Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate.

Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.

Interleukin-22 receptor 1-mediated stimulation of T-type Ca2+ channels enhances sensory neuronal excitability through the tyrosine-protein kinase Lyn-dependent PKA pathway.

BACKGROUND: Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear. METHODS: Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca2+ channels (T-type channels). RESULTS: IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2. CONCLUSION: Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management.

Effects of MAL gene knockout on lung tissue morphology and on E-cad and α-SMA expression in asthma mouse models.

OBJECTIVES: To investigate the effects of myelin- and lymphocyte-associated protein (MAL) gene knockout on the morphological structure of lung tissue and the expression of E-cadherin (E-cad) and alpha-smooth muscle actin (α-SMA) in an asthmatic mouse model. METHODS: Twenty-four specific pathogen-free (SPF) C57BL/6J mice were divided into four groups: the wild-type normal (WT/SAL), wild-type asthmatic (WT/OVA), gene knockout normal (MAL-/-/SAL), and gene knockout asthmatic (MAL-/-/OVA) groups. The establishment of the asthma mouse models was confirmed by evaluating behavioral symptoms and histopathological H&E and Masson staining. Western blotting and RT-qPCR were used to measure E-cad and α-SMA expression levels in lung tissues. RESULTS: H&E staining of mouse lung tissues from WT/OVA, MAL-/-/SAL, and MAL-/-/OVA groups revealed a thickened bronchial wall, irregular lumen edge, locally fallen mucosal epithelium, and inflammatory cell infiltration compared with those of the WT/SAL group. In the WT and MAL-/- groups, the proportion of Masson-stained tissues in the OVA group was greater than that in the SAL group (p < 0.05). Compared with those in the WT/SAL group, the expression levels of α-SMA mRNA and protein were increased, while those of E-cad were decreased in the WT/OVA group (p < 0.01). Similarly, compared with those in the MAL-/-/SAL group, the expression levels of E-cad mRNA and protein were increased, while those of α-SMA were decreased in the MAL-/-/OVA group (p < 0.01). All these differences were statistically significant (p < 0.01). CONCLUSIONS: The MAL gene contributes to EMT inhibition and the stability of the airway barrier under normal physiological conditions by regulating E-cad and α-SMA expression.

Generating multi-focus beams with a spatial non-uniform coherence structure.

We introduce a class of structured light beams, named multi-focus beams, which exhibit self-focusing at multiple propagation distances. We show that the proposed beams not only have the ability to produce multiple longitudinal focal spots, but also that the number, intensity, and position of the foci can be controlled by adjusting the initial beam parameters. Furthermore, we demonstrate that these beams still exhibit self-focusing in the shadow of an obstacle. We have experimentally generated such beams and the results are consistent with the theoretical predictions. Our studies may find application where fine control of the longitudinal spectral density is needed, such as longitudinal optical trapping and manipulation of multiple particles, and transparent material cutting.

A Machine Learning-Based Unenhanced Radiomics Approach to Distinguishing Between Benign and Malignant Breast Lesions Using T2-Weighted and Diffusion-Weighted MRI.

