Indazole to 2-cyanoindole scaffold progression for mycobacterial lipoamide dehydrogenase inhibitors achieves extended target residence time and improved antibacterial activity.

Tuberculosis remains a leading cause of death from a single infection worldwide. Drug resistance to existing and even new antimycobacterials calls for research into novel targets and unexplored mechanisms of action. Recently we reported on the development of tight-binding inhibitors of Mycobacterium tuberculosis (Mtb) lipoamide dehydrogenase (Lpd), which selectively inhibit the bacterial but not the human enzyme based on a differential modality of inhibitor interaction with these targets. Here we report on the striking improvement in inhibitor residence time on the Mtb enzyme associated with scaffold progression from an indazole to 2-cyanoindole. Cryo-EM of Lpd with the bound 2-cyanoindole inhibitor 19 confirmed displacement of the buried water molecule deep in the binding channel with a cyano group. The ensuing hours-long  improvement in on-target residence time is associated with enhanced antibacterial activity in axenic culture and in primary mouse macrophages. Resistance to 2-cyanoindole inhibitors involves mutations within the inhibitor binding site that have little effect on inhibitor affinity but change the modality of inhibitor-target interaction, resulting in fast dissociation from Lpd. These findings underscore that on-target residence time is a major determinant of antibacterial activity and in vivo efficacy.

Association between maternal HIV status and postpartum depressive symptoms in Botswana.

Few studies have evaluated postpartum depression (PPD) in women living with HIV (WLHIV) in Botswana, a high prevalence HIV setting. The Edinburgh Postnatal Depression Scale (EPDS) was used to evaluate PPD symptoms in WLHIV (n = 300) and women who are HIV-uninfected (n = 131) in the Tshilo Dikotla study, an observational cohort study with a nested randomized trial. The EPDS was administered at 2, 6, and 12 months postpartum. We assessed the association of (1) HIV infection and (2) antiretroviral therapy (ART) with odds of PPD symptoms (EPDS ≥ 10 or thoughts of self-harm) in the first year postpartum using generalized estimating equations. Of WLHIV, 24 (8.00%) had PPD symptoms at one or more follow-up time points, compared to 9 (6.9%) women who were HIV-seronegative. There was no association between HIV status and PPD symptoms (adjusted odds ratio [aOR]:1.69, 95% confidence interval [CI]: 0.73-3.93, p = 0.225); however, WLHIV on efavirenz-based ART regimens had higher odds of experiencing PPD symptoms compared to dolutegravir-based ART (aOR:3.05, 95% CI:1.16-8.03, p = 0.024).

Pushing Trap-Controlled Persistent Luminescence Materials toward Multi-Responsive Smart Platforms: Recent Advances, Mechanism, and Frontier Applications.

Smart stimuli-responsive persistent luminescence materials, combining the various advantages and frontier applications prospects, have gained booming progress in recent years. The trap-controlled property and energy storage capability to respond to external multi-stimulations through diverse luminescence pathways make them attractive in emerging multi-responsive smart platforms. This review aims at the recent advances in trap-controlled luminescence materials for advanced multi-stimuli-responsive smart platforms. The design principles, luminescence mechanisms, and representative stimulations, i.e., thermo-, photo-, mechano-, and X-rays responsiveness, are comprehensively summarized. Various emerging multi-responsive hybrid systems containing trap-controlled luminescence materials are highlighted. Specifically, temperature dependent trapping and de-trapping performance is discussed, from extreme-low temperature to ultra-high temperature conditions. Emerging applications and future perspectives are briefly presented. It is hoped that this review would provide new insights and guidelines for the rational design and performance manipulation of multi-responsive materials for advanced smart platforms.

ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.

Cryptic diversity and rampant hybridization in annual gentians on the Qinghai-Tibet Plateau revealed by population genomic analysis.

