Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.

Trimodal single-cell profiling reveals a novel pediatric CD8αα+ T cell subset and broad age-related molecular reprogramming across the T cell compartment.

Age-associated changes in the T cell compartment are well described. However, limitations of current single-modal or bimodal single-cell assays, including flow cytometry, RNA-seq (RNA sequencing) and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile >300,000 single T cells from healthy children (aged 11-13 years) and older adults (aged 55-65 years) by using the trimodal assay TEA-seq (single-cell analysis of mRNA transcripts, surface protein epitopes and chromatin accessibility), which revealed that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4+ T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8αα+ T cell subset lost with age that is epigenetically poised for rapid effector responses and has distinct inhibitory, costimulatory and tissue-homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.

Multifunctional ytterbium oxide buffer for perovskite solar cells.

Perovskite solar cells (PSCs) comprise a solid perovskite absorber sandwiched between several layers of different charge-selective materials, ensuring unidirectional current flow and high voltage output of the devices1,2. A 'buffer material' between the electron-selective layer and the metal electrode in p-type/intrinsic/n-type (p-i-n) PSCs (also known as inverted PSCs) enables electrons to flow from the electron-selective layer to the electrode3-5. Furthermore, it acts as a barrier inhibiting the inter-diffusion of harmful species into or degradation products out of the perovskite absorber6-8. Thus far, evaporable organic molecules9,10 and atomic-layer-deposited metal oxides11,12 have been successful, but each has specific imperfections. Here we report a chemically stable and multifunctional buffer material, ytterbium oxide (YbOx), for p-i-n PSCs by scalable thermal evaporation deposition. We used this YbOx buffer in the p-i-n PSCs with a narrow-bandgap perovskite absorber, yielding a certified power conversion efficiency of more than 25%. We also demonstrate the broad applicability of YbOx in enabling highly efficient PSCs from various types of perovskite absorber layer, delivering state-of-the-art efficiencies of 20.1% for the wide-bandgap perovskite absorber and 22.1% for the mid-bandgap perovskite absorber, respectively. Moreover, when subjected to ISOS-L-3 accelerated ageing, encapsulated devices with YbOx exhibit markedly enhanced device stability.

TRIM71 reactivation enhances the mitotic and hair cell-forming potential of cochlear supporting cells.

Cochlear hair cell loss is a leading cause of deafness in humans. Neighboring supporting cells have some capacity to regenerate hair cells. However, their regenerative potential sharply declines as supporting cells undergo maturation (postnatal day 5 in mice). We recently reported that reactivation of the RNA-binding protein LIN28B restores the hair cell-regenerative potential of P5 cochlear supporting cells. Here, we identify the LIN28B target Trim71 as a novel and equally potent enhancer of supporting cell plasticity. TRIM71 is a critical regulator of stem cell behavior and cell reprogramming; however, its role in cell regeneration is poorly understood. Employing an organoid-based assay, we show that TRIM71 re-expression increases the mitotic and hair cell-forming potential of P5 cochlear supporting cells by facilitating their de-differentiation into progenitor-like cells. Our mechanistic work indicates that TRIM71's RNA-binding activity is essential for such ability, and our transcriptomic analysis identifies gene modules that are linked to TRIM71 and LIN28B-mediated supporting cell reprogramming. Furthermore, our study uncovers that the TRIM71-LIN28B target Hmga2 is essential for supporting cell self-renewal and hair cell formation.

Increasing and widespread vulnerability of intact tropical rainforests to repeated droughts.

