemic Stroke.

BACKGROUND: Novel oral anticoagulants (NOACs) are currently recommended for the secondary prevention of stroke in patients with acute ischemic stroke (AIS) accompanied by atrial fibrillation (AF). However, the impact of NOACs on clinical outcomes in real-world practice remains ambiguous. This study analyzes the trend of clinical events in patients with AF-related AIS and determines how much the introduction of NOACs has mediated this trend. METHODS: We identified patients with AIS and AF between January 2011 and December 2019 using a multicenter stroke registry. Annual rates of NOAC prescriptions and clinical events within 1 year were evaluated. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. To assess the mediation effect of NOACs on the relationship between the calendar year and these outcomes, we used natural effect models and conducted exposure-mediator, exposure-outcome, and mediator-outcome analyses using multivariable regression models or accelerated failure time models, adjusting for potential confounders. RESULTS: Among the 12 977 patients with AF-related AIS, 12 500 (average age: 74.4 years; 51.3% male) were analyzed after excluding cases of valvular AF. Between 2011 and 2019, there was a significant decrease in the 1-year incidence of the primary composite outcome from 28.3% to 21.7%, while the NOAC prescription rate increased from 0% to 75.6%. A 1-year increase in the calendar year was independently associated with delayed occurrence of the primary outcome (adjusted time ratio, 1.10 [95% CI, 1.07-1.14]) and increased NOAC prescription (adjusted odds ratio, 2.20 [95% CI, 2.14-2.27]). Increased NOAC prescription was associated with delayed occurrence of the primary outcome (adjusted time ratio, 3.82 [95% CI, 3.17 to 4.61]). Upon controlling for NOAC prescription (mediator), the calendar year no longer influenced the primary outcome (adjusted time ratio, 0.97 [95% CI, 0.94-1.00]). This suggests that NOAC prescription mediates the association between the calendar year and the primary outcome. CONCLUSIONS: Our study highlights a temporal reduction in major clinical events or death in Korean patients with AF-related AIS, mediated by increased NOAC prescription, emphasizing NOAC use in this population.

CMOS-Integrated Ternary Content Addressable Memory using Nanocavity CBRAMs for High Sensing Margin.

The development of data-intensive computing methods imposes a significant load on the hardware, requiring progress toward a memory-centric paradigm. Within this context, ternary content-addressable memory (TCAM) can become an essential platform for high-speed in-memory matching applications of large data vectors. Compared to traditional static random-access memory (SRAM) designs, TCAM technology using non-volatile resistive memories (RRAMs) in two-transistor-two-resistor (2T2R) configurations presents a cost-efficient alternative. However, the limited sensing margin between the match and mismatch states in RRAM structures hinders the potential of using memory-based TCAMs for large-scale architectures. Therefore, this study proposes a practical device engineering method to improve the switching response of conductive-bridge memories (CBRAMs) integrated with existing complementary metal-oxide-semiconductor (CMOS) transistor technology. Importantly, this work demonstrates a significant improvement in memory window reaching 1.87 × 107 by incorporating nanocavity arrays and modifying electrode geometry. Consequently, TCAM cells using nanocavity-enhanced CBRAM devices can exhibit a considerable increase in resistance ratio up to 6.17 × 105, thereby closely approximating the sensing metrics observed in SRAM-based TCAMs. The improved sensing capability facilitates the parallel querying of extensive data sets. TCAM array simulations using experimentally verified device models indicate a substantial sensing margin of 65× enabling a parallel search of 2048 bits.

Association between Smoking Habit Changes and the Risk of Myocardial Infarction in Ischemic Stroke Patients: a Nationwide cohort study.