BACKGROUND: Breast MRI has been recommended as supplemental screening tool to mammography and breast ultrasound of breast cancer by international guidelines, but its long examination time and use of contrast material remains concerning. PURPOSE: To develop an unenhanced radiomics model with using non-gadolinium based sequences for detecting breast cancer based on T2-weighted (T2W) and diffusion-weighted (DW) MRI. STUDY TYPE: Retrospective analysis followed by retrospective and prospective cohorts study. POPULATION: 1760 patients: Of these, 1293 for model construction (n = 775 for training and 518 for validation). The remaining patients for model testing in internal retrospective (n = 167), internal prospective (n = 188), and external retrospective (n = 112) cohorts. FIELD STRENGTH/SEQUENCE: 3.0T MR scanners from two institution. T2WI, DWI, and first contrast-enhanced T1-weighted sequence. ASSESSMENT: AUCs in distinguishing breast cancer were compared between combined model with gadolinium agent sequence and unenhanced model. Subsequently, the AUCs in testing cohorts of unenhanced model was compared with two radiologists' diagnosis for this research. Finally, patient subgroup analysis in testing cohorts was performed based on clinical subgroups and different types of malignancies. STATISTICAL TESTS: Mann-Whitney U test, Kruskal-Wallis H test, chi-square test, weighted kappa test, and DeLong's test. RESULTS: The unenhanced radiomics model performed best under Gaussian process (GP) classifiers (AUC: training, 0.893; validation, 0.848) compared to support vector machine (SVM) and logistic, showing favorable prediction in testing cohorts (AUCs, 0.818-0.840). The AUCs for the unenhanced radiomics model were not statistically different in five cohorts from those of the combined radiomics model (P, 0.317-0.816), as well as the two radiologists (P, 0.181-0.918). The unenhanced radiomics model was least successful in identifying ductal carcinoma in situ, whereas did not show statistical significance in other subgroups. DATA CONCLUSION: An unenhanced radiomics model based on T2WI and DWI has comparable diagnostic accuracy to the combined model using the gadolinium agent. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Risk stratification for 1- to 2-cm gastric gastrointestinal stromal tumors: visual assessment of CT and EUS high-risk features versus CT radiomics analysis.

OBJECTIVES: To investigate the ability of CT and endoscopic sonography (EUS) in predicting the malignant risk of 1-2-cm gastric gastrointestinal stromal tumors (gGISTs) and to clarify whether radiomics could be applied for risk stratification. METHODS: A total of 151 pathologically confirmed 1-2-cm gGISTs from seven institutions were identified by contrast-enhanced CT scans between January 2010 and March 2021. A detailed description of EUS morphological features was available for 73 gGISTs. The association between EUS or CT high-risk features and pathological malignant potential was evaluated. gGISTs were randomly divided into three groups to build the radiomics model, including 74 in the training cohort, 37 in validation cohort, and 40 in testing cohort. The ROIs covering the whole tumor volume were delineated on the CT images of the portal venous phase. The Pearson test and least absolute shrinkage and selection operator (LASSO) algorithm were used for feature selection, and the ROC curves were used to evaluate the model performance. RESULTS: The presence of EUS- and CT-based morphological high-risk features, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not differ between very-low and intermediate risk 1-2-cm gGISTs (p > 0.05). The radiomics model consisting of five radiomics features showed favorable performance in discrimination of malignant 1-2-cm gGISTs, with the AUC of the training, validation, and testing cohort as 0.866, 0.812, and 0.766, respectively. CONCLUSIONS: Instead of CT- and EUS-based morphological high-risk features, the CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs. KEY POINTS: • The presence of EUS- and CT-based morphological high-risk factors, including calcification, necrosis, intratumoral heterogeneity, irregular border, or surface ulceration, did not correlate with the pathological malignant potential of 1-2-cm gGISTs. • The CT radiomics model could potentially be applied for preoperative risk stratification of 1-2-cm gGISTs.

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model.

BACKGROUND: Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA). METHODS: Five familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aß deposition level was detected by immunohistochemistry after the intervention; The number of BrdU+/CaR+ cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention. RESULTS: Cognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aß plaques in the DG without any impact on Wnt5a. CONCLUSION: EA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.

Gate-Tunable Transport in Quasi-One-Dimensional α-Bi4I4 Field Effect Transistors.

Bi4I4 belongs to a novel family of quasi-one-dimensional (1D) topological insulators (TIs). While its ß phase was demonstrated to be a prototypical weak TI, the α phase, long thought to be a trivial insulator, was recently predicted to be a rare higher order TI. Here, we report the first gate tunable transport together with evidence for unconventional band topology in exfoliated α-Bi4I4 field effect transistors. We observe a Dirac-like longitudinal resistance peak and a sign change in the Hall resistance; their temperature dependences suggest competing transport mechanisms: a hole-doped insulating bulk and one or more gate-tunable ambipolar boundary channels. Our combined transport, photoemission, and theoretical results indicate that the gate-tunable channels likely arise from novel gapped side surface states, two-dimensional (2D) TI in the bottommost layer, and/or helical hinge states of the upper layers. Markedly, a gate-tunable supercurrent is observed in an α-Bi4I4 Josephson junction, underscoring the potential of these boundary channels to mediate topological superconductivity.