Intact tropical rainforests have been exposed to severe droughts in recent decades, which may threaten their integrity, their ability to sequester carbon, and their capacity to provide shelter for biodiversity. However, their response to droughts remains uncertain due to limited high-quality, long-term observations covering extensive areas. Here, we examined how the upper canopy of intact tropical rainforests has responded to drought events globally and during the past 3 decades. By developing a long pantropical time series (1992 to 2018) of monthly radar satellite observations, we show that repeated droughts caused a sustained decline in radar signal in 93%, 84%, and 88% of intact tropical rainforests in the Americas, Africa, and Asia, respectively. Sudden decreases in radar signal were detected around the 1997-1998, 2005, 2010, and 2015 droughts in tropical Americas; 1999-2000, 2004-2005, 2010-2011, and 2015 droughts in tropical Africa; and 1997-1998, 2006, and 2015 droughts in tropical Asia. Rainforests showed similar low resistance (the ability to maintain predrought condition when drought occurs) to severe droughts across continents, but American rainforests consistently showed the lowest resilience (the ability to return to predrought condition after the drought event). Moreover, while the resistance of intact tropical rainforests to drought is decreasing, albeit weakly in tropical Africa and Asia, forest resilience has not increased significantly. Our results therefore suggest the capacity of intact rainforests to withstand future droughts is limited. This has negative implications for climate change mitigation through forest-based climate solutions and the associated pledges made by countries under the Paris Agreement.

DGW1, encoding an hnRNP-like RNA binding protein, positively regulates grain size and weight by interacting with GW6 mRNA.

Grain size and weight determine rice yield. Although numerous genes and pathways involved in regulating grain size have been identified, our knowledge of post-transcriptional control of grain size remains elusive. In this study, we characterize a rice mutant, decreased grain width and weight 1 (dgw1), which produces small grains. We show that DGW1 encodes a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family protein and preferentially expresses in developing panicles, positively regulating grain size by promoting cell expansion in spikelet hulls. Overexpression of DGW1 increases grain weight and grain numbers, leading to a significant rise in rice grain yield. We further demonstrate that DGW1 functions in grain size regulation by directly binding to the mRNA of Grain Width 6 (GW6), a critical grain size regulator in rice. Overexpression of GW6 restored the grain size phenotype of DGW1-knockout plants. DGW1 interacts with two oligouridylate binding proteins (OsUBP1a and OsUBP1b), which also bind the GW6 mRNA. In addition, the second RRM domain of DGW1 is indispensable for its mediated protein-RNA and protein-protein interactions. In summary, our findings identify a new regulatory module of DGW1-GW6 that regulates rice grain size and weight, providing important insights into the function of hnRNP-like proteins in the regulation of grain size.

Anthropogenic disturbance exacerbates resilience loss in the Amazon rainforests.

Uncovering the mechanisms that lead to Amazon forest resilience variations is crucial to predict the impact of future climatic and anthropogenic disturbances. Here, we apply a previously used empirical resilience metrics, lag-1 month temporal autocorrelation (TAC), to vegetation optical depth data in C-band (a good proxy of the whole canopy water content) in order to explore how forest resilience variations are impacted by human disturbances and environmental drivers in the Brazilian Amazon. We found that human disturbances significantly increase the risk of critical transitions, and that the median TAC value is ~2.4 times higher in human-disturbed forests than that in intact forests, suggesting a much lower resilience in disturbed forests. Additionally, human-disturbed forests are less resilient to land surface heat stress and atmospheric water stress than intact forests. Among human-disturbed forests, forests with a more closed and thicker canopy structure, which is linked to a higher forest cover and a lower disturbance fraction, are comparably more resilient. These results further emphasize the urgent need to limit deforestation and degradation through policy intervention to maintain the resilience of the Amazon rainforests.

Metabolically healthy obesity, transition from metabolic healthy to unhealthy status, and carotid atherosclerosis.

