Absence of the Klotho Function Causes Cornea Degeneration with Specific Features Resembling Fuchs Endothelial Corneal Dystrophy and Bullous Keratopathy.

The Klotho loss-of-function mutation is known to cause accelerated senescence in many organs, but its effects on the cornea have not been published. The present study aims to investigate the effects of the Klotho null mutation on cornea degeneration and to characterize the pathological features. Mouse corneas of Klotho homozygous, heterozygous, and wild-type mice at 8 weeks of age for both genders were subject to pathological and immunohistological examinations. The results show an irregular topography on the corneal surface with a Klotho null mutation. Histological examinations revealed a reduced corneal epithelial cell density, endothelial cell-shedding, and decreased cornea stromal layer thickness in the absence of the Klotho function. Furthermore, guttae formation and the desquamation of wing cells were significantly increased, which was comparable to the characteristics of Fuchs endothelial corneal dystrophy and bullous keratopathy. The mechanism analysis showed multi-fold abnormalities, including oxidative stress-induced cornea epithelium apoptosis and inflammation, extracellular matrix remodeling in the stroma, and a disruption of epithelial repair, presumably through the epithelial-mesenchymal transition. In conclusion, cornea degeneration was observed in the Klotho loss-of-function mutant mice. These pathological features support the use of Klotho mutant mice for investigating age-related cornea anomalies, including Fuchs endothelial corneal dystrophy, bullous keratopathy, and dry eye diseases.

Klotho Null Mutation Indirectly Leads to Age-Related Lacrimal Gland Degeneration in Mutant Mice.

The Klotho null mutation is known to lead to accelerated aging in many organs, but its effects on tear secretion and lacrimal gland (LG) senescence have not been addressed. This study investigated whether the Klotho null mutation would lead to a dry eye status and the outcome of LG without Klotho function. The Klotho (-/-) mutant mice showed reduced LG size and tear volume on the 8th week, as compared to their littermates (+/+, +/-). Hematoxylin-Eosin and Masson's trichrome staining were performed to determine morphological changes and collagen deposition. Traits of LG aging, including acinar atrophy, thickened capsules, and more collagen depositions, were observed. Immunohistochemical detections for Klotho, α-SMA, MDA, 8-OHdG, vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), MMP-2, MMP-9, and FGF-23 were performed and compared among the three genotypes (+/+, +/-, -/-) at 6 and 8 weeks of age for mechanism analyses. Unexpectedly, the Klotho protein was not detected in the LG of all the three genotypes, indicating indirect effects from the Klotho null mutation. Further analyses showed abundant MDA and 8-OHdG detected in the Klotho (-/-) LG on the 8th week, indicating elevated oxidative stress. In addition, both sympathetic and parasympathetic neural transducing activities, as represented by TH and VIP expression, respectively, and α-SMA were increased in LGs with Klotho mutations. Furthermore, MMP-2 and MMP-9 expression were elevated, with FGF-23 expression being decreased on the 8th week in the Klotho (-/-) LG. In conclusion, characteristics of age-related LG degeneration were found in the Klotho null mutant mice. These traits support the use of Klotho mutant mice as a model of age-related dry eye disease.

Fabrication of a reusable electrochemical platform based on acid-responsive host-guest interaction with ß- cyclodextrin.

A reusable electrochemical glassy carbon electrode (GCE) platform based on the acid-responsive host-guest interaction between ß-cyclodextrin (ß-CD) and benzimidazole (BM) derivatives was developed. The ß-CD can specifically recognize the BM derivative through the acid -responsive host-guest interaction. The electrode was first modified by eletrografting to immobilize a diamine linker (Boc-EDA), resulting in GCEBoc-EDA in which one amine was used for covalent immobilization to the electrode and another Boc protected amine was used to solid-phase synthesis on following step-by-step modifications on the electrode. After deprotection of the Boc group on the GCEBoc-EDA, carbonyldiimidazole (CDI)-activated ß-CD was coupled with -NH2 on the electrode to result in GCEß-CD. Due to the nonspecific interaction, we further improved the GCEß-CD electrode by introducing immobilized poly(ethylene glycol) methyl ether (PEG-Me) to result in GCEß-CD/PEG-Me, along with optimized procedures. CV, DPV, and EIS methods were applied for recording the electrochemistry signals. We utilized GCEß-CD/PEG-Me to investigate the host-guest interaction and found the electrochemical signal exhibited dynamic behavior. The GCEß-CD/PEG-Me was able to regenerate the ß-CD surface more than 20 times after HCl acidic washes. We further investigated the interaction of carbendazim (CBZ), a commonly used fungicide in the agriculture and food industry, and observed a positive electrochemical response. The sensor design has potential applications in ensuring food safety.