INTRODUCTION: Smoking is a well-known risk factor for cardiovascular diseases, including myocardial infarction (MI) and ischemic stroke (IS). While the relationship between smoking and the risk of cardiovascular diseases is established, the impact of changing smoking habits post-IS on the risk of subsequent MI remains unclear. This study aims to elucidate the effects of alterations in smoking behavior following an IS diagnosis on the likelihood of experiencing an MI. METHODS: Utilizing data from the Korean National Health Insurance Services Database, this nationwide population-based cohort study included 199,051 participants diagnosed with IS between January 2010 and December 2016. Smoking status was categorized based on changes in smoking habits before and after IS diagnosis. The association between changes in smoking behavior and the risk of subsequent MI was analyzed using multivariable Cox proportional hazard regression models. RESULTS: During a median follow-up of 4.17 person-years, a total of 5,734 (2.88%) patients were diagnosed with MI after IS. Smoking quitters (2.93%) or former smokers (2.47%) have a similar or lower rate of MI than the average, even if they have smoked cigarettes, while sustained smokers (3.46%) or new smokers (3.81%) have much higher rates of MI. Among sustained and new smokers, the risk of incident MI were significantly higher than never smokers (new smoker adjusted HR [aHR]: 1.496, 95% CI 1.262-1.774; sustained smoker aHR 1.494, 95% CI 1.361-1.641). Also, among the study participants, approximately two-thirds continued smoking after their IS diagnosis. CONCLUSION: Changing smoking habits after an IS diagnosis significantly influences the risk of subsequent MI. Specifically, continuing or starting to smoke after an IS diagnosis is associated with a higher risk of MI. These results underscore the importance of targeted smoking cessation interventions for stroke patients to reduce the risk of subsequent myocardial infarction.

Solution-processable low-voltage carbon nanotube field-effect transistors with high-krelaxor ferroelectric polymer gate insulator.

Achieving energy-efficient and high-performance field-effect transistors (FETs) is one of the most important goals for future electronic devices. This paper reports semiconducting single-walled carbon nanotube FETs (s-SWNT-FETs) with an optimized high-krelaxor ferroelectric insulator P(VDF-TrFE-CFE) thickness for low-voltage operation. The s-SWNT-FETs with an optimized thickness (∼800 nm) of the high-kinsulator exhibited the highest average mobility of 14.4 cm2V-1s-1at the drain voltage (ID) of 1 V, with a high current on/off ratio (Ion/off>105). The optimized device performance resulted from the suppressed gate leakage current (IG) and a sufficiently large capacitance (>50 nF cm-2) of the insulating layer. Despite the extremely high capacitance (>100 nF cm-2) of the insulating layer, an insufficient thickness (<450 nm) induces a highIG, leading to reducedIDand mobility of s-SWNT-FETs. Conversely, an overly thick insulator (>1200 nm) cannot introduce sufficient capacitance, resulting in limited device performance. The large capacitance and sufficient breakdown voltage of the insulating layer with an appropriate thickness significantly improved p-type performance. However, a reduced n-type performance was observed owing to the increased electron trap density caused by fluorine proportional to the insulator thickness. Hence, precise control of the insulator thickness is crucial for achieving low-voltage operation with enhanced s-SWNT-FET performance.

Association between physical activity changes and incident myocardial infarction after ischemic stroke: a nationwide population-based study.

BACKGROUND: The impact of changes in physical activity after ischemic stroke (IS) on the subsequent myocardial infarction (MI) risk is not fully understood. We aimed to investigate the effects of changes in physical activity on the risk of MI after acute IS using data from the Korean National Health Insurance Services Database. METHODS: 224,764 patients newly diagnosed with IS between 2010 and 2016 who underwent two serial biannual health checkups were included. The participants were divided into four categories according to changes in their physical activity: persistent non-exercisers, new exercisers, exercise dropouts, and exercise maintainers. The primary outcome was a new diagnosis of incident MI. Multivariable Cox proportional models were used to assess the effects of changes in exercise habits on the risk of MI. RESULTS: After a median of 4.25 years of follow-up, 6,611 (2.94%) MI cases were observed. After adjusting for confounders, new exercisers and exercise maintainers were significantly associated with a lower risk of incident MI than persistent non-exercisers (aHR, 0.849; 95% CI, 0.792-0.911; P-value < 0.001; and aHR, 0.746; 95% CI, 0.696-0.801; P-value < 0.001, respectively). Effects were consistent across sexes, more pronounced in those > 65 years. Notably, any level of physical activity after stroke was associated with a reduced MI risk compared to no exercise. CONCLUSIONS: In this nationwide cohort study, commencing or sustaining physical activity after an IS corresponded to a diminished likelihood of subsequent MI development. Advocating physical activity in ambulatory stroke survivors could potentially attenuate the prospective risk of MI.

Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Evaluation of a Photo Captioning Cognitive Empathy Intervention for Dementia Caregivers.

