A molecular switch for neuroprotective astrocyte reactivity.

The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system degeneration and repair remain poorly understood. Here we show that injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2)1,2, which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cyclic adenosine monophosphate derived from soluble adenylyl cyclase and show that proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show that raising nuclear or depleting cytoplasmic cyclic AMP in reactive astrocytes inhibits deleterious microglial or macrophage cell activation and promotes retinal ganglion cell survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cyclic adenosine monophosphate in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand on and define new reactive astrocyte subtypes and represent a step towards the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.

NF1 mutation drives neuronal activity-dependent initiation of optic glioma.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase.

Copper is an essential trace element for the human body, and its requirement for optimistic immune functions has been recognized for decades. How copper is involved in the innate immune pathway, however, remains to be clarified. Here, we report that copper serves as a signal molecule to regulate the kinase activity of alpha-kinase 1 (ALPK1), a cytosolic pattern-recognition receptor (PRR), and therefore promotes host cell defense against bacterial infection. We show that in response to infection, host cells actively accumulate copper in the cytosol, and the accumulated cytosolic copper enhances host cell defense against evading pathogens, including intracellular and, unexpectedly, extracellular bacteria. Subsequently, we demonstrate that copper activates the innate immune pathway of host cells in an ALPK1-dependent manner. Further mechanistic studies reveal that copper binds to ALPK1 directly and is essential for the kinase activity of this cytosolic PRR. Moreover, the binding of copper to ALPK1 enhances the sensitivity of ALPK1 to the bacterial metabolite ADP-heptose and eventually prompts host cells to elicit an enhanced immune response during bacterial infection. Finally, using a zebrafish in vivo model, we show that a copper-treated host shows an increased production of proinflammatory cytokines, enhanced recruitment of phagosome cells, and promoted bacterial clearance. Our findings uncover a previously unrecognized role of copper in the modulation of host innate immune response against bacterial pathogens and advance our knowledge on the cross talk between cytosolic copper homeostasis and immune system.

Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4.

Clinical exome sequencing has yielded extensive disease-related missense single-nucleotide variants (SNVs) of uncertain significance, leading to diagnostic uncertainty. KCNQ4 is one of the most commonly responsible genes for autosomal dominant nonsyndromic hearing loss. According to the gnomAD cohort, approximately one in 100 people harbors missense variants in KCNQ4 (missense variants with minor allele frequency > 0.1% were excluded), but most are of unknown consequence. To prospectively characterize the function of all 4085 possible missense SNVs of human KCNQ4, we recorded the whole-cell currents using the patch-clamp technique and categorized 1068 missense SNVs as loss of function, as well as 728 loss-of-function SNVs located in the transmembrane domains. Further, to mimic the heterozygous condition in Deafness nonsyndromic autosomal dominant 2 (DFNA2) patients caused by KCNQ4 variants, we coexpressed loss-of-function variants with wild-type KCNQ4 and found 516 variants showed impaired or only partially rescued heterogeneous channel function. Overall, our functional classification is highly concordant with the auditory phenotypes in Kcnq4 mutant mice and the assessments of pathogenicity in clinical variant interpretations. Taken together, our results provide strong functional evidence to support the pathogenicity classification of newly discovered KCNQ4 missense variants in clinical genetic testing.

Adaptive Space Search-based Molecular Evolution Optimization Algorithm.

MOTIVATION: In drug development process, a significant portion of budget and research time are dedicated to the lead compound optimization procedure in order to identify potential drugs. This procedure focuses on enhancing the pharmacological and bioactive properties of compounds by optimizing their local substructures. However, due to the vast and discrete chemical structure space and the unpredictable element combinations within this space, the optimization process is inherently complex. Various structure enumeration-based combinatorial optimization methods have shown certain advantages. However, they still have limitations. Those methods fail to consider the differences between molecules and struggle to explore the unknown outer search space. RESULTS: In this study, we propose an adaptive space search-based molecular evolution optimization algorithm (ASSMOEA). It consists of three key modules: construction of molecule-specific search space, molecular evolutionary optimization, and adaptive expansion of molecule-specific search space. Specifically, we design a fragment similarity tree in molecule-specific search space, and apply a dynamic mutation strategy in this space to guide molecular optimization. Then we utilize an encoder-encoder structure to adaptively expand the space. Those three modules are circled iteratively to optimize molecules. Our experiments demonstrate that ASSMOEA outperforms existing methods in terms of molecular optimization. It not only enhances the efficiency of the molecular optimization process, but also exhibits a robust ability to search for correct solutions. AVAILABILITY AND IMPLEMENTATION: The code is freely available on the web at https://github.com/bbbbb-b/MEOAFST. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A domain-label-guided translation model for molecular optimization.