Understanding the evolutionary and ecological processes involved in population differentiation and speciation provides critical insights into biodiversity formation. In this study, we employed 29,865 single nucleotide polymorphisms (SNPs) and complete plastomes to examine genomic divergence and hybridization in Gentiana aristata, which is endemic to the Qinghai-Tibet Plateau (QTP) region. Genetic clustering revealed that G. aristata is characterized by geographic genetic structures with five clusters (West, East, Central, South and North). The West cluster has a specific morphological character (i.e., blue corolla) and higher values of FST compared to the remaining clusters, likely the result of the geological barrier formed by the Yangtze River. The West cluster diverged from the other clusters in the Early Pliocene; these remaining clusters diverged from one another in the Early Quaternary. Phylogenetic reconstructions based on SNPs and plastid data revealed substantial cyto-nuclear conflicts. Genetic clustering and D-statistics demonstrated rampant hybridization between the Central and North clusters, along the Bayankala Mountains, which form the geological barrier between the Central and North clusters. Species distribution modeling demonstrated the range of G. aristata expanded since the Last Interglacial period. Our findings provide genetic and morphological evidence of cryptic diversity in G. aristata, and identified rampant hybridization between genetic clusters along a geological barrier. These findings suggest that geological barriers and climatic fluctuations have an important role in triggering diversification as well as hybridization, indicating that cryptic diversity and hybridization are essential factors in biodiversity formation within the QTP region.

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway.

Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.

Exploring the Prevalence of Tinnitus and Ear-Related Symptoms in China After the COVID-19 Pandemic: Online Cross-Sectional Survey.

BACKGROUND: Tinnitus is a complex and heterogeneous disease that has been identified as a common manifestation of COVID-19. To gain a comprehensive understanding of tinnitus symptoms in individuals following COVID-19 infection, we conducted an online survey called the China Ear Nose and Throat Symptom Survey in the COVID-19 Pandemic (CENTSS) among the Chinese population. OBJECTIVE: Our objective was to investigate tinnitus and ear-related symptoms after COVID-19 infection in the Chinese population, with the aim of providing a solid empirical foundation for improved health care. The findings from CENTSS can contribute to the development of enhanced management strategies for tinnitus in the context of long COVID. By gaining a better understanding of the factors contributing to tinnitus in individuals with COVID-19, health care providers can tailor interventions to address the specific needs of affected patients. Furthermore, this study serves as a basis for research on the long-term consequences of COVID-19 infection and its associated tinnitus symptoms. METHODS: A quantitative, online, cross-sectional survey study design was used to explore the impact of the COVID-19 pandemic on experiences with tinnitus in China. Data were collected through an online questionnaire designed to identify the presence of tinnitus and its impacts. Descriptive statistics were used to analyze individuals' demographic characteristics, COVID-19 infection-related ear symptoms, and the cognitive and emotional implications of tinnitus. Univariable and multivariable logistic regression analyses were used to model the cross-sectional baseline associations between demographic characteristics, noise exposure, educational level, health and lifestyle factors, and the occurrence of tinnitus. RESULTS: Between December 19, 2022, and February 1, 2023, we obtained responses from 1262 Chinese participants representing 24 regions, with an average age of 37 years. Among them, 540 patients (42.8%) reported experiencing ear-related symptoms after COVID-19 infection. Only 114 (9%) of these patients sought medical attention specifically for their ear symptoms, while 426 (33.8%) did not seek hospital care. Tinnitus emerged as the most prevalent and impactful symptom among all ear-related symptoms experienced after COVID-19 infection. Of the respondents, female participants (688/888, 77.78%), younger individuals (<30 years), individuals with lower education levels, participants residing in western China, and those with a history of otolaryngology diseases were more likely to develop tinnitus following COVID-19 infection. CONCLUSIONS: In summary, tinnitus was identified as the most common ear-related symptom during COVID-19 infection. Individuals experiencing tinnitus after COVID-19 infection were found to have poorer cognitive and emotional well-being. Different ear-related symptoms in patients post-COVID-19 infection may suggest viral invasion of various parts of the ear. It is therefore crucial to monitor and manage hearing-related changes resulting from COVID-19 as clinical services resume.

Research strategies of small molecules as chemotherapeutics to overcome multiple myeloma resistance.

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.

Design and preparation of NMN nanoparticles based on protein-marine polysaccharide with increased NAD+ level in D-galactose induced aging mice model.