Function and regulation of GPX4 in the development and progression of fibrotic disease.

Fibrosis is a common feature of fibrotic diseases that poses a serious threat to global health due to high morbidity and mortality in developing countries. There exist some chemical compounds and biomolecules associated with the development of fibrosis, including cytokines, hormones, and enzymes. Among them, glutathione peroxidase 4 (GPX4), as a selenoprotein antioxidant enzyme, is widely found in the embryo, testis, brain, liver, heart, and photoreceptor cells. Moreover, it is shown that GPX4 elicits diverse biological functions by suppressing phospholipid hydroperoxide at the expense of decreased glutathione (GSH), including loss of neurons, autophagy, cell repair, inflammation, ferroptosis, apoptosis, and oxidative stress. Interestingly, these processes are intimately related to the occurrence of fibrotic disease. Recently, GPX4 has been reported to exhibit a decline in fibrotic disease and inhibit fibrosis, suggesting that alterations of GPX4 can change the course or dictate the outcome of fibrotic disease. In this review, we summarize the role and underlying mechanisms of GPX4 in fibrosis diseases such as lung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, and myelofibrosis.

Electroacupuncture Increases the Hippocampal Synaptic Transmission Efficiency and Long-Term Plasticity to Improve Vascular Cognitive Impairment.

Studies have shown that electroacupuncture (EA) can effectively improve vascular cognitive impairment (VCI), but its mechanisms have not been clearly elucidated. This study is aimed at investigating the mechanisms underlying the effects of EA treatment on hippocampal synaptic transmission efficiency and plasticity in rats with VCI. Methods. Sprague-Dawley rats were subjected to VCI with bilateral common carotid occlusion (2VO). EA stimulation was applied to Baihui (GV20) and Shenting (GV24) acupoints for 30 min once a day, five times a week, for four weeks. Our study also included nonacupoint groups to confirm the specificity of EA therapy. The Morris water maze (MWM) was used to assess cognitive function. Electrophysiological techniques were used to detect the field characteristics of the hippocampal CA3-CA1 circuit in each group of rats, including input-output (I/O), paired-pulse facilitation ratios (PPR), field excitatory postsynaptic potential (fEPSP), and excitatory postsynaptic current (EPSC). The expression of synapse- and calcium-mediated signal transduction associated proteins was detected through western blotting. Results. The MWM behavioural results showed that EA significantly improved cognitive function in VCI model rats. EA increased the I/O curve of VCI model rats from 20 to 90 µA. No significant differences were observed in hippocampal PPR. The fEPSP of the hippocampal CA3-CA1 circuit was significantly increased after EA treatment compared with that after nonacupuncture treatment. We found that EA led to an increase in the EPSC amplitude and frequency, especially in the decay and rise times. In addition, the protein expression and phosphorylation levels of N-methyl-D-aspartate receptor 2B, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor 1, and Ca2+-calmodulin-dependent protein kinase II increased to varying degrees in the hippocampus of VCI model rats. Conclusion. EA at GV20 and GV24 acupoints increased the basic synaptic transmission efficiency and synaptic plasticity of the hippocampal CA3-CA1 circuit, thereby improving learning and memory ability in rats with VCI.

Cross-cultural adaptation, reliability, and validity of the Chinese version of the Acceptance and Action Questionnaire-Adult Hearing Loss.