OBJECTIVES: The goal of this study was to develop and evaluate an intervention aimed at increasing cognitive empathy, improving mental health, and reducing inflammation in dementia caregivers, and to examine the relevant neural and psychological mechanisms. METHODS: Twenty dementia caregivers completed an intervention that involved taking 3-5 daily photographs of their person living with dementia (PLWD) over a period of 10 days and captioning those photos with descriptive text capturing the inner voice of the PLWD. Both before and after the intervention, participants completed questionnaires, provided a blood sample for measures of inflammation, and completed a neuroimaging session to measure their neural response to viewing photographs of their PLWD and others. RESULTS: 87% of enrolled caregivers completed the intervention. Caregivers experienced pre- to post-intervention increases in cognitive empathy (i.e. Perspective-Taking) and decreases in both burden and anxiety. These changes were paralleled by an increased neural response to photographs of their PLWD within brain regions implicated in cognitive empathy. CONCLUSION: These findings warrant a larger replication study that includes a control condition and follows participants to establish the duration of the intervention effects. CLINICAL IMPLICATIONS: Cognitive empathy interventions may improve caregiver mental health and are worthy of further investigation.

Downregulation of AP1S1 causes the lysosomal degradation of EGFR in non-small cell lung cancer.

Matrix stiffness has been shown to play a critical role in cancer progression by influencing various cellular processes, including epidermal growth factor (EGF) signaling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1), a component of adaptor protein complex-1, in the regulation of EGF receptor (EGFR) intracellular trafficking during cancer cell progression. We found that AP1S1 expression was upregulated under stiff matrix conditions, resulting in the regulation of EGFR trafficking in non-small cell lung adenocarcinoma cells. Knockout of AP1S1 caused the lysosomal degradation of EGFR, leading to suppressed EGF-induced anaplastic lymphoma receptor tyrosine kinase phosphorylation. In addition, the downregulation of AP1S1 increased the sensitivity of H1975 cancer cells, which are resistant to tyrosine kinase inhibitors, to erlotinib. Collectively, our results suggest that AP1S1 could regulate EGFR recycling under stiff matrix conditions, and AP1S1 inhibition could be a novel strategy for treating cancer cells resistant to EGFR-targeted anticancer drugs.

Nontypical Wulff-Shape Silicon Nanosheets with High Catalytic Activity.

Nanostructured silicon with an equilibrium shape has exhibited hydrogen evolution reaction activity mainly owing to its high surface area, which is distinct from that of bulk silicon. Such a Wulff shape of silicon favors low-surface-energy planes, resulting in silicon being an anisotropic and predictably faceted solid in which certain planes are favored, but this limits further improvement of the catalytic activity. Here, we introduce nanoporous silicon nanosheets that possess high-surface-energy crystal planes, leading to an unconventional Wulff shape that bolsters the catalytic activity. The high-index plane, uncommonly seen in the Wulff shape of bulk Si, has a band structure optimally aligned with the redox potential necessary for hydrogen generation, resulting in an apparent quantum yield (AQY) of 12.1% at a 400 nm wavelength. The enhanced light absorption in nanoporous silicon nanosheets also contributes to the high photocatalytic activity. Collectively, the strategy of making crystals with nontypical Wulff shapes can provide a route toward various classes of photocatalysts for hydrogen production.

Predicting Role of Prestroke Glycemic Variability Estimated by Glycated Albumin for Reperfusion and Prognosis after Endovascular Treatment.