Molecular optimization, which aims to improve molecular properties by modifying complex molecular structures, is a crucial and challenging task in drug discovery. In recent years, translation models provide a promising way to transform low-property molecules to high-property molecules, which enables molecular optimization to achieve remarkable progress. However, most existing models require matched molecular pairs, which are prone to be limited by the datasets. Although some models do not require matched molecular pairs, their performance is usually sacrificed due to the lack of useful supervising information. To address this issue, a domain-label-guided translation model is proposed in this paper, namely DLTM. In the model, the domain label information of molecules is exploited as a control condition to obtain different embedding representations, enabling the model to generate diverse molecules. Besides, the model adopts a classifier network to identify the property categories of transformed molecules, guiding the model to generate molecules with desired properties. The performance of DLTM is verified on two optimization tasks, namely the quantitative estimation of drug-likeness and penalized logP. Experimental results show that the proposed DLTM is superior to the compared baseline models.

Solanum aculeatissimum and Solanum torvum chloroplast genome sequences: a comparative analysis with other Solanum chloroplast genomes.

BACKGROUND: Solanum aculeatissimum and Solanum torvum belong to the Solanum species, and they are essential plants known for their high resistance to diseases and adverse conditions. They are frequently used as rootstocks for grafting and are often crossbred with other Solanum species to leverage their resistance traits. However, the phylogenetic relationship between S. aculeatissimum and S. torvum within the Solanum genus remains unclear. Therefore, this paper aims to sequence the complete chloroplast genomes of S. aculeatissimum and S. torvum and analyze them in comparison with 29 other previously published chloroplast genomes of Solanum species. RESULTS: We observed that the chloroplast genomes of S. aculeatissimum and S. torvum possess typical tetrameric structures, consisting of one Large Single Copy (LSC) region, two reverse-symmetric Inverted Repeats (IRs), and one Small Single Copy (SSC) region. The total length of these chloroplast genomes ranged from 154,942 to 156,004 bp, with minimal variation. The highest GC content was found in the IR region, while the lowest was in the SSC region. Regarding gene content, the total number of chloroplast genes and CDS genes remained relatively consistent, ranging from 128 to 134 and 83 to 91, respectively. Nevertheless, there was notable variability in the number of tRNA genes and rRNAs. Relative synonymous codon usage (RSCU) analysis revealed that both S. aculeatissimum and S. torvum preferred codons that utilized A and U bases. Analysis of the IR boundary regions indicated that contraction and expansion primarily occurred at the junction between SSC and IR regions. Nucleotide polymorphism analysis and structural variation analysis demonstrated that chloroplast variation in Solanum species mainly occurred in the LSC and SSC regions. Repeat sequence analysis revealed that A/T was the most frequent base pair in simple repeat sequences (SSR), while Palindromic and Forward repeats were more common in long sequence repeats (LSR), with Reverse and Complement repeats being less frequent. Phylogenetic analysis indicated that S. aculeatissimum and S. torvum belonged to the same meristem and were more closely related to Cultivated Eggplant. CONCLUSION: These findings enhance our comprehension of chloroplast genomes within the Solanum genus, offering valuable insights for plant classification, evolutionary studies, and potential molecular markers for species identification.

Vacancies-Induced Delocalized States Cobalt Phosphide for Binder-Free Anode Toward Stable and High-Rate Sodium-Ion Batteries.