OBJECTIVE: Few mental health assessment tools are available for people with hearing loss (HL) in China. The Acceptance and Action Questionnaire-Adult Hearing Loss (AAQ-AHL) has been specifically designed to assess psychological inflexibility in adults with HL and may help assess mental health status promptly for targeted psychological interventions. The study aimed to investigate the cross-cultural validity and reliability of the Chinese version of the AAQ-AHL to assess its applicability to teenagers and adults with HL in China. DESIGN: A descriptive and correlational study of a convenience sample of students aged above 12 years. All participants were invited to complete an online questionnaire. STUDY SAMPLES: Participants included 402 students with HL. RESULTS: The Chinese version of the AAQ-AHL was shown to be an excellent, reliable, and valid instrument that can be used to assess psychological inflexibility in teenagers and adults with HL by clinicians working with Mandarin-speaking populations. CONCLUSION: Although the AAQ-AHL showed very good psychometric properties in hearing-impaired students aged above 12 years, further testing is needed to validate the measure across other age groups and validate its feasibility and utility in clinical applications.

Cross-cultural adaptation, reliability, and validity of the Chinese version of the Acceptance and Action Questionnaire-Management of Child Hearing Loss.

OBJECTIVE: The current study aims to translate and cross-culturally adapt the Acceptance and Action Questionnaire-Management of Child Hearing Loss (AAQ-MCHL) scale to Chinese caregivers of children with hearing loss (CHL) and verify its psychometric characteristics. DESIGN: This is a cross-sectional design of psychometric validation study. STUDY SAMPLE: In total, 135 caregivers of CHL were invited to participate in the study, and complete data from 125 participants were used to analyse internal consistency, test-retest reliability, content validity, structural validity, criterion validity, and the optimal cut-off score of AAQ-MCHL. RESULTS: Through careful and complete translation and adaptation, the Chinese version of AAQ-MCHL was successfully created. The Chinse version of the AAQ-MCHL had good internal consistency, test-retest reliability, content validity, structural validity, and criterion validity. Our results also showed that poorer speech performance in CHL was a strong predictor of parental psychological inflexibility. CONCLUSIONS: The Chinese version of the AAQ-MCHL could be used as an outcome indicator to evaluate the psychological inflexibility of caregivers of CHL in mainland China, and we suggest that early interventionists should be aware of signs of elevated psychological inflexibility in caregivers of CHL.

Controllable high-performance memristors based on 2D Fe2GeTe3oxide for biological synapse imitation.

Memristors are an important component of the next-generation artificial neural network, high computing systems, etc. In the past, two-dimensional materials based memristors have achieved a high performance and low power consumption, though one at the cost of the other. Furthermore, their performance can not be modulated frequently once their structures are fixed, which remains the bottleneck in the development. Herein, a series of forming free memristors are fabricated with the same Cu/Fe3GeTe2oxide/Fe3GeTe2/Al structure, yet the On/Off ratio and set voltage is modulated continuously by varying the oxidation time during fabrication. With an optimal oxidation time, a large On/Off ratio (1.58 × 103) and low set voltage (0.74 V) is achieved in a single device. The formation and rapture of Al conductive filaments are found to be responsible for the memristors, and the filaments density and the cross-section area increase with the increase of current compliance, which achieves a higher On/Off ratio. The memristor can imitate basic biological synaptic functions using voltage pulses, demonstrating the potential for low-power consuming neuromorphic computing applications.

Demand Analysis of Telenursing for Community-Dwelling Empty-Nest Elderly Based on the Kano Model.

Background: In recent years, the increasing number of empty-nest elderly has become a significant global social problem, and the rapid development of medical technology and information technology has improved the feasibility of telenursing. However, few studies have been conducted on needs of telenursing among the empty-nest elderly. The aim of this study is to explore the needs of telenursing for community-dwelling empty-nest elderly who are completely independent in activities of daily living (ADL), or who are mildly disabled, and to provide a reference for improving the remote care quality. Methods: A questionnaire survey aiming to explore telenursing needs of the elderly was conducted among 268 community-dwelling empty-nest elderly who were selected using random sampling and then data were analyzed based on the Kano Model. Results: Chi-square goodness-of-fit test showed that there were significant differences between actual and expected counts for each item of telenursing needs (p < 0.01 for all), indicating that the sample had specific individual preference for the Kano category. The desired degree of telenursing service ranged from 48.37% to 80.86%, the better values (satisfaction) were between 57.09% and 67.56%, and the worse values (dissatisfaction) were between 11.92% and 37.93%. The items, remote one-button emergency caller and remote emergency assistance arrangement, were considered to be one-dimensional qualities by empty nesters and the rest were attractive qualities. In the quadrant analysis diagram, all the remote care services were categorized as attractive qualities. Discussion: The community-dwelling empty-nest elderly with ADL independence or mild impairment have positive attitudes toward telenursing services, especially the needs of remote first aid nursing. Medical policy makers and nursing managers can provide targeted telenursing services according to empty nesters' requirements, thus improving nursing care quality and satisfaction of the elderly.

