Recent developments in the use of nanocrystals to improve bioavailability of APIs.

Nanocrystals refer to materials with at least one dimension smaller than 100 nm, composing of atoms arranged in single crystals or polycrystals. Nanocrystals have significant research value as they offer unique advantages over conventional pharmaceutical formulations, such as high bioavailability, enhanced targeting selectivity and controlled release ability and are therefore suitable for the delivery of a wide range of drugs such as insoluble drugs, antitumor drugs and genetic drugs with broad application prospects. In recent years, research on nanocrystals has been progressively refined and new products have been launched or entered the clinical phase of studies. However, issues such as safety and stability still stand that need to be addressed for further development of nanocrystal formulations, and significant gaps do exist in research in various fields in this pharmaceutical arena. This paper presents a systematic overview of the advanced development of nanocrystals, ranging from the preparation approaches of nanocrystals with which the bioavailability of poorly water-soluble drugs is improved, critical properties of nanocrystals and associated characterization techniques, the recent development of nanocrystals with different administration routes, the advantages and associated limitations of nanocrystal formulations, the mechanisms of physical instability, and the enhanced dissolution performance, to the future perspectives, with a final view to shed more light on the future development of nanocrystals as a means of optimizing the bioavailability of drug candidates. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Diminishing carryover benefits of earlier spring vegetation growth.

Spring vegetation growth can benefit summer growth by increasing foliage area and carbon sequestration potential, or impair it by consuming additional resources needed for sustaining subsequent growth. However, the prevalent driving mechanism and its temporal changes remain unknown. Using satellite observations and long-term atmospheric CO2 records, here we show a weakening trend of the linkage between spring and summer vegetation growth/productivity in the Northern Hemisphere during 1982-2021. This weakening is driven by warmer and more extreme hot weather that becomes unfavourable for peak-season growth, shifting peak plant functioning away from earlier periods. This is further exacerbated by seasonally growing ecosystem water stress due to reduced water supply and enhanced water demand. Our finding suggests that beneficial carryover effects of spring growth on summer growth are diminishing or even reversing, acting as an early warning sign of the ongoing shift of climatic effects from stimulating to suppressing plant photosynthesis during the early to peak seasons.

Construction of the novel immune risk scoring system related to CD8+ T cells in uterine corpus endometrial carcinoma.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is a gynecological malignant tumor with high incidence and poor prognosis. Although immunotherapy has brought significant survival benefits to advanced UCEC patients, traditional evaluation indicators cannot accurately identify all potential beneficiaries of immunotherapy. Consequently, it is necessary to construct a new scoring system to predict patient prognosis and responsiveness of immunotherapy. METHODS: CIBERSORT combined with weighted gene co-expression network analysis (WGCNA), non-negative matrix factorization (NMF), and random forest algorithms to screen the module associated with CD8+ T cells, and key genes related to prognosis were selected out by univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses to develop the novel immune risk score (NIRS). Kaplan-Meier (K-M) analysis was used to compare the difference of survival between high- and low- NIRS groups. We  also explored the correlations between NIRS, immune infiltration and immunotherapy, and three external validation sets were used to verify the predictive performance of NIRS. Furthermore, clinical subgroup analysis, mutation analysis, differential expression of immune checkpoints, and drug sensitivity analysis were performed to generate individualized treatments for patients with different risk scores. Finally, gene set variation analysis (GSVA) was conducted to explore the biological functions of NIRS, and qRT-PCR was applied to verify the differential expressions of three trait genes at cellular and tissue levels. RESULTS: Among the modules clustered by WGCNA, the magenta module was most positively associated with CD8+ T cells. Three genes (CTSW, CD3D and CD48) were selected to construct NIRS after multiple screening procedures. NIRS was confirmed as an independent prognostic factor of UCEC, and patients with high NIRS had significantly worse prognosis compared to those with low NIRS. The high NIRS group showed lower levels of infiltrated immune cells, gene mutations, and expression of multiple immune checkpoints, indicating reduced sensitivity to immunotherapy. Three module genes were identified as protective factors positively correlated with the level of CD8+ T cells. CONCLUSIONS: In this study, we constructed NIRS as a novel predictive signature of UCEC. NIRS not only differentiates patients with distinct prognoses and immune responsiveness, but also guides their therapeutic regimens.