Metal phosphides with easy synthesis, controllable morphology, and high capacity are considered as potential anodes for sodium-ion batteries (SIBs). However, the inherent shortcomings of metal phosphating materials, such as conductivity, kinetics, volume strain, etc are not satisfactory, which hinders their large-scale application. Here, a CoP@carbon nanofibers-composite containing rich Co─N─C heterointerface and phosphorus vacancies grown on carbon cloth (CoP1-x@MEC) is synthesized as SIB anode to accomplish extraordinary capacity and ultra-long cycle life. The hybrid composite nanoreactor effectively impregnates defective CoP as active reaction center while offering Co─N─C layer to buffer the volume expansion during charge-discharge process. These vast active interfaces, favored electrolyte infiltration, and a well-structured ion-electron transport network synergistically improve Na+ storage and electrode kinetics. By virtue of these superiorities, CoP1-x@MEC binder-free anode delivers superb SIBs performance including a high areal capacity (2.47 mAh cm-2@0.2 mA cm-2), high rate capability (0.443 mAh cm-2@6 mA cm-2), and long cycling stability (300 cycles without decay), thus holding great promise for inexpensive binder-free anode-based SIBs for practical applications.

Characterization of a patient-derived variant of GPX4 for precision therapy.

Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.

Evolutionary Multiobjective Molecule Optimization in an Implicit Chemical Space.

Optimization techniques play a pivotal role in advancing drug development, serving as the foundation of numerous generative methods tailored to efficiently design optimized molecules derived from existing lead compounds. However, existing methods often encounter difficulties in generating diverse, novel, and high-property molecules that simultaneously optimize multiple drug properties. To overcome this bottleneck, we propose a multiobjective molecule optimization framework (MOMO). MOMO employs a specially designed Pareto-based multiproperty evaluation strategy at the molecular sequence level to guide the evolutionary search in an implicit chemical space. A comparative analysis of MOMO with five state-of-the-art methods across two benchmark multiproperty molecule optimization tasks reveals that MOMO markedly outperforms them in terms of diversity, novelty, and optimized properties. The practical applicability of MOMO in drug discovery has also been validated on four challenging tasks in the real-world discovery problem. These results suggest that MOMO can provide a useful tool to facilitate molecule optimization problems with multiple properties.

Preparation of cellulose acetate based flexible separator and its application in zinc-air batteries.

Flexible solid-state zinc-air batteries as a wearable energy storage device with great potential, and their separators, which control ion permeability, inhibit zinc dendrite generation, and regulate catalytic active sites, have been developed as gel electrolyte separators with high retention of electrolyte uptake. However, the gel electrolyte separator still has problems such as poor affinity with the electrolyte and poor ionic conductivity, which limits its further application. In order to further improve the electrolyte absorption, ionic conductivity and mechanical strength of cellulose acetate(CA)/polyvinyl alcohol (PVA) nanofibers, TiO2was added to CA/PVA to increase the porosity, and glutaraldehyde (GA) was used to modify the CA/PVA/TiO2separator by acetal reaction with CA and PVA to make the molecules closely linked. The results shows that the optimal mass fractions of TiO2and GA were 2% and 5%, respectively. At this time, the porosity and absorption rate of the separator increased from 48% to 68.2% and 142.4% to 285.3%, respectively. The discharge capacity reached 179 mA cm-3, and the cycle stability rate was 89% after 7 stable constant current charge/discharge cycles.

Atrial fibrillation accelerates functional decline in older adults: a 15-year follow-up population-based study.

AIMS: Atrial fibrillation (AF) has been associated with functional impairment. However, the role exerted by AF on the long-term trajectories of functional mobility remains to be elucidated. This study aimed to evaluate the impact of AF on functional mobility by tracing walking speed (WS) trajectories over 15 years of follow-up in a population-based cohort of individuals aged 60+ years. METHODS AND RESULTS: This population-based cohort study included 3141 community-dwelling participants (mean age 73.7 years; 63.6% women) from the Swedish National Study on Aging and Care in Kungsholmen, who were regularly examined from 2001-2004 to 2016-2019. Functional mobility was assessed by measuring WS in a standardized way. The association between AF and WS trajectories was assessed by multivariable joint models accounting for the longitudinal dropouts due to death. Stratified analyses by demographic and clinical factors were performed. The effect-modifying role of oral anticoagulant therapy (OAC), incident heart failure (HF), and incident stroke was finally investigated. At baseline, 285 (9.1%) participants were ascertained to have AF. A faster annual WS decline was observed in persons with AF than in non-AF peers (adjusted ß coefficient per year = -0.011, 95% confidence interval: -0.016 to -0.005). Incident HF and stroke were associated with greater WS decline in participants with AF. OAC use was not associated with a slower functional decline. CONCLUSION: Atrial fibrillation is associated with a faster physical function decline in older individuals. Incident HF and stroke possibly accelerate WS decline over time in AF participants.