INTRODUCTION: Glycated hemoglobin is widely used for the diagnosis of diabetes, but it is not accurately correlated with blood glucose fluctuations. We evaluated the impact of prestroke glycemic variability, measured by glycated albumin (GA) on reperfusion rate and stroke outcomes after endovascular treatment (EVT). METHODS: We consecutively collected 310 EVT-treated patients for 60 months using a multicenter registry database. Primary outcome was unsuccessful reperfusion defined by modified Thrombolysis in Cerebral Infarction grade 0 to 2a. Secondary outcomes were occurrence of early neurologic deterioration (END), symptomatic hemorrhagic transformation (SHT) and a 3-month poor outcome (modified Rankin Scale >2). GA was measured in the morning after hospital admission with overnight fasting and determined to reflect high prestroke glycemic variability (GA ≥16.0%). RESULTS: Over the median follow-up of 60 months of 310 patients, there were 64 (20.6%) events of unsuccessful reperfusion, 66 (21.3%) of END, 21 (6.8%) of SHT, and 180 (58.1%) of 3-month poor outcome. In the higher GA group (130, 41.9%), proportion of unsuccessful reperfusion, END, SHT, and poor outcome were higher than lower GA group. The multivariate analysis showed that higher GA was associated with unsuccessful reperfusion after EVT (adjusted odds ratio 4.13; 95% confidence interval [CI], 1.93-8.85). The area under the receiver operating characteristic of GA (0.644; 95% CI: 0.634-0.740) for predicting poor outcome was better than that of glycated hemoglobin (0.586; 95% CI: 0.529-0.642, p for DeLong's pairwise comparison = 0.005). CONCLUSION: GA, reflecting prestroke glycemic variability, could be a reliable parameter for predicting reperfusion rate and acute ischemic stroke outcome in this study.

Cerebral Small Vessel Disease Burden and Futile Reperfusion after Endovascular Treatment for Patients with Acute Ischemic Stroke.

INTRODUCTION: Cerebral small vessel disease (SVD) burden includes increased risk of poor functional outcomes after acute ischemic stroke (AIS). We aimed to investigate the impact of cerebral SVD on 3-month functional outcomes in patients with AIS who received endovascular treatment (EVT) and to determine whether SVD is associated with futile reperfusion (FR). METHODS: Using a multicenter stroke registry, we analyzed consecutive patients with AIS with either intracranial and/or extracranial anterior circulation large artery occlusion, who were treated with EVT and achieved successful reperfusion (thrombolysis in cerebral infarction grade 2b-3). The cerebral SVD burden was evaluated using baseline brain magnetic resonance imaging using a modified Fazekas score (mFS). The main outcome variable was FR, defined as poor functional outcomes (modified Rankin scale 3-6) at 3 months after stroke, despite successful recanalization. Secondary outcomes included stroke progression/recurrence and any hemorrhagic transformation. RESULTS: Among 10,890 patients with AIS, 577 (5.3%) received EVT within 12 h of onset, including 354 who met study eligibility criteria. FR was observed in 191 patients (53.5%) and was positively associated with SVD burden. After adjustment for covariates including age, sex, stroke etiology, initial stroke severity, collateral status, Alberta stroke program early CT score, initial serum glucose, systemic blood pressure, and vascular risk factors, mFS grade 3 was significantly associated with FR (odds ratio: 3.93, 95% confidence interval: 1.602-9.619; p = 0.003). CONCLUSIONS: We demonstrated that cerebral SVD assessed with baseline brain MRI is associated with the futility of successful recanalization after EVT and any hemorrhagic transformation but not with early stroke progression or recurrence. Nevertheless, our findings do not justify withholding EVT in otherwise eligible patients with AIS based on the presence of severe SVD.

The association between malnutrition status and hemorrhagic transformation in patients with acute ischemic stroke receiving intravenous thrombolysis.

OBJECTIVES: We evaluated the impact of malnutrition as estimated by the controlling nutritional status (CONUT) score and prognostic nutritional index (PNI) on hemorrhagic transformation (HT) and stroke outcomes after intravenous thrombolysis (IVT). MATERIALS AND METHODS: Using a multicenter registry database, we enrolled 808 patients with acute ischemic stroke who received IVT between August 2013 and May 2021. We defined malnutrition as a CONUT score ≥ 2 and low PNI. The primary outcome measure was the occurrence of symptomatic HT contributing to early neurologic deterioration (END-SHT) after IVT. Multivariable analysis was performed to analyze the association between CONUT score, PNI, and END-SHT after IVT. RESULTS: The rate of END-SHT was higher with increasing CONUT scores and PNI values. In the multivariable analysis, CONUT score ≥ 5 and low PNI were significantly associated with END-SHT (odds ratio [95% confidence interval], CONUT score ≥ 5: 12.23 [2.41-62.07], p = 0.003; low PNI: 4.98 [1.76-14.09], p = 0.003). The receiver operating characteristic curve showed that both the CONUT score and PNI had good predictive ability. The cutoff values for CONUT and PNI were 5 and 42.3, respectively, for END-SHT. CONCLUSION: Malnutrition, as denoted by a higher CONUT score and lower PNI, was associated with END-SHT. The joint application of both nutritional markers could be useful in predicting END-SHT after IVT.