The association between parental risks and childhood development: findings from a community-based survey in East China.

BACKGROUND: Nurturing care is necessary for optimal early childhood development. This study aimed to investigate the prevalence of parental risks in rural East China and assess their impacts on early development in children younger than three years old. METHODS: This community-based cross-sectional survey was conducted among 3852 caregiver-child pairs in Zhejiang Province from December 2019 to January 2020. Children aged 0 to 3 years were recruited from China's Early Childhood Development Program (ECD). Local child health care providers conducted face-to-face interviews with the primary caregivers. Demographic information of the participants was collected by questionnaire. Each child was screened for parental risk through the Parental Risk Checklist designed by the ECD program. The Ages and Stages Questionnaire (ASQ) was used to identify children with potential developmental delays. Multinomial logistic regression model and linear trend test were applied to assess the association between parental risks and suspected developmental delays. RESULTS: Among the 3852 children included in the analyses, 46.70% had at least one parental risk and 9.01% presented suspected developmental delays in any domain of ASQ. Parental risk was statistically associated with the overall suspected developmental delay in young children (Relative Risk Ratio (RRR): 1.36; 95% confidence interval (CI): 1.08, 1.72; P = 0.010) after adjusting potential confounders. Compared with children with no parental risk, children exposed to 3 or more parental risks had 2.59, 5.76, 3.95, and 2.84 times higher risk of the suspected developmental delay in overall ASQ, communication, problem-solving, and personal-social domain, respectively (P values < 0.05). The linear trend tests found that the more parental risks, the higher possibility of developmental delay (P values < 0.05). CONCLUSIONS: Parental risks are prevalent among children under three years in rural East China, which may increase the risk of developmental delays in children. Meanwhile, parental risk screening can be used to recognize poor nurturing care in primary health care settings. Targeted interventions are warranted to improve nurturing care for optimal early childhood development.

Construction of a novel molecular typing and scoring system for anoikis distinguishes between different prognostic risks and treatment responsiveness in low-grade glioma.

Background: The main factors responsible for low-grade glioma (LGG)s' poor prognosis and treatment effectiveness include recurrence and malignant progression. A specific type of programmed cell death, known as anoikis, which is crucial for tumor invasion and metastasis, however, has not yet been investigated in LGGs. Methods: We downloaded data of 509 samples from the TCGA-LGG cohort, carried out cluster analysis for typing twice on the basis of 19 anoikis-associated genes, and the subtypes were evaluated the differences in clinicopathological and biological features. ESTIMATE and single-sample gene set enrichment analysis were employed to examine the immunological milieu of LGGs, and enrichment analysis was used to look into the underlying biological mechanisms in LGGs. Cox regression analysis and the Least Absolute Shrinkage and Selection Operator regression algorithm were used to create a prediction scoring system. The scoring system was used for classifying LGG into high- and low- anoikis riskscore (anoiS) groups. The impact of the anoiS on the prognosis, standard treatment, and immunotherapy of patients with LGG was assessed using survival analysis and drug sensitivity analysis. Cell experiments were employed for the verification of the differential expression between LGG cells and normal cells of the anoikis gene team that regard CCT5 as the core. Results: Based on the expression profiles of the 19 anoikis-associated genes, all individuals with LGG were classified into four subtypes and two macrosubtypes. The different macrosubtypes had significantly different biological characteristics, and the anoirgclusterBD subtype manifested a significantly bad prognosis and a high immune level of infiltration. And subsequent secondary genotyping also showed good prognostic discrimination. We further constructed an anoikis scoring system, anoiS. LGG patients having a high anoiS had a worse prognosis in comparison to those having a low anoiS. The high anoiS group exhibited larger levels of immune infiltration and superior immunotherapy efficacy than the low anoiS group. The high anoiS group was also more susceptible to temozolomide (TMZ) than the low anoiS group, according to a drug sensitivity analysis of TMZ. Conclusion: This study constructed a scoring system for predicting the prognosis of patients with LGG and their responsive to TMZ and immunotherapy.

Molecular subtypes based on centrosome-related genes can predict prognosis and therapeutic responsiveness in patients with low-grade gliomas.