Computational design of CO-tolerant Pt3M anode electrocatalysts for proton-exchange membrane fuel cells.

CO is a common contaminant in hydrogen fuel produced via steam reforming. Development of a CO-tolerant Pt-based anode for the proton-exchange membrane fuel cells (PEMFC) is of great interest to avoid catalyst deactivation caused by strong CO adsorption on Pt. Pt-Ru, Pt-Mo, and Pt3Sn are three known Pt-based bimetallic CO-tolerant anode materials. The enhanced CO-tolerance of these alloys has been generally attributed to a bifunctional effect enabling oxidative CO removal at low applied potential and a ligand effect between the two metals which weakens CO bonding and reduces CO surface coverage. In this study, we use density functional theory to calculate surface adsorption states under reaction conditions for Pt-based alloys. Our calculations provide a molecular-level understanding of the enhanced CO-tolerance of Pt alloys induced by the second metal. We find that Mo and Sn dopants promote CO-tolerance by reducing CO surface coverage and enabling CO oxidative removal at low applied potential. On the other hand, Ru is not able to promote CO electro-oxidation at the low applied potential of the operating conditions of a PEMFC anode. The CO-tolerance induced by Ru is attributed to the reduction of CO coverage on Pt sites. Based on these mechanisms, we carried out a computational screening of Pt3M electrocatalysts for CO-tolerant PEMFC anodes. A number of promising candidates have been identified for experimental examination.

Characterization of a novel multi-domain xylanase from Clostridium clariflavum with application in hydrolysis of corn cobs.

OBJECTIVES: To develop a novel multi-catalytic domain (CD) xylanase Xyn2083 from Clostridium clariflavum by expression of its truncated forms in Escherichia coli and cooperation of xylanase with cellulase in the hydrolysis of waste lignocellulosic resources. RESULTS: Xyn2083 has two glycoside hydrolase family (GH) domains GH11 and GH10. These two catalytic domains functioned synergistically in xylan hydrolysis. The recombinant protein with GH11 domain, Xyn2083GH11, had the highest xylanase activity among three constructed truncated forms. The deletion of N-terminal extra amino acid residues of Xyn2083GH11 decreased catalytic activity as well as the stability of the enzyme. The hydrolysis rates of cellulose and xylan in the pretreated corn cobs were 90.56% and 72.80% with the addition of Xyn2083GH11 and cellulase, whereas those were 67.95% and 34.45% using sole cellulase respectively. The structural analysis of substrates indicated that the addition of Xyn2083GH11 led to a looser structure and more exposure of crystal cellulose for cellulase to approach. CONCLUSIONS: Since the native multi-CDs' xylanases are rare, the thermostable Xyn2083 provides a good source for functional studies of two CDs coexisted in one xylanase and for potential applications after modification.

A computational study of supported Cu-based bimetallic nanoclusters for CO oxidation.

In this study, we used DFT calculations to investigate the bi-functional nature of Cu-based alloy nanoclusters (NCs) supported on CeO2(111) for CO oxidation. More specifically, we studied the reaction pathways on Cu3Pt7 and Cu3Rh7via the O2 associative (OCOO) and dissociative mechanisms. We find that CO oxidation on Cu3Pt7 proceeds via the O2 dissociation pathway, while Cu3Rh7 prefers the OCOO mechanism. Combined with our previous results on Cu3Au7, we find that bi-functional CO oxidation on Cu-based alloys follows a Brønsted-Evans-Polanyi relationship, which provides a useful metric for the design of bi-functional alloyed catalysts.