BACKGROUND: Evidence of the effects of metabolically healthy obesity (MHO) on atherosclerosis is limited; the transition effects of metabolic health and obesity phenotypes have been ignored. We examined the association between metabolic health and the transition to atherosclerosis risk across body mass index (BMI) categories in a community population. METHODS: This cross-sectional study was based on a national representative survey that included 50,885 community participants aged ≥40 years. It was conducted from 01 December 2017 to 31 December 2020, in 13 urban and 13 rural regions across Hunan China. Metabolic health was defined as meeting less than three abnormalities in blood pressure, glucose, high-density lipoprotein cholesterol, triglycerides, or waist circumference. The participants were cross-classified at baseline based on their metabolic health and obesity. In addition, the relationship between atherosclerosis and transitions in metabolic health status based on 4733 participants from baseline to the second survey after 2 years was considered. The relationship between metabolic health status and the risk of transition to Carotid atherosclerosis (CA) was assessed using logistic regression and Cox proportional hazards regression analyses. RESULTS: In this study, the mean age of the participants was 60.7 years (standard deviation [SD], 10.91), 53.0% were female, and 51.2% had CA. As compared with metabolically healthy normal weight (MHN), those with MHO phenotype (odd ratio [OR] 1.10, 95% confidence interval [CI] 1.02-1.21), metabolically unhealthy normal weight (OR 1.27, 95% CI 1.19-1.35), metabolically unhealthy overweight (OR 1.41, 95% CI 1.33-1.48), and metabolically unhealthy obese (OR 1.54, 95% CI 1.44-1.64) had higher risk for CA. However, during the follow-up of 2 years, almost 33% of the participants transitioned to a metabolically unhealthy status. As compared with stable healthy normal weight, transition from metabolically healthy to unhealthy status (hazard ratios [HR] 1.21, 95% [CI] 1.02-1.43) and stable metabolically unhealthy overweight or obesity (MUOO) (HR 1.32, 95% CI 1.17-1.48) were associated with higher risk of CA. CONCLUSIONS: In the community population, obesity remains a risk factor for CA despite metabolic health. However, the risks were highest for metabolically unhealthy status across all BMI categories. A large proportion of metabolically healthy overweight or participants with obesity converts to an unhealthy phenotype over time, which is associated with an increased risk of CA.

Raman spectroscopy coupled with chemometrics for identification of adulteration and fraud in muscle foods: a review.

Muscle foods, valued for their significant nutrient content such as high-quality protein, vitamins, and minerals, are vulnerable to adulteration and fraud, stemming from dishonest vendor practices and insufficient market oversight. Traditional analytical methods, often limited to laboratory-scale., may not effectively detect adulteration and fraud in complex applications. Raman spectroscopy (RS), encompassing techniques like Surface-enhanced RS (SERS), Dispersive RS (DRS), Fourier transform RS (FTRS), Resonance Raman spectroscopy (RRS), and Spatially offset RS (SORS) combined with chemometrics, presents a potent approach for both qualitative and quantitative analysis of muscle food adulteration. This technology is characterized by its efficiency, rapidity, and noninvasive nature. This paper systematically summarizes and comparatively analyzes RS technology principles, emphasizing its practicality and efficacy in detecting muscle food adulteration and fraud when combined with chemometrics. The paper also discusses the existing challenges and future prospects in this field, providing essential insights for reviews and scientific research in related fields.

Cloning, tissue expression and imprinting status analysis of the NDN gene in Dolang sheep.

BACKGROUND: Genomic imprinting refers to expressing parent-specific genes in mammalian diploid cells. The NDN gene is maternally imprinted in humans and mice and correlates with the timing of puberty. This study aimed to investigate its imprinting status and its relationship with the onset of puberty in Dolang sheep. METHODS AND RESULTS: In this study, cloning and sequencing obtained the NDN gene cDNA sequence of 1082 bp of Dolang sheep, coding for 325 amino acids. Similarity analysis and phylogenetic tree showed that the NDN gene conformed to the law of speciation and was highly conserved among mammals. RT-qPCR results showed the highest expression of NDN mRNA was found in the hypothalamus at puberty, and the expression was significantly increased and then significantly decreased from prepuberty to postpuberty in the hypothalamus, pituitary, and ovary and oviduct. Based on expressed single nucleotide polymorphism (SNP), the NDN gene was expressed monoallelically in the tissues of adult and neonatal umbilical cords, and the expressed allele was paternally inherited. The NDN promoter region of 3400 bp was obtained by cloning and identified in monoallelic-expressing tissues (hypothalamus, ovary, spleen) as a differentially methylated region (DMR). CONCLUSION: These findings will enrich the number of imprinted genes in sheep and suggest that the NDN gene could be a candidate gene for studying puberty initiation in Dolang sheep.