Nutrition Status Plays a Partial Mediation Role in the Relationship between Number of Teeth and Frailty: A Cross-Sectional Multicenter Study.

INTRODUCTION: Although the relationship between the number of teeth and frailty has been extensively studied, the mediating role of nutrition status in the association between the number of teeth and frailty remains to be clarified. METHODS: A number of 6,664 participants lived in the communities of West China were analyzed in our study. Physical frailty was determined based on the phenotype established by Fried. Nutrition status was evaluated using the Mini Nutrition Assessment-Short Form (MNA-SF) scale. Multiple linear regression was employed to evaluate the direct relationships between the number of teeth, nutrition, and frailty. Mediation models and structural equation model (SEM) pathway analysis were used to test the mediating role of nutrition status in the relationship between the number of teeth and frailty. RESULTS: Among the 6,664 participants aged over 50 years old, the prevalence of frailty was 6.2%. Multiple linear regression analysis showed a significant total relationship between the number of teeth (ß = -0.359, 95% CI: -0.473 to -0.244, p < 0.001) and frailty. After adjusting for MNA-SF scores, the relationship between the number of teeth and frailty remained significant (ß = -0.327, 95% CI: -0.443 to -0.211, p < 0.001), indicating a partial mediating effect of nutrition. Mediation analysis verified that nutrition partially mediated the relationship between the number of teeth and frailty (indirect effect estimate = -0.0121, bootstrap 95% CI: -0.0151 to -0.0092; direct effect estimate = -0.0874, bootstrap 95% CI: -0.1086 to -0.0678) in the fully adjusted model. This mediating effect occurred through influencing weight loss, low level of physical activity, and debility. SEM framework pathway analysis confirmed the association between the number of teeth, nutrition, and frailty. CONCLUSIONS: Our findings demonstrated that frailty was correlated with the number of teeth and poorer nutritional status, with nutrition partially mediating the correlation between the number of teeth and frailty. Our results supported early nutritional evaluation and intervention in oral health to decrease the risk of frailty.

Functional and Genetic Analyses Unveil the Implication of CDC27 in Hemifacial Microsomia.

Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. CDC27 was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of CDC27. cdc27 knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in cdc27-/- mutants. cdc27 mRNA injections and cdkn1a or tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia, while sox9a mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between CDC27 and HFM, primarily through the inhibition of CNCC proliferation and disruption of pharyngeal chondrocyte differentiation.

Environmental Impact Assessment for the Use of an Orally Aerosolized Adenovirus Type-5 Vector-Based COVID-19 Vaccine in Randomized Clinical Trials.

BACKGROUND: An orally aerosolized adenovirus type-5 vector-based coronavirus disease 2019 (COVID-19) vaccine (Ad5-nCoV) has recently been authorized for boosting immunization in China. Our study aims to assess the environmental impact of the use of aerosolized Ad5-nCoV. METHODS: We collected air samples from rooms, swabs from the desks on which the vaccine nebulizer was set, mask samples from participants, and blood samples of nurses who administered the inoculation in the clinical trials. The viral load of adenovirus type-5 vector in the samples and the antibody levels against the wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain in serum were detected. RESULTS: Only one (4.00%) air sample collected before initiation of vaccination was positive and most air samples collected during and after vaccination were positive (97.96%, 100%, respectively). All nurses in trial A showed at least 4-fold increase of the neutralizing antibody against SARS-CoV-2 after initiation of the study. In trial B, the proportion of positive mask samples was 72.97% at 30 minutes after vaccination, 8.11% at day 1, and 0% at days 3, 5, and 7. CONCLUSIONS: Vaccination with the orally aerosolized Ad5-nCoV could result in some spillage of the vaccine vector viral particles in the environment and cause human exposure. Clinical Trials Registration. NCT04840992 and NCT05303584.

[Study on mechanism of icariin-induced ferroptosis in HepG2 hepatoma carcinoma cells through PPARG/FABP4/GPX4 pathway].