The robust reciprocal relationship between loneliness and depressive symptoms among the general population: Evidence from a quantitative analysis of 37 studies.

BACKGROUND: Loneliness has long been associated with depressive symptoms, but there is no evidence on the question of "which comes first". To help us to answer this question, this study conducted a meta-analysis using a cross-lagged formula to examine the reciprocal relations between loneliness and depressive symptoms, as well as potential moderators. METHODS: The meta-analytic dataset consisted of 37 studies with sample sizes ranging from 52 to 5991. Effect sizes (including autoregressive effects and lagged coefficients) were included. We computed weighted mean effect sizes for the correlation effect and cross-lagged effect between loneliness and depressive symptoms. We also performed a meta-regression to investigate potential moderators. RESULTS: The results showed that loneliness and depressive symptoms reciprocally predicted each other over time with similar effect sizes. There was no moderation of our overall effect size in either direction by time interval between measurements, the proportion of female participants, mean age of the sample, or type of measurement. LIMITATIONS: Caution should be taken in drawing final conclusions about the relative strength of reciprocal effects between loneliness and depressive symptoms due to the potential influence of varied research focus in the included studies, which could affect the effect size. CONCLUSIONS: These findings advance the study of the relationship between loneliness and depressive symptoms by providing evidence that the link between them is symmetrically reciprocal and robust, which may help clinicians to develop effective intervention methods.

Adaptive evolution of the enigmatic Takakia now facing climate change in Tibet.

The most extreme environments are the most vulnerable to transformation under a rapidly changing climate. These ecosystems harbor some of the most specialized species, which will likely suffer the highest extinction rates. We document the steepest temperature increase (2010-2021) on record at altitudes of above 4,000 m, triggering a decline of the relictual and highly adapted moss Takakia lepidozioides. Its de-novo-sequenced genome with 27,467 protein-coding genes includes distinct adaptations to abiotic stresses and comprises the largest number of fast-evolving genes under positive selection. The uplift of the study site in the last 65 million years has resulted in life-threatening UV-B radiation and drastically reduced temperatures, and we detected several of the molecular adaptations of Takakia to these environmental changes. Surprisingly, specific morphological features likely occurred earlier than 165 mya in much warmer environments. Following nearly 400 million years of evolution and resilience, this species is now facing extinction.

A selective fluorescent turn-on probe for imaging and sensing of hydrogen peroxide in living cells.

Fluorescent turn-on probes have been extensively used in disease diagnosis and research on pathological disease mechanisms because of their low background interference. Hydrogen peroxide (H2O2) plays a vital role in regulating various cellular functions. In the current study, a fluorescent probe, HCyB, based on hemicyanine and arylboronate structures, was designed to detect H2O2. HCyB reacted with H2O2 and exhibited a good linear relationship for H2O2 concentrations ranging from 15 to 50 µM and good selectivity over other species. The fluorescent detection limit was 76 nM. Moreover, HCyB exhibited less toxicity and mitochondrial-targeting abilities. HCyB was successfully used to monitor exogenous or endogenous H2O2 in mouse macrophage RAW 264.7, human skin fibroblast WS1, breast cancer cell MDA-MB-231, and human leukemia monocytic THP1 cells.

Assessing the social sustainability impact on suppliers: the role of global value chains governance strategies.

Stakeholder awareness of social sustainability issues is growing, but few recognize what motivates companies to implement social sustainability in their supply chain management or return on investment in developing countries, where cultural norms might vary widely. We address this question by broadening stakeholder and institutional perspectives to investigate how customers, sustainability culture, management, and external stakeholders influence companies' acceptance of social sustainability in their supply chains. We collected information on 356 apparel and footwear manufacturers from 5 South Asian countries that sell to customers in Western Europe and North America. Our findings highlight the interdependence of organizational and institutional structures and define the boundaries of GVC governance mechanisms within a social sustainability framework. Our research shows that the success of examining social sustainability interventions applied by leading firms or the effects of collaboration-based global value chains depend on the supplier's local institutional framework. Social sustainability organizational practices influence supplier perceptions and responses to key corporate needs in the supplier's country. We demonstrate that GVC governance models are most conducive to suppliers' social sustainability implementation when contextualized with the local institutional needs for social sustainability in the supplier's country.

Klotho Null Mutation Involvement in Adenosine A2B Receptor-Related Skeletal Muscle Degeneration.