Resolution of N-acetyl-DL-methionine methyl ester by the lipase from Brucella thiophenivorans.

In this study, lipase-catalyzed resolution of N-acetyl-DL-methionine methyl ester (N-Ac-DL-MetOMe) was evaluated. A lipase from Brucella thiophenivorans was prone to exhibit high activity and excellent enantioselectivity toward N-Ac-DL-MetOMe to produce the key chiral intermediate N-acetyl-L-methionine methyl ester (N-Ac-L-MetOMe). The results showed that the enzymatic reaction was carried out in 100 g/L racemic substrate for 2 h, the conversion reached 51.3%, the enantiomeric excess value N-Ac-L-MetOMe exceeded 99%, and the enantiomeric ratio value >200. Therefore, the lipase from B. thiophenivorans has potential prospects for the resolution of N-Ac-DL-MetOMe to produce the important intermediate N-Ac-L-MetOMe.

Peptide nucleic acid-dependent artifact can lead to false-positive triplex gene editing signals.

Triplex gene editing relies on binding a stable peptide nucleic acid (PNA) sequence to a chromosomal target, which alters the helical structure of DNA to stimulate site-specific recombination with a single-strand DNA (ssDNA) donor template and elicits gene correction. Here, we assessed whether the codelivery of PNA and donor template encapsulated in Poly Lactic-co-Glycolic Acid (PLGA)-based nanoparticles can correct sickle cell disease and x-linked severe combined immunodeficiency. However, through this process we have identified a false-positive PCR artifact due to the intrinsic capability of PNAs to aggregate with ssDNA donor templates. Here, we show that the combination of PNA and donor templates but not either agent alone results in different degrees of aggregation that result in varying but highly reproducible levels of false-positive signal. We have identified this phenomenon in vitro and confirmed that the PNA sequences producing the highest supposed correction in vitro are not active in vivo in both disease models, which highlights the importance of interrogating and eliminating carryover of ssDNA donor templates in assessing various gene editing technologies such as PNA-mediated gene editing.

Acute kidney injury comorbidity analysis based on international classification of diseases-10 codes.

OBJECTIVE: Acute kidney injury (AKI) is a clinical syndrome that occurs as a result of a dramatic decline in kidney function caused by a variety of etiological factors. Its main biomarkers, serum creatinine and urine output, are not effective in diagnosing early AKI. For this reason, this study provides insight into this syndrome by exploring the comorbidities of AKI, which may facilitate the early diagnosis of AKI. In addition, organ crosstalk in AKI was systematically explored based on comorbidities to obtain clinically reliable results. METHODS: We collected data from the Medical Information Mart for Intensive Care-IV database on patients aged [Formula: see text] 18 years in intensive care units (ICU) who were diagnosed with AKI using the criteria proposed by Kidney Disease: Improving Global Outcomes. The Apriori algorithm was used to mine association rules on the diagnoses of 55,486 AKI and non-AKI patients in the ICU. The comorbidities of AKI mined were validated through the Electronic Intensive Care Unit database, the Colombian Open Health Database, and medical literature, after which comorbidity results were visualized using a disease network. Finally, organ diseases were identified and classified from comorbidities to investigate renal crosstalk with other distant organs in AKI. RESULTS: We found 579 AKI comorbidities, and the main ones were disorders of lipoprotein metabolism, essential hypertension, and disorders of fluid, electrolyte, and acid-base balance. Of the 579 comorbidities, 554 were verifiable and 25 were new and not previously reported. In addition, crosstalk between the kidneys and distant non-renal organs including the liver, heart, brain, lungs, and gut was observed in AKI with the strongest heart-kidney crosstalk, followed by lung-kidney crosstalk. CONCLUSION: The comorbidities mined in this study using association rules are scientific and may be used for the early diagnosis of AKI and the construction of AKI predictive models. Furthermore, the organ crosstalk results obtained through comorbidities may provide supporting information for the management of short- and long-term treatment practices for organ dysfunction.