The aim of this study was to explore the mechanism of icaritin-induced ferroptosis in hepatoma HepG2 cells. By bioinformatics screening, the target of icariin's intervention in liver cancer ferroptosis was selected, the protein-protein interaction(PPI) network was constructed, the related pathways were focused, the binding ability of icariin and target protein was evaluated by molecular docking, and the impact on patients' survival prognosis was predicted and the clinical prediction model was built. CCK-8, EdU, and clonal formation assays were used to detect cell viability and cell proliferation; colorimetric method and BODIPY 581/591 C1 fluorescent probe were used to detect the levels of Fe~(2+), MDA and GSH in cells, and the ability of icariin to induce HCC cell ferroptosis was evaluated; RT-qPCR and Western blot detection were used to verify the mRNA and protein levels of GPX4, xCT, PPARG, and FABP4 to determine the expression changes of these ferroptosis-related genes in response to icariin. Six intervention targets(AR, AURKA, PPARG, AKR1C3, ALB, NQO1) identified through bioinformatic analysis were used to establish a risk scoring system that aids in estimating the survival prognosis of HCC patients. In conjunction with patient age and TNM staging, a comprehensive Nomogram clinical prediction model was developed to forecast the 1-, 3-, and 5-year survival of HCC patients. Experimental results revealed that icariin effectively inhibited the activity and proliferation of HCC cells HepG2, significantly modulating levels of Fe~(2+), MDA, and lipid peroxidation ROS while reducing GSH levels, hence revealing its potential to induce ferroptosis in HCC cells. Icariin was found to diminish the expression of GPX4 and xCT(P<0.01), inducing ferroptosis in HCC cells, potentially in relation to inhibition of PPARG and FABP4(P<0.01). In summary, icariin induces ferroptosis in HCC cells via the PPARG/FABP4/GPX4 pathway, providing an experimental foundation for utilizing the traditional Chinese medicine icariin in the prevention or treatment of HCC.

Quantitative BONCAT Allows Identification of Newly Synthesized Proteins after Optic Nerve Injury.

Retinal ganglion cells (RGCs) die after optic nerve trauma or in degenerative disease. However, acute changes in protein expression that may regulate RGC response to injury are not fully understood, and detailed methods to quantify new protein synthesis have not been tested. Here, we develop and apply a new in vivo quantitative measure of newly synthesized proteins to examine changes occurring in the retina after optic nerve injury. Azidohomoalanine, a noncanonical amino acid, was injected intravitreally into the eyes of rodents of either sex with or without optic nerve injury. Isotope variants of biotin-alkyne were used for quantitative BONCAT (QBONCAT) mass spectrometry, allowing identification of protein synthesis and transport rate changes in more than 1000 proteins at 1 or 5 d after optic nerve injury. In vitro screening showed several newly synthesized proteins regulate axon outgrowth in primary neurons in vitro This novel approach to targeted quantification of newly synthesized proteins after injury uncovers a dynamic translational response within broader proteostasis regulation and enhances our understanding of the cellular response to injury.SIGNIFICANCE STATEMENT Optic nerve injury results in death and degeneration of retinal ganglion cells and their axons. The specific cellular response to injury, including changes in new protein synthesis, is obscured by existing proteins and protein degradation. In this study, we introduce QBONCAT to isolate and quantify acute protein synthesis and subsequent transport between cellular compartments. We identify novel candidate protein effectors of the regenerative response and uncover their regulation of axon growth in vitro, validating the utility of QBONCAT for the discovery of novel regulatory and therapeutic candidates after optic nerve injury.

The Protective Role of Non-Photochemical Quenching in PSII Photo-Susceptibility: A Case Study in the Field.