Nicotinamide mononucleotide (NMN) is being investigated for its ability to address the decline in NAD+ level during aging. This study aimed to construct a delivery system based on ovalbumin and fucoidan nanoparticles to ameliorate the bioaccessibility of NMN by increasing NAD+ level in aging mouse model. The NMN-loaded ovalbumin and fucoidan nanoparticles (OFNPs) were about 177 nm formed by the interplay of hydrogen bonds between ovalbumin and fucoidan. Compared with free NMN, NMN-loaded OFNPs intervention could obviously improve the antioxidant enzyme activity of senescent cell induced by D-galactose. The NMN-loaded OFNPs treatment could ameliorate the loss of weight and organ index induced by senescence, and maintain the water content for the aging mice. The Morris maze test indicated that hitting blind side frequency and escape time of NMN-loaded OFNPs group decreased by 13% and 35% compared with that of free NMN group. Furthermore, the NMN-loaded OFNPs significantly alleviated the age-related oxidative stress and increased the generation of NAD+ 1.34 times by improving the bioaccessibility of NMN. Our data in this study supplied a strategy to enhance the bioavailability of NMN in senescence treatment.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.

Lower Insulin Sensitivity Through 36 Months of Life With in Utero HIV and Antiretroviral Exposure in Botswana: Results From the Tshilo Dikotla Study.

BACKGROUND: There are little data on changes in insulin sensitivity during the first few years of life following in utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure. METHODS: The Tshilo Dikotla study enrolled pregnant persons with HIV (PWH) (receiving tenofovir/emtricitabine or lamivudine plus dolutegravir or efavirenz) and pregnant individuals without HIV, as well as their liveborn children. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was assessed at birth and 1, 18, 24, and 36 months of life. We fit linear mixed-effects models to evaluate the association between in utero HIV/ARV exposure and average HOMA-IR from birth through 36 months of life, adjusting for confounders. RESULTS: A total of 419 children were included (287 with in utero HIV/ARV exposure and uninfected [CHEU] and 132 without in utero HIV/ARV exposure [CHUU]). CHEU were born to older women (29.6 vs 25.3 years of age) with higher gravidity (3 vs 1). HOMA-IR was persistently higher in CHEU versus CHUU in adjusted analyses (mean difference of 0.07 in log10 HOMA-IR, P  = .02) from birth through 36 months of life. Among CHEU, no differences in HOMA-IR were observed from birth through 36 months by in utero ARV exposure status or between AZT and NVP infant prophylaxis arms. CONCLUSIONS: In utero HIV/ARV exposure was associated with lower insulin sensitivity throughout the first 36 months of life, indicating persistent early life metabolic disturbances which may raise concern for poorer metabolic health later in life.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Effects of ocean acidification and polystyrene microplastics on the oysters Crassostrea gigas: An integrated biomarker and metabolomic approach.

The adverse impacts of microplastics (MPs) or ocean acidification (OA) on mollusks have been widely reported, however, little is known about their combined effects on mollusks. The oysters Crassostrea gigas were exposed to two sizes of polystyrene MPs with 1 × 104 particles/L (small polystyrene MPs (SPS-MPs): 6 µm, large polystyrene MPs (LPS-MPs): 50-60 µm) at two pH levels (7.7 and 8.1) for 14 days. The antagonistic effects between MPs and OA on oysters were mainly observed. Single SPS-MPs exposure can induce CAT enzyme activity and LPO level in gills, while LPS-MPs exposure alone can increase PGK and PEPCK gene expression in digestive glands. Ocean acidification can increase clearance rate and inhibit antioxidant enzyme activity, whereas combined exposure of OA and SPS-MPs can affect the metabolomic profile of digestive glands. This study emphasized that the potential toxic effects of MPs under the scene of climate change should be concerned.

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during early life developmental periods is associated with impaired memory function, particularly for hippocampus (HPC)-dependent processes. We developed an early life WD rodent model associated with long-lasting HPC dysfunction to investigate the neurobiological mechanisms mediating these effects. Rats received either a cafeteria-style WD (ad libitum access to various high-fat/high-sugar foods; CAF) or standard healthy chow (CTL) during the juvenile and adolescent stages (postnatal days 26-56). Behavioral and metabolic assessments were performed both before and after a healthy diet intervention period beginning at early adulthood. Results revealed HPC-dependent contextual episodic memory impairments in CAF rats that persisted despite the healthy diet intervention. Given that dysregulated HPC acetylcholine (ACh) signaling is associated with memory impairments in humans and animal models, we examined protein markers of ACh tone in the dorsal HPC (HPCd) in CAF and CTL rats. Results revealed significantly lower protein levels of vesicular ACh transporter in the HPCd of CAF vs. CTL rats, indicating chronically reduced ACh tone. Using intensity-based ACh sensing fluorescent reporter (iAChSnFr) in vivo fiber photometry targeting the HPCd, we next revealed that ACh release during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Neuropharmacological results showed that alpha 7 nicotinic ACh receptor agonist infusion in the HPCd during training rescued memory deficits in CAF rats. Overall, these findings reveal a functional connection linking early life WD intake with long-lasting dysregulation of HPC ACh signaling, thereby identifying an underlying mechanism for WD-associated memory impairments.