Klotho is known for its age-suppressing function and has been implicated in sarcopenia pathology. It has recently been proposed that the adenosine A2B receptor plays a crucial role in skeletal muscle energy expenditure. However, the association between Klotho and A2B remains elusive. In this study, Klotho knockout mice, aged 10 weeks, and wild-type mice, aged 10 and 64 weeks, were used for comparison in indicators of sarcopenia (n = 6 for each group). PCR was performed to confirm the mice genotypes. Skeletal muscle sections were analyzed using hematoxylin and eosin staining as well as immunohistochemistry staining. The skeletal muscle cross-sectional area was significantly reduced in Klotho knockout mice and wild-type mice, aged 64 weeks, when compared with wild-type mice, aged 10 weeks, with a decreased percentage of type IIa and IIb myofibers. Likely impaired regenerative capacity, as reflected by the reduction of paired box 7 (Pax7)- and myogenic differentiation protein 1 (MyoD)-positive cells, was also observed in Klotho knockout mice and aged wild-type mice. 8-Hydroxy-2-deoxyguanosine expression was enhanced with Klotho knockout and aging, indicating higher oxidative stress. Adenosine A2B signaling was impaired, with a lower expression of the A2B receptor and the cAMP-response element binding protein in Klotho knockout and aged mice. The present study provides the novel finding that sarcopenia involves adenosine signaling under the influence of Klotho knockout.

Low-Temperature Hypergolic Ignition of 1-Octene with Low Ignition Delay Time.

The attainment of the efficient ignition of traditional liquid hydrocarbons of scramjet combustors at low flight Mach numbers is a challenging task. In this study, a novel chemical strategy to improve the reliable ignition and efficient combustion of hydrocarbon fuels was proposed. A directional hydroboration reaction was used to convert hydrocarbon fuel into highly active alkylborane, thereby leading to changes in the combustion reaction pathway of hydrocarbon fuel. A directional reaction to achieve the hypergolic ignition of 1-octene was designed and developed by using Gaussian simulation. Borane dimethyl sulfide (BDMS), a high-energy additive, was allowed to react spontaneously with 1-octene to achieve the hypergolic ignition of liquid hydrocarbon fuel at -15 °C. Compared with the ignition delay time of pure 1-octene (565 °C), the ignition delay time of 1-octene/BDMS (9:1.2) decreased by 3850% at 50 °C. Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry confirmed the directional reaction of the hypergolic ignition reaction pathway of 1-octene and BDMS. Moreover, optical measurements showed the development trend of hydroxyl radicals (OH·) in the lower temperature hypergolic ignition and combustion of 1-octene. Finally, this study indicates that the enhancement of the low-temperature ignition performance of 1-octene by hydroboration in the presence of BDMS is feasible and promising for jet propellant design with tremendous future applications.

Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205.

CPT-11 (irinotecan) is a derivative of camptothecin which is a natural product derived from the Chinese tree Camptotheca acuminta and widely used in antitumor therapy. Here, the in vitro anti-tumor activity and associated mechanisms of a novel derivative of camptothecin, ZBH-1205, were investigated in a panel of 9 human tumor cell lines, as well as in HEK 293 and SK-OV-3/DPP, a multi-drug resistant (MDR) cell line, and compared to CPT-11 and 7-ethyl-10-hydroxy-camptothecin (SN38). Comparisons between the different compounds were made on the basis of IC50 values as determined by the MTT assay, and flow cytometry was used to evaluate cell cycle progression, apoptosis, and the levels of pro- and active caspase-3 among different treatment groups. Interaction between the molecules and topoisomerase-1 (Topo-1)-DNA complexes was detected by a DNA relaxation assay. Our results demonstrated that IC50 values for ZBH-1205 ranged from 0.0009 µmol/L to 2.5671 µmol/L, which were consistently lower than IC50 values of CPT-11 or SN38 in the panel of cell lines, including SK-OV-3/DPP. Furthermore, ZBH-1205 was more effective than CPT-11 or SN38 at stabilizing Topo-1-DNA complexes and inducing tumor cell apoptosis. Therefore, ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials.

Self-adaptive prediction of cloud resource demands using ensemble model and subtractive-fuzzy clustering based fuzzy neural network.

In IaaS (infrastructure as a service) cloud environment, users are provisioned with virtual machines (VMs). To allocate resources for users dynamically and effectively, accurate resource demands predicting is essential. For this purpose, this paper proposes a self-adaptive prediction method using ensemble model and subtractive-fuzzy clustering based fuzzy neural network (ESFCFNN). We analyze the characters of user preferences and demands. Then the architecture of the prediction model is constructed. We adopt some base predictors to compose the ensemble model. Then the structure and learning algorithm of fuzzy neural network is researched. To obtain the number of fuzzy rules and the initial value of the premise and consequent parameters, this paper proposes the fuzzy c-means combined with subtractive clustering algorithm, that is, the subtractive-fuzzy clustering. Finally, we adopt different criteria to evaluate the proposed method. The experiment results show that the method is accurate and effective in predicting the resource demands.