Non-photochemical quenching (NPQ) has been regarded as a safety valve to dissipate excess absorbed light energy not used for photochemistry. However, there exists no general consensus on the photoprotective role of NPQ. In the present study, we quantified the Photosystem II (PSII) photo-susceptibilities (mpi) in the presence of lincomycin, under red light given to five shade-acclimated tree species grown in the field. Photosynthetic energy partitioning theory was applied to investigate the relationships between mpi and each of the regulatory light-induced NPQ [Y(NPQ)], the quantum yield of the constitutive nonregulatory NPQ [Y(NO)] and the PSII photochemical yield in the light-adapted state [Y(PSII)] under different red irradiances. It was found that in the low to moderate irradiance range (50-800 µmol m-2 s-1) when the fraction of open reaction centers (qP) exceeded 0.4, mpi exhibited no association with Y(NPQ), Y(NO) and Y(PSII) across species. However, when qP < 0.4 (1,500 µmol m-2 s-1), there existed positive relationships between mpi and Y(NPQ) or Y(NO) but a negative relationship between mpi and Y(PSII). It is postulated that both Y(NPQ) and Y(NO) contain protective and damage components and that using only Y(NPQ) or Y(NO) metrics to identify the photo-susceptibility of a species is a risk. It seems that qP regulates the balance of the two components for each of Y(NPQ) and Y(NO). Under strong irradiance, when both protective Y(NPQ) and Y(NO) are saturated/depressed, the forward electron flow [i.e. Y(PSII)] acts as the last defense to resist photoinhibition.

The age-dependent association of Life's Simple 7 with transitions across cognitive states after age 60.

BACKGROUND: Life's Simple 7 (LS7) aims to promote ideal cardiovascular health (CVH). Its association with different cognitive states in the older old is unclear. OBJECTIVES: To assess the associations of LS7 with transitions across normal cognition, cognitive impairment, no dementia (CIND), and dementia and evaluate cognitive impairment-free years of life by LS7-defined CVH levels in older adults. METHODS: This cohort study included 2746 participants from the Swedish National Study on Aging and Care in Kungsholmen, regularly examined over 15 years. Total LS7 scores were created and dichotomized into worse and better CVH categories. The associations of LS7 total scores and CVH categories with cognitive states were assessed with multistate models in the whole sample and in younger old (<78 years) and older old adults (≥78 years) separately. Cognitive impairment-free life years by CVH categories were then predicted. RESULTS: A 1-point increment in the LS7 total score was associated with lower dementia risk in younger old adults (hazard ratio: 0.87 [0.78-0.97]) but not in older old adults (1.04 [0.97-1.13]). Better CVH was also associated with a lower risk of transition from normal cognition to CIND (0.76 [0.61-0.95]) and from normal cognition to dementia (0.42 [0.21-0.82]) in younger old adults. In younger old adults, those with better CVH were predicted to have two-to-three more cognitive impairment-free life years than those with worse CVH. CONCLUSION: Maintaining LS7-defined ideal CVH seems relevant in younger old adults but not in older old adults when considering the potential protective effects against cognitive impairment.

Multimorbidity patterns and 18-year transitions from normal cognition to dementia and death: A population-based study.

BACKGROUND: Several chronic diseases accelerate cognitive decline; however, it is still unknown how different patterns of multimorbidity influence individuals' trajectories across the cognitive continuum. OBJECTIVES: We aimed to investigate the impact of multimorbidity and of specific multimorbidity patterns on the transitions across cognitive stages (normal cognition, cognitive impairment, no dementia [CIND], dementia) and death. METHODS: We included 3122 dementia-free individuals from the Swedish National study on Aging and Care in Kungsholmen. Using fuzzy c-means cluster analysis, multimorbid participants were classified into mutually exclusive groups characterized by commonly coexisting chronic diseases. Participants were followed up to 18 years to detect incident CIND, dementia, or death. Transition hazard ratios (HRs), life expectancies, and time spent in different cognitive stages were estimated using multistate Markov models. RESULTS: At baseline, five multimorbidity patterns were identified: neuropsychiatric, cardiovascular, sensory impairment/cancer, respiratory/metabolic/musculoskeletal, and unspecific. Compared to the unspecific pattern, the neuropsychiatric and sensory impairment/cancer ones showed reduced hazards of reverting from CIND to normal cognition (HR 0.53, 95% CI 0.33-0.85 and HR 0.60, 95% CI 0.39-0.91). Participants in the cardiovascular pattern exhibited an increased hazard of progression from CIND to dementia (HR 1.70, 95% CI 1.15-2.52) and for all transitions to death. Subjects with the neuropsychiatric and cardiovascular patterns showed reduced life expectancy at age 75, with an anticipation of CIND (up to 1.6 and 2.2 years, respectively) and dementia onset (up to 1.8 and 3.3 years, respectively). CONCLUSIONS: Multimorbidity patterns differentially steer individual trajectories across the cognitive continuum of older adults and may be used as a risk stratification tool.