Background: Abnormalities in centrosome regulatory genes can induce chromosome instability, cell differentiation errors, and tumorigenesis. However, a limited number of comprehensive analyses of centrosome-related genes have been performed in low-grade gliomas (LGG). Methods: LGG data were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The ConsensusClusterPlus" R package was used for unsupervised clustering. We constructed a centrosome-related genes (CRGs) signature using a random forest model, lasso Cox model, and multivariate Cox model, and quantified the centrosome-related risk score (centS). The prognostic prediction efficacy of centS was evaluated using a Receiver Operating Characteristic (ROC) curve. Immune cell infiltration and genomic mutational landscapes were evaluated using the ESTIMATE algorithm, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm, and "maftools" R package, respectively. Differences in clinical features, isocitrate dehydrogenase (IDH) mutation, 1p19q codeletion, O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, and response to antitumor therapy between the high- and low-centS groups were explored. "pRRophetic" R packages were used for temozolomide (TMZ) sensitivity analysis. qRT-PCR verified the differential expression of the centrosomal gene team, the core of which is CEP135, between LGG cells and normal cells. Results: Two distinct CRG-based clusters were identified using consensus unsupervised clustering analysis. The prognosis, biological characteristics, and immune cell infiltration of the two clusters differed significantly. A well-performing centS signature was developed to predict the prognosis of patients with LGG based on 12 potential CRGs. We found that patients in the high-centS group showed poorer prognosis and lower proportion of IDH mutation and 1p19q codeletion compared to those in the low-centS group. Furthermore, patients in the high-centS group showed higher sensitivity to TMZ, higher tumor mutation burden, and immune cell infiltration. Finally, we identified a centrosomal gene team whose core was CEP135, and verified their differential expression between LGG cells and normal glial cells. Conclusion: Our findings reveal a novel centrosome-related signature for predicting the prognosis and therapeutic responsiveness of patients with LGG. This may be helpful for the accurate clinical treatment of LGG.

Satellite solar-induced chlorophyll fluorescence tracks physiological drought stress development during 2020 southwest US drought.

Monitoring and estimating drought impact on plant physiological processes over large regions remains a major challenge for remote sensing and land surface modeling, with important implications for understanding plant mortality mechanisms and predicting the climate change impact on terrestrial carbon and water cycles. The Orbiting Carbon Observatory 3 (OCO-3), with its unique diurnal observing capability, offers a new opportunity to track drought stress on plant physiology. Using radiative transfer and machine learning modeling, we derive a metric of afternoon photosynthetic depression from OCO-3 solar-induced chlorophyll fluorescence (SIF) as an indicator of plant physiological drought stress. This unique diurnal signal enables a spatially explicit mapping of plants' physiological response to drought. Using OCO-3 observations, we detect a widespread increasing drought stress during the 2020 southwest US drought. Although the physiological drought stress is largely related to the vapor pressure deficit (VPD), our results suggest that plants' sensitivity to VPD increases as the drought intensifies and VPD sensitivity develops differently for shrublands and grasslands. Our findings highlight the potential of using diurnal satellite SIF observations to advance the mechanistic understanding of drought impact on terrestrial ecosystems and to improve land surface modeling.

Cuproptosis status affects treatment options about immunotherapy and targeted therapy for patients with kidney renal clear cell carcinoma.

The development of immunotherapy has changed the treatment landscape of advanced kidney renal clear cell carcinoma (KIRC), offering patients more treatment options. Cuproptosis, a novel cell death mode dependent on copper ions and mitochondrial respiration has not yet been studied in KIRC. We assembled a comprehensive cohort of The Cancer Genome Atlas (TCGA)-KIRC and GSE29609, performed cluster analysis for typing twice using seven cuproptosis-promoting genes (CPGs) as a starting point, and assessed the differences in biological and clinicopathological characteristics between different subtypes. Furthermore, we explored the tumor immune infiltration landscape in KIRC using ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) and the potential molecular mechanisms of cuproptosis in KIRC using enrichment analysis. We constructed a cuproptosis score (CUS) using the Boruta algorithm combined with principal component analysis. We evaluated the impact of CUS on prognosis, targeted therapy, and immunotherapy in patients with KIRC using survival analysis, the predictions from the Cancer Immunome Atlas database, and targeted drug susceptibility analysis. We found that patients with high CUS levels show poor prognosis and efficacy against all four immune checkpoint inhibitors, and their immunosuppression may depend on TGFB1. However, the high-CUS group showed higher sensitivity to sunitinib, axitinib, and elesclomol. Sunitinib monotherapy may reverse the poor prognosis and result in higher progression free survival. Then, we identified two potential CPGs and verified their differential expression between the KIRC and the normal samples. Finally, we explored the effect of the key gene FDX1 on the proliferation of KIRC cells and confirmed the presence of cuproptosis in KIRC cells. We developed a targeted therapy and immunotherapy strategy for advanced KIRC based on CUS. Our findings provide new insights into the relationship among cuproptosis, metabolism, and immunity in KIRC.

