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In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Background Parkinson’s disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies (LB). During the course of disease, misfolded α-synuclein, the major constituent of LB, spreads to different regions of the brain in a prion-like fashion, giving rise to successive non-motor and motor symptoms. Etiology is likely multifactorial, and involves interplay among aging, genetic susceptibility and environmental factors. Main body The prevalence of PD rises exponentially with age, and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death. However, the majority of those over the age of 80 do not have PD, thus other factors in addition to aging are needed to cause disease. Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk. Nevertheless, the causality of most environmental factors is not conclusively established, and alternative explanations such as reverse causality and recall bias cannot be excluded. The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD. Rare mutations as well as common variants in genes such as SNCA, LRRK2 and GBA are associated with risk of PD, but Mendelian causes collectively only account for 5% of PD and common polymorphisms are associated with small increase in PD risk. Heritability of PD has been estimated to be around 30%. Thus, aging, genetics and environmental factors each alone is rarely sufficient to cause PD for most patients. Conclusion PD is a multifactorial disorder involving interplay of aging, genetics and environmental factors. This has implications on the development of appropriate animal models of PD which take all these factors into account. Common converging pathways likely include mitochondrial dysfunction, impaired autophagy, oxidative stress and neuroinflammation, which are associated with the accumulation and spread of misfolded α-synuclein and neurodegeneration. Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

Critical Thermal maximum (CT max ) is often used to characterize the upper thermal limits of organisms and represents a key trait for evaluating the fitness of ectotherms. The lack of standardization in CT max assays has, however, introduced methodological problems in its measurement, which can lead to questionable estimates of species’ upper thermal limits. Focusing on ants, which are model organisms for research on thermal ecology, we aim to obtain a reliable ramping rate that will yield the most rigorous measures of CT max for the most species. After identifying three commonly used ramping rates (i.e., 0.2, 0.5 and 1.0°C min -1 ) in the literature, we experimentally determine their effects on the CT max values of 27 species measured using dynamic assays. Next, we use static assays to evaluate the accuracy of these values in function of the time of exposure. Finally, we use field observations of species’ foraging activities across a wide range of ground temperatures to identify the most biologically relevant CT max values and to develop a standardized method. Our results demonstrate that the use of a 1°C min -1 ramping rate in dynamic assays yields the most reliable CT max values for comparing ant species’ upper thermal limits, which are further validated in static assays and field observations. We further illustrate how methodological biases in physiological trait measurements can affect subsequent analyses and conclusions on community comparisons between strata and habitats, and the detection of phylogenetic signal (Pagel’s λ and Bloomberg’s K ). Overall, our study presents a methodological framework for identifying a reliable and standardized ramping rate to measure CT max in ants, which can be applied to other ectotherms. Particular attention should be given to CT max values obtained with less suitable ramping rates, and the potential biases they may introduce to trait-based research on global warming and habitat conversion, as well as inferences about phylogenetic conservatism.

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert β-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the β-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester β-carbons as nucleophiles (β-carbon activation) using N -heterocyclic carbene organocatalysts. The catalytically generated nucleophilic β-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester β-carbons to open a valuable new arena for new and useful reactions and synthetic strategies. Direct β-carbon activation of saturated carbonyl compounds represents a significant fundamental challenge in organic chemistry. Here, the catalytic activation of saturated ester β- sp 3 carbon as nucleophile via N -heterocyclic carbene organocatalysis is reported. The catalytically generated nucleophilic β-carbon undergoes enantioselective reactions with various electrophiles.

By substituting the A site in P21/c-A(CN)2 and varying the lattice parameters a, b, c, and the unit-cell angles, along with using crystal graph convolutional neural networks to calculate their cohesive energy, the candidate compounds, Al(CN)2 and Si(CN)2, were selected from the structure with the lowest cohesive energy. The two candidate structures were then optimized using first-principles calculations, and their phonon, electronic, and elastic properties were computed. As a result, two dynamically stable structures were found: Al(CN)2 with a space group of Cmcm and Si(CN)2 with a space group of R3¯m. Their phonon spectra exhibited no imaginary frequencies; thus, their elastic constants satisfied the mechanical stability criteria. Structurally, Si(CN)2 is similar to 6H-SiC and 15R-SiC. Its elastic constants indicated that it is harder than those SiC materials. Al(CN)2 exhibits metallic properties and the indirect wide-bandgap of Si(CN)2 was calculated by the generalized gradient approximation, the local density approximation, and the screened hybrid functional of Heyd, Scuseria, and Ernzerhof (HSE06) is found to be 3.093, 3.048, and 4.589 eV, respectively. According to this wide bandgap, we can conclude that Si(CN)2 has the potential to be used in high-temperature and high-power environments, making it usable in a broad range of applications.