An oligopeptide permease, OppABCD, requires an iron-sulfur cluster domain for functionality.

Oligopeptide permease, OppABCD, belongs to the type I ABC transporter family. Its role is to import oligopeptides into bacteria for nutrient uptake and to modulate the host immune response. OppABCD consists of a cluster C substrate-binding protein (SBP), OppA, membrane-spanning OppB and OppC subunits, and an ATPase, OppD, that contains two nucleotide-binding domains (NBDs). Here, using cryo-electron microscopy, we determined the high-resolution structures of Mycobacterium tuberculosis OppABCD in the resting state, oligopeptide-bound pre-translocation state, AMPPNP-bound pre-catalytic intermediate state and ATP-bound catalytic intermediate state. The structures show an assembly of a cluster C SBP with its ABC translocator and a functionally required [4Fe-4S] cluster-binding domain in OppD. Moreover, the ATP-bound OppABCD structure has an outward-occluded conformation, although no substrate was observed in the transmembrane cavity. Here, we reveal an oligopeptide recognition and translocation mechanism of OppABCD, which provides a perspective on how this and other type I ABC importers facilitate bulk substrate transfer across the lipid bilayer.

Cumulative Genetic Scores Interact with Maternal and Paternal Parenting in Predicting Parent-Adolescent Cohesion and Conflict.

Previous research concerning the interplay between genetics and parenting in the development of the parent-child relationship during adolescence has been extremely scarce, predominantly adopting single-gene designs. This limited body of work has largely overlooked the distinct effects of maternal and paternal roles, as well as potential gender differences. Additionally, existing gene-by-environment (G × E) studies have mainly concentrated on adverse environmental factors and associated negative outcomes, somewhat neglecting positive environments and outcomes. The present study examined the interactions of cumulative genetic scores (CGS, dopamine receptor D2 TaqIA and oxytocin receptor gene rs53576 polymorphisms) with both positive and negative parenting on parent-adolescent cohesion and conflict. Furthermore, this study aimed to ascertain with which gene-environment model the potential G × E interactions would align. A total of 745 Chinese Han adolescents (Mage = 13.36 ± 0.96 years; 46.8% girls) from grades 7 to 9 participated in this study. Results revealed a significant effect of CGS and negative maternal parenting on mother-adolescent conflict among males, consistent with the weak differential susceptibility model. As CGS increased, the effects of negative maternal parenting on mother-son conflict were magnified. These findings have implications for the timing and focus of interventions aimed at improving parent-adolescent relationships.

Giardia Antagonizes Beneficial Functions of Indigenous and Therapeutic Intestinal Bacteria during Malnutrition.

Undernutrition in children commonly disrupts the structure and function of the small intestinal microbial community, leading to enteropathies, compromised metabolic health, and impaired growth and development. The mechanisms by which diet and microbes mediate the balance between commensal and pathogenic intestinal flora remain elusive. In a murine model of undernutrition, we investigated the direct interactions Giardia lamblia, a prevalent small intestinal pathogen, on indigenous microbiota and specifically on Lactobacillus strains known for their mucosal and growth homeostatic properties. Our research reveals that Giardia colonization shifts the balance of lactic acid bacteria, causing a relative decrease in Lactobacillus spp . and an increase in Bifidobacterium spp . This alteration corresponds with a decrease in multiple indicators of mucosal and nutritional homeostasis. Additionally, protein-deficient conditions coupled with Giardia infection exacerbate the rise of primary bile acids and susceptibility to bile acid-induced intestinal barrier damage. In epithelial cell monolayers, Lactobacillus spp . mitigated bile acid-induced permeability, showing strain-dependent protective effects. In vivo, L. plantarum, either alone or within a Lactobacillus spp consortium, facilitated growth in protein-deficient mice, an effect attenuated by Giardia , despite not inhibiting Lactobacillus colonization. These results highlight Giardia's potential role as a disruptor of probiotic functional activity, underscoring the imperative for further research into the complex interactions between parasites and bacteria under conditions of nutritional deficiency.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.