Developing active and intelligent biodegradable packaging from food waste and byproducts: A review of sources, properties, film production methods, and their application in food preservation.

Food waste and byproducts (FWBP) are a global issue impacting economies, resources, and health. Recycling and utilizing these wastes, due to processing and economic constraints, face various challenges. However, valuable components in food waste inspire efficient solutions like active intelligent packaging. Though research on this is booming, its material selectivity, effectiveness, and commercial viability require further analysis. This paper categorizes FWBP and explores their potential for producing packaging from both animal and plant perspectives. In addition, the preparation/fabrication methods of these films/coatings have also been summarized comprehensively, focusing on the advantages and disadvantages of these methods and their commercial adaptability. Finally, the functions of these films/coatings and their ultimate performance in protecting food (meat, dairy products, fruits, and vegetables) are also reviewed systematically. FWBP provide a variety of methods for the application of edible films, including being made into coatings, films, and fibers for food preservation, or extracting active substances directly or indirectly from them (in the form of encapsulation) and adding them to packaging to endow them with functions such as barrier, antibacterial, antioxidant, and pH response. In addition, the casting method is the most commonly used method for producing edible films, but more film production methods (extrusion, electrospinning, 3D printing) need to be tried to make up for the shortcomings of the current methods. Finally, researchers need to conduct more in-depth research on various active compounds from FWBP to achieve better application effects and commercial adaptability.

Effectiveness of internet-based nursing interventions for the treatment of patients with periodontitis.

BACKGROUND: Periodontitis, one of the most common oral diseases, is a chronic inflammatory condition occur in response to bacterial plaque biofilms. Plaque control and oral hygiene instructions are the most widely used and effective nonsurgical treatment for periodontitis, which is based on a partnership between patient and clinician and requires a life-long commitment. The objective of this study was to analyze the effectiveness of internet-based nursing interventions for the treatment of patients with periodontitis. The findings from this study may help to enhance the therapeutic outcomes for patients with periodontitis. METHODS: A total of 80 patients with periodontitis treated in Zhejiang Province Stomatology hospital from December 2021 to January 2023 were randomly selected and divided into control group and intervention group with 40 cases each. The control group was given routine oral health guidance and the intervention group received internet based nursing intervention. The periodontal pocket depth, percentage of periodontal pocket depth (PD) ≥ 4 mm, bleeding on probing (BOP)%, and self-efficacy scale for oral health care (SESS) were assessed and compared at four time points: initial visit, 6-8-weeks follow-up, 3-months follow-up, and 6-months follow-up. RESULTS: There was no significant difference between the two groups in terms of age, gender, initial visit PD, initial visit PD ≥ 4 mm (%), initial visit BOP (%), and initial visit SESS (P > 0.05). The intervention group showed a significantly decreased percentage of PD ≥ 4 mm at 6-8 weeks and 6-months follow-up compared to the control group (P < 0.05). The PD, BOP%, and SESS scores of the intervention group were significantly better than those of the control group at 6-months follow-up (P < 0.05). There was no statistically significant difference in patient satisfaction between the two groups. CONCLUSIONS: This study confirmed that the internet-based nursing intervention in conjunction with periodontal treatment was able to improve the periodontal pocket depth, gingival bleeding and the level of self-efficacy of patients, suggesting that it is necessary to carry out the extended oral hygiene instructions via internet-based platforms for the patients in clinical practice.

LncRNA H19: A Novel Biomarker in Cardiovascular Disease.

Cardiovascular disease is a major cause of death and disability worldwide. Recently, increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) play critical roles in the pathogenesis of cardiovascular diseases, including atherosclerosis, coronary artery disease, dilated cardiomyopathy, diabetic cardiomyopathy, aortic dissection, and more. LncRNA H19 was the first to be described as a non-protein-coding mRNA-like molecule. A large number of studies have found that lncRNA H19 is related to the pathophysiological processes of cardiovascular diseases, and it is emerging as a potential key regulator of various heart diseases. In this review, we aim to summarize the role of lncRNA H19 in cardiovascular diseases in order to provide a theoretical basis for its potential use as a new therapeutic target in the future.