CHARACTERISTICS OF THE MACULAR MICROVASCULATURE IN IDIOPATHIC EPIRETINAL MEMBRANE PATIENTS WITH AN ECTOPIC INNER FOVEAL LAYER.

PURPOSE: To identify the characteristics of the retinal microvasculature in epiretinal membrane patients with ectopic inner foveal layer (EIFL). METHODS: Patients were classified into two groups: those without EIFL (Group 1) and those with EIFL (Group 2). The vessel density (VD), perfusion density (PD), and the foveal avascular zone (FAZ) parameters were compared using optical coherence tomography angiography. Linear regression analysis was performed to identify the optical coherence tomography angiography parameters associated with best-corrected visual acuity. RESULTS: The VD of the central area in Group 1 and Group 2 was 11.6 ± 3.3 and 17.2 ± 2.8 mm -1 , respectively ( P < 0.001), the PD of the central area was 21.7 ± 6.2 and 32.0 ± 5.5%, respectively ( P < 0.001), and the FAZ area was 0.24 ± 0.11 and 0.09 ± 0.08 mm 2 , respectively ( P < 0.001). Based on the linear regression analysis, the VD of the central area (B = 0.018, P = 0.003), the PD of the central area (B = 0.009, P = 0.004), and FAZ area (B = -0.489, P = 0.013) were significantly associated with best-corrected visual acuity in patients with epiretinal membrane. CONCLUSION: The VD and PD of the foveal area were significantly higher in patients with EIFL, and the FAZ area was lower in patients with EIFL than in those without EIFL. In addition, the VD and PD of the foveal area were negatively associated with best-corrected visual acuity, and the FAZ area was positively associated with best-corrected visual acuity in patients with epiretinal membrane.

CHARACTERISTICS OF AGE-RELATED MACULAR DEGENERATION SHOWING A POOR RESPONSE TO THREE LOADING DOSES OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR.

PURPOSE: To analyze the clinical features of refractory age-related macular degeneration patients associated with the response to three consecutive loading doses of anti-vascular endothelial growth factor. METHODS: A retrospective chart review was performed on typical exudative age-related macular degeneration patients treated by three consecutive anti-vascular endothelial growth factor injections. The patients were divided into a group without residual fluid on optical coherence tomography images (Group 1) and a group with residual fluid (Group 2). We analyzed qualitative and quantitative morphologic features of optical coherence tomography and optical coherence tomography angiography. We performed univariate and multivariate logistic regression analyses to identify factors associated with the treatment response. RESULTS: We enrolled a total of 90 patients (Group 1: n = 60, Group 2: n = 30). Under optical coherence tomography, the choroidal thickness differed significantly between groups 1 and 2 (246.60 ± 67.67 vs. 286.90 ± 40.92 µ m, P = 0.001). Under optical coherence tomography angiography, the presence of branching (48.3% vs. 73.3%, P = 0.024), loops (31.7% vs. 66.7%, P = 0.002), and a peripheral arcade (40.0% vs. 76.7%, P = 0.001) differed significantly. Logistic regression analysis showed that the initial CT (B = 0.012; P = 0.007), presence of loops (B = 1.289; P = 0.015), and peripheral arcade (B = 1.483; P = 0.008) significantly affected the anti-vascular endothelial growth factor treatment response. CONCLUSION: A thicker choroid and the presence of loops and a peripheral arcade were significantly associated with a poorer response to three loading anti-vascular endothelial growth factor injections in typical exudative age-related macular degeneration patients.

Type 6 secretion system components hcp and vgrG support mutualistic partnership between Xenorhabdus bovienii symbiont and Steinernema jollieti host.