Ptch2 shares overlapping functions with Ptch1 in Smo regulation and limb development.

Ptch1 and Ptch2 are highly conserved vertebrate homologs of Drosophila ptc, the receptor of the Hedgehog (Hh) signaling pathway. The vertebrate Ptch1 gene encodes a potent tumor suppressor and is well established for its role in embryonic development. In contrast, Ptch2 is poorly characterized and dispensable for embryogenesis. In flies and mice, ptc/Ptch1 controls Hh signaling through the regulation of Smoothened (Smo). In addition, Hh pathway activation also up-regulates ptc/Ptch1 expression to restrict the diffusion of the ligand. Recent studies have implicated Ptch2 in this ligand dependent antagonism, however whether Ptch2 encodes a functional Shh receptor remains unclear. In this report, we demonstrate that Ptch2 is a functional Shh receptor, which regulates Smo localization and activity in vitro. We also show that Ptch1 and Ptch2 are co-expressed in the developing mouse limb bud and loss of Ptch2 exacerbates the outgrowth defect in the limb-specific Ptch1 knockout mutants, demonstrating that Ptch1 and Ptch2 co-operate in regulating cellular responses to Shh in vivo.

A bacterial acetyltransferase destroys plant microtubule networks and blocks secretion.

The eukaryotic cytoskeleton is essential for structural support and intracellular transport, and is therefore a common target of animal pathogens. However, no phytopathogenic effector has yet been demonstrated to specifically target the plant cytoskeleton. Here we show that the Pseudomonas syringae type III secreted effector HopZ1a interacts with tubulin and polymerized microtubules. We demonstrate that HopZ1a is an acetyltransferase activated by the eukaryotic co-factor phytic acid. Activated HopZ1a acetylates itself and tubulin. The conserved autoacetylation site of the YopJ / HopZ superfamily, K289, plays a critical role in both the avirulence and virulence function of HopZ1a. Furthermore, HopZ1a requires its acetyltransferase activity to cause a dramatic decrease in Arabidopsis thaliana microtubule networks, disrupt the plant secretory pathway and suppress cell wall-mediated defense. Together, this study supports the hypothesis that HopZ1a promotes virulence through cytoskeletal and secretory disruption.

Cognitive reserve over the life course and risk of dementia: a systematic review and meta-analysis.

Background: The number of people with dementia is soaring. Cognitive reserve has been thought to be associated with dementia risk. It is not clear at which period in the life course and which cognitive reserve proxies contribute to the reduced risk of dementia. Methods: By scanning four databases (PubMed, Embase, Web of Science, and MEDLINE) up to Jun 3, 2023, longitudinal studies of life-course cognitive reserve and risk of dementia were found. The HRs and 95% CIs for each study were summarized using random effects models. Subgroup analyses and sensitivity analyses were conducted. Utilizing funnel plots, Begg and Egger tests, publication bias was investigated. Results: A total of 27 studies were included, containing 10 in early-life, 10 in middle-life, and 13 in late-life. All studies used validated questionnaires to measure cognitive reserve, and dementia diagnosis followed recognized worldwide guidelines. All included studies were of medium or low risk. Cognitive reserve in early-life (Hazard ratio (HR): 0.82; 95% confidence interval (CI): 0.79-0.86), middle-life (HR: 0.91; 95% CI: 0.84-0.98) and late-life (HR: 0.81; 95% CI: 0.75-0.88) all have protective effects on dementia risk. Multiple sensitivity analyses showed consistent results. Conclusion: Dementia risk is reduced by the buildup of cognitive reserves during life-course. Accumulation of proxies for cognitive reserve in early and late life had the greatest effect on dementia risk reduction. Social connection may be an effective approach to lower dementia risk.