The Antimicrobial and Antibiofilm Activity of Oregano Essential Oil against Enterococcus faecalis and Its Application in Chicken Breast.

Oregano essential oil (OEO) possesses anti-inflammatory, antioxidant, and cancer-suppressive properties. Enterococcus faecalis is a foodborne opportunistic pathogen that can be found in nature and the food processing industry. The goal of this investigation was to explore the antimicrobial action and mechanism of OEO against E. faecalis, inactivation action of OEO on E. faecalis in mature biofilms, and its application in chicken breast. The minimum inhibitory concentration (MIC) of OEO against E. faecalis strains (ATCC 29212 and nine isolates) ranged from 0.25 to 0.50 µL/mL. OEO therapy reduced intracellular adenosine triphosphate (ATP) levels, caused cell membrane hyperpolarization, increased the intracellular reactive oxygen species (ROS), and elevated extracellular malondialdehyde (MDA) concentrations. Furthermore, OEO treatment diminished cell membrane integrity and caused morphological alterations in the cells. In biofilms on stainless-steel, OEO showed effective inactivation activity against E. faecalis. OEO reduced the number of viable cells, cell viability and exopolysaccharides in the biofilm, as well as destroying its structure. Application of OEO on chicken breast results in a considerable reduction in E. faecalis counts and pH values, in comparison to control samples. These findings suggest that OEO could be utilized as a natural antibacterial preservative and could effectively control E. faecalis in food manufacturing.

The long noncoding RNA KTN1-AS1 promotes bladder cancer tumorigenesis via KTN1 cis-activation and the consequent initiation of Rho GTPase-mediated signaling.

BACKGROUND: Accumulating evidence support the hypothesis that long noncoding RNAs (lncRNAs) are involved in several physiological and pathological conditions, including cancer. Here, we investigated the potential role of lncRNAs in bladder cancer. METHODS: We first looked at available datasets retrieved from the TCGA database and discovered that the lncRNA KTN 1 antisense RNA 1 (KTN1-AS1) was significantly up-regulated in several cancer types including bladder cancer, but was decreased in some other tumors. Therefore, we focused our attention on KTN1-AS1. Using both in vitro and in vivo systems that allowed the modulation of KTN1-AS1 and expression of other relevant proteins, we investigated in-depth the role of KTN1-AS1 in bladder cancer (and the mechanism behind). We further investigated the potential KTN1-AS1-interacting proteins using RNA immunoprecipitation, and explored the KTN1-AS1-related epigenetic landscape (with a particular emphasis on acetylation) using chromatin immunoprecipitation (ChIP) assays. RESULTS: KTN1-AS1 silencing inhibited the proliferation, invasion, and migration of bladder cancer cells, while KTN1-AS1 overexpression had the obvious opposite effects. Mechanistically, KTN1-AS1 promoted the recruitment of EP300, a histone acetyltransferase that enriched acetylation of histone H3 at lysine 27 (H3K27Ac) in the KTN1 promoter region. This epigenetic modulation contributed to the up-regulation of KTN1, which affected bladder cancer growth and progression via the regulation of Rho GTPase (RAC1, RHOA, and CDC42)-mediated signaling. CONCLUSION: Overall, our data support the idea that the lncRNA KTN1-AS1 promotes bladder cancer tumorigenesis via modulation of the KTN1/Rho GTPase axis and is a promising new therapeutic target for the treatment of bladder cancer.