Wireless communications play an important role in ensuring ease of access to shared electronic health records (EHR) across health service providers which is essential and significant for prompt patients’ care, especially in cases of emergency medical conditions. With the need to support anytime, anywhere access to, potentially bandwidth hungry, medical records, electronic healthcare applications will continue to benefit from advanced wireless network technologies such as 5G and beyond. With sharing, it is crucial to provide patients with security and privacy guarantees, and allow them to certain control of access to their data. Existing solutions mostly assume that patients are available to authorize requests to access their EHR, which is impractical as the patient may be unconscious. This paper proposes a secure and privacy protecting protocol whereby the patient can pre-delegate the authorization for the access of his/her EHR. Our patient(user)-centric proposal combines Self-Sovereign Identity (SSI) concepts and model with Secure Multi-party Computation (SMPC) and Threshold Cryptography (TC) to enable secure identity and authorization verification. A block cipher encryption sharing approach is adopted for the threshold SMPC which extends the AES-GCM symmetric encryption model into a full-fledged cryptographic platform. Two mechanisms are implemented for the block cipher encryption, namely XOR and Cascade, and experiments are conducted to compare them. We conclude that the XOR mechanism can scale for larger thresholds, while Cascade performed better for a lower threshold (≤ 3). This paper also performs a threat analysis of the protocol and approach, and validates its correctness and complexity. We conclude that the approach can achieve the security and privacy protection of the patient’s personal EHR, as well as the autonomy of the patient to control the authorization for the access and sharing.

Supramolecular molecular amphiphiles that are photoresponsive have been intensively developed for a wide range of smart functional materials. As a photoswitch that displays high chemical and thermal stabilities, the azobenzene motif has been intensively incorporated into distinct soft materials to control properties and provide high temporal and high spatial resolution. However, only limited examples of molecular azobenzene amphiphiles (AAs) with chiral character have been reported with complicated synthetic manifold and photochemical studies. Herein, we design a novel molecular AA, AAPhe, with a simple molecular design and an L-amino acid motif. In addition to excellent photoresponsibility in organic media, AAPhe exhibits a high capacity for supramolecular transformation in aqueous media, as well as supramolecular chirality controlled by noninvasive photostimulation, as found in encouraging photochemical studies. Investigations of supramolecular behavior show that the supramolecular chiral structure induced by AAPhe assembles from microscopic to macroscopic length scales. The current design and studies of supramolecular assemblies of AAPhe provide us with fundamental concepts for constructing macroscopic functional materials with supramolecular chirality.Photoresponsive molecular amphiphiles have been incorporated into distinct soft materials to control properties in high temporal and high spatial manners. We demonstrate molecular azobenzene amphiphiles for construction of chiral supramolecular assemblies with excellent photoresponsibility and a high capacity for supramolecular transformation in aqueous media. Supramolecular chiral structures of azobenzene amphiphiles can assemble from microscopic to macroscopic length scales

Mutations in leucine-rich repeat kinase 2 ( LRRK2 ) and glucocerebrosidase ( GBA ) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

Dysregulation of microRNAs has a critical role in cancer progression. Here we identify an intronic microRNA, miR-135b that is upregulated in highly invasive non-small-cell lung cancer cells. Expression of miR-135b enhances cancer cell invasive and migratory abilities in vitro and promotes cancer metastasis in vivo , while specific inhibition of miR-135b by a miR-135b-specific molecular sponge and antagomirs suppresses cancer cell invasion, orthotopic lung tumour growth and metastasis in a mouse model. miR-135b targets multiple key components in the Hippo pathway, including LATS2, β-TrCP and NDR2, as well as LZTS1. Expression of miR-135b, LZTS1, LATS2 and nuclear TAZ predicts poor outcomes of non-small-cell lung cancer. We find that miR-135b is dually regulated by DNA demethylation and nuclear factor-kappaB signalling, implying that abnormal expression of miR-135b in cancer may result from inflammatory and epigenetic modulations. We conclude that miR-135b is an oncogenic microRNA and a potential therapeutic target for non-small-cell lung cancer. Lung cancers have a high potential to become metastatic, which is a major cause of treatment failure. Here, the authors identify a microRNA that is upregulated in non-small-cell lung cancer and is associated with Hippo pathway modulation metastasis and poor clinical outcome.

Knowing how biomarker levels vary within biological fluids over time can produce valuable insight into tissue physiology and pathology, and could inform personalised clinical treatment. We describe here a wearable sensor for monitoring biomolecule levels that combines continuous fluid sampling with in situ analysis using wet-chemical assays (with the specific assay interchangeable depending on the target biomolecule). The microfluidic device employs a droplet flow regime to maximise the temporal response of the device, using a screw-driven push-pull peristaltic micropump to robustly produce nanolitre-sized droplets. The fully integrated sensor is contained within a small (palm-sized) footprint, is fully autonomous, and features high measurement frequency (a measurement every few seconds) meaning deviations from steady-state levels are quickly detected. We demonstrate how the sensor can track perturbed glucose and lactate levels in dermal tissue with results in close agreement with standard off-line analysis and consistent with changes in peripheral blood levels. Continuous real-time measurement of biomarker levels in body fluids offers many exciting possibilities. Here, the authors develop an integrated wearable droplet microfluidic sensor that combines continuous sampling of tissue fluid with in situ analysis using wet-chemical assays.