Xenorhabdus, like other Gram-negative bacteria, possesses a Type 6 Secretion System (T6SS) which acts as a contact-dependent molecular syringe, delivering diverse proteins (effectors) directly into other cells. The number of T6SS loci encoded in Xenorhabdus genomes are variable both at the inter and intraspecific level. Some environmental isolates of Xenorhabdus bovienii, encode at least one T6SS locus while others possess two loci. Previous work conducted by our team demonstrated that X. bovienii [Jollieti strain SS-2004], which has two T6SSs (T6SS-1 and T6SS-2), hcp genes are required for biofilm formation. Additionally, while T6SS-1 hcp gene plays a role in the antibacterial competition, T6SS-2 hcp does not. In this study, we tested the hypothesis that vgrG genes are also involved in mutualistic and pathogenic interactions. For this purpose, targeted mutagenesis together with wet lab experiments including colonization, competition, biofilm, and virulence experiments, were carried out to assess the role of vgrG in the mutualistic and antagonistic interactions in the life cycle of XBJ. Our results revealed that vgrG genes are not required for biofilm formation but play a role in outcompeting other Xenorhabdus bacteria. Additionally, both vgrG and hcp genes are required to fully colonize the nematode host. We also demonstrated that hcp and vgrG genes in both T6SS clusters are needed to support the reproductive fitness of the nematodes. Overall, results from this study revealed that in X. bovieni jollieti strain, the twoT6SS clusters play an important role in the fitness of the nematodes in relation to colonization and reproduction. These results lay a foundation for further investigations on the functional significance of T6SSs in the mutualistic and pathogenic lifecycle of Xenorhabdus spp.

Retinal microvasculature and choriocapillaris impairments according to the stage of dry age-related macular degeneration.

BACKGROUND: We aimed to analyse the retinal microvasculature and choriocapillaris according to the dry age-related macular degeneration (AMD) stage and to identify factors associated with their microvasculatures. METHODS: Patients were divided into four groups: normal controls, early, intermediate and advanced AMD groups. The vessel density (VD) of superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris was compared using optical coherence tomography angiography among the groups. Linear regression analysis was performed to identify factors associated with the VD. RESULTS: The VDs of the SCP were 22.1 ± 5.7, 19.1 ± 5.4, 18.0 ± 6.4 and 12.2 ± 6.4% (p < 0.001); the VDs of the DCP were 22.4 ± 4.5, 20.7 ± 4.3, 18.1 ± 5.3 and 14.6 ± 5.8% (p < 0.001); the VDs of the choriocapillaris were 29.4 ± 3.7, 26.4 ± 4.8, 24.5 ± 4.9 and 24.2 ± 3.7% (p < 0.001) in the control, early, intermediate, and advanced groups, respectively. AMD stage and age were significantly associated with the VDs of all layers, and the VDs of the SCP and DCP were associated with visual acuity (both p < 0.001). Additionally, hypertension was associated with the VDs of the DCP (p = 0.027) and choriocapillaris (p = 0.024). CONCLUSIONS: The retinal microvasculature and choriocapillaris tended to become more impaired as the AMD stage progressed. Age was significantly associated with the microvasculature impairments of all layers, and hypertension was significantly associated with impairments of the DCP microvasculature and choriocapillaris.

Functional Characterization of the GNAT Family Histone Acetyltransferase Elp3 and GcnE in Aspergillus fumigatus.

Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a pivotal role in the regulation of gene expression and diverse biological processes. However, the function of GNAT family HATs, especially Elp3, in the opportunistic human pathogenic fungus Aspergillus fumigatus is largely unknown. To investigate the roles of the GNAT family HATs Elp3 and GcnE in the A. fumigatus, we have generated and characterized individual null Δelp3 and ΔgcnE mutants. The radial growth of fungal colonies was significantly decreased by the loss of elp3 or gcnE, and the number of asexual spores (conidia) in the ΔgcnE mutant was significantly reduced. Moreover, the mRNA levels of the key asexual development regulators were also significantly low in the ΔgcnE mutant compared to wild type (WT). Whereas both the Δelp3 and ΔgcnE mutants were markedly impaired in the formation of adherent biofilms, the ΔgcnE mutant showed a complete loss of surface structure and of intercellular matrix. The ΔgcnE mutant responded differently to oxidative stressors and showed significant susceptibility to triazole antifungal agents. Furthermore, Elp3 and GcnE function oppositely in the production of secondary metabolites, and the ΔgcnE mutant showed attenuated virulence. In conclusion, Elp3 and GcnE are associated with diverse biological processes and can be potential targets for controlling the pathogenic fungus.