Tailoring the Position of Ester Group on N-Alkyl Chains of Benzotriazole-based Small Molecule Acceptors for High-Performance Organic Solar Cells.

Side chain engineering plays a vital role in exploring high-performance small molecule acceptors (SMAs) for organic solar cells (OSCs). In this work, we designed and synthesized a series of A-DA'D-A type SMAs by introducing different N-substituted alkyl and ester alkyl side chains on benzotriazole (BZ) central unit and aimed to investigate the effect of different ester substitution positions on photovoltaic performances. All the new SMAs with ester groups exhibit lower the lowest unoccupied molecular orbital (LUMO) energy levels and more blue-shifted absorption, but relatively higher absorption coefficients than alkyl chain counterpart. After blending with the donor PM6, the ester side chain-based devices demonstrate enhanced charge mobility, reduced amorphous intermixing domain size and long-lived charge transfer state compared to the alkyl chain counterpart, which are beneficial to achieve higher short-circuit current density (Jsc ) and fill factor (FF), simultaneously. Thereinto, the PM6 : BZ-E31 based device achieves a higher power conversion efficiency (PCE) of 18.33 %, which is the highest PCE among the OSCs based on the SMAs with BZ-core. Our work demonstrated the strategy of ester substituted side chain is a feasible and effective approach to develop more efficient SMAs for OSCs.

Cellular mechanisms of wound closure under cyclic stretching.

Wound closure is a fundamental process in many physiological and pathological processes, but the regulating effects of external force on the closure process are still unclear. Here, we systematically studied the closure process of wounds of different shape under cyclic stretching. We found that the stretching amplitude and direction had significant effect on the healing speed and healing mode. For instance, there was a biphasic dependence of the healing speed on the stretching amplitude. That is, the wound closure was faster under relatively small and large amplitude, while it was slower under intermediate amplitude. At the same time, the stretching could regulate the healing pattern. We showed that the stretching would increase the healing speed along the direction perpendicular to the stretching direction. Specifically, when the stretching was along the major axis of the wound, it accelerated the healing speed along the short axis, which induced a rosette to stitching-line mode transition. In contrast, stretching along the minor axis accelerated the healing speed along the long axis, inducing a stitching-line to rosette mode transition. Our theoretical analyses demonstrated that the wound closure process was coregulated by the mechanical factors including prestress in the cytoskeleton, the protrusion of cells, and the contraction of the actin ring, as well as the geometry of the wound. The cyclic stretch could further modulate the roles of these factors. For example, the stretching changed the stress field in the cell layer, and switched the direction of cell protrusions. This article reveals important cellular mechanisms of the wound healing process under cyclic stretching, and provides an insight into possible approaches of regulating cell collective behaviors via mechanical forces.

A Ferric-Superoxide Intermediate Initiates P450-Catalyzed Cyclic Dipeptide Dimerization.

The cytochrome P450 (CYP) AspB is involved in the biosynthesis of the diketopiperazine (DKP) aspergilazine A. Tryptophan-linked dimeric DKP alkaloids are a large family of natural products that are found in numerous species and exhibit broad and often potent bioactivity. The proposed mechanisms for C-N bond formation by AspB, and similar C-C bond formations by related CYPs, have invoked the use of a ferryl-intermediate as an oxidant to promote substrate dimerization. Here, the parallel application of steady-state and transient kinetic approaches reveals a very different mechanism that involves a ferric-superoxide species as a primary oxidant to initiate DKP-assembly. Single turnover kinetic isotope effects and a substrate analog suggest the probable nature and site for abstraction. The direct observation of CYP-superoxide reactivity rationalizes the atypical outcome of AspB and reveals a new reaction manifold in heme enzymes.