FSH blockade improves cognition in mice with Alzheimer's disease.

Alzheimer's disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3-7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-ß and Tau deposition and impair cognition in mice displaying features of Alzheimer's disease. Blocking FSH action in these mice abrogates the Alzheimer's disease-like phenotype by inhibiting the neuronal C/EBPß-δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer's disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer's disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.

Neurocomputational mechanisms underlying fear-biased adaptation learning in changing environments.

Humans are able to adapt to the fast-changing world by estimating statistical regularities of the environment. Although fear can profoundly impact adaptive behaviors, the computational and neural mechanisms underlying this phenomenon remain elusive. Here, we conducted a behavioral experiment (n = 21) and a functional magnetic resonance imaging experiment (n = 37) with a novel cue-biased adaptation learning task, during which we simultaneously manipulated emotional valence (fearful/neutral expressions of the cue) and environmental volatility (frequent/infrequent reversals of reward probabilities). Across 2 experiments, computational modeling consistently revealed a higher learning rate for the environment with frequent versus infrequent reversals following neutral cues. In contrast, this flexible adjustment was absent in the environment with fearful cues, suggesting a suppressive role of fear in adaptation to environmental volatility. This suppressive effect was underpinned by activity of the ventral striatum, hippocampus, and dorsal anterior cingulate cortex (dACC) as well as increased functional connectivity between the dACC and temporal-parietal junction (TPJ) for fear with environmental volatility. Dynamic causal modeling identified that the driving effect was located in the TPJ and was associated with dACC activation, suggesting that the suppression of fear on adaptive behaviors occurs at the early stage of bottom-up processing. These findings provide a neuro-computational account of how fear interferes with adaptation to volatility during dynamic environments.

Identification of a conserved G-quadruplex within the E165R of African swine fever virus (ASFV) as a potential antiviral target.

Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV.

m6 A deposition is regulated by PRMT1-mediated arginine methylation of METTL14 in its disordered C-terminal region.

The N6-methyladenosine (m6 A) RNA modification serves crucial functions in RNA metabolism; however, the molecular mechanisms underlying the regulation of m6 A are not well understood. Here, we establish arginine methylation of METTL14, a component of the m6 A methyltransferase complex, as a novel pathway that controls m6 A deposition in mammalian cells. Specifically, protein arginine methyltransferase 1 (PRMT1) interacts with, and methylates the intrinsically disordered C terminus of METTL14, which promotes its interaction with RNA substrates, enhances its RNA methylation activity, and is crucial for its interaction with RNA polymerase II (RNAPII). Mouse embryonic stem cells (mESCs) expressing arginine methylation-deficient METTL14 exhibit significantly reduced global m6 A levels. Transcriptome-wide m6 A analysis identified 1,701 METTL14 arginine methylation-dependent m6 A sites located in 1,290 genes involved in various cellular processes, including stem cell maintenance and DNA repair. These arginine methylation-dependent m6 A sites are associated with enhanced translation of genes essential for the repair of DNA interstrand crosslinks; thus, METTL14 arginine methylation-deficient mESCs are hypersensitive to DNA crosslinking agents. Collectively, these findings reveal important aspects of m6 A regulation and new functions of arginine methylation in RNA metabolism.

A fully differentiable ligand pose optimization framework guided by deep learning and a traditional scoring function.

The recently reported machine learning- or deep learning-based scoring functions (SFs) have shown exciting performance in predicting protein-ligand binding affinities with fruitful application prospects. However, the differentiation between highly similar ligand conformations, including the native binding pose (the global energy minimum state), remains challenging that could greatly enhance the docking. In this work, we propose a fully differentiable, end-to-end framework for ligand pose optimization based on a hybrid SF called DeepRMSD+Vina combined with a multi-layer perceptron (DeepRMSD) and the traditional AutoDock Vina SF. The DeepRMSD+Vina, which combines (1) the root mean square deviation (RMSD) of the docking pose with respect to the native pose and (2) the AutoDock Vina score, is fully differentiable; thus is capable of optimizing the ligand binding pose to the energy-lowest conformation. Evaluated by the CASF-2016 docking power dataset, the DeepRMSD+Vina reaches a success rate of 94.4%, which outperforms most reported SFs to date. We evaluated the ligand conformation optimization framework in practical molecular docking scenarios (redocking and cross-docking tasks), revealing the high potentialities of this framework in drug design and discovery. Structural analysis shows that this framework has the ability to identify key physical interactions in protein-ligand binding, such as hydrogen-bonding. Our work provides a paradigm for optimizing ligand conformations based on deep learning algorithms. The DeepRMSD+Vina model and the optimization framework are available at GitHub repository https://github.com/zchwang/DeepRMSD-Vina_Optimization.

Thy1-ApoE4/C/EBPß double transgenic mice act as a sporadic model with Alzheimer's disease.

Early onset familial Alzheimer's disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPß double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation. Using the clinical diagnosis criteria, we show that this mouse model exhibits tempo-spatial features in AD patient brains, including progressive cognitive decline associated with brain atrophy, which is accompanied with extensive neuronal degeneration. Remarkably, the mice display gradual Aß aggregation and neurofibrillary tangles formation in the brain validated by Aß PET and Tau PET. Moreover, the mice reveal widespread neuroinflammation as shown in AD brains. Hence, Thy1-ApoE4/C/EBPß mouse model acts as a sporadic AD mouse model, reconstituting the major AD pathologies.

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease.

Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

Bacteriophage protein Gp46 is a cross-species inhibitor of nucleoid-associated HU proteins.

The architectural protein histone-like protein from Escherichia coli strain U93 (HU) is the most abundant bacterial DNA binding protein and highly conserved among bacteria and Apicomplexan parasites. It not only binds to double-stranded DNA (dsDNA) to maintain DNA stability but also, interacts with RNAs to regulate transcription and translation. Importantly, HU is essential to cell viability for many bacteria; hence, it is an important antibiotic target. Here, we report that Gp46 from bacteriophage SPO1 of Bacillus subtilis is an HU inhibitor whose expression prevents nucleoid segregation and causes filamentous morphology and growth defects in bacteria. We determined the solution structure of Gp46 and revealed a striking negatively charged surface. An NMR-derived structural model for the Gp46-HU complex shows that Gp46 occupies the DNA binding motif of the HU and therefore, occludes DNA binding, revealing a distinct strategy for HU inhibition. We identified the key residues responsible for the interaction that are conserved among HUs of bacteria and Apicomplexans, including clinically significant Mycobacterium tuberculosis, Acinetobacter baumannii, and Plasmodium falciparum, and confirm that Gp46 can also interact with these HUs. Our findings provide detailed insight into a mode of HU inhibition that provides a useful foundation for the development of antibacteria and antimalaria drugs.

Crystal Facet Engineering on SrTiO3 Enhances Photocatalytic Overall Water Splitting.

Single-crystal semiconductor-based photocatalysts exposing unique crystallographic facets show promising applications in energy and environmental technologies; however, crystal facet engineering through solid-state synthesis for photocatalytic overall water splitting is still challenging. Herein, we develop a novel crystal facet engineering strategy through solid-state recrystallization to synthesize uniform SrTiO3 single crystals exposing tailored {111} facets. The presynthesized low-crystalline SrTiO3 precursors enable the formation of well-defined single crystals through kinetically improved crystal structure transformation during solid-state recrystallization process. By employing subtle Al3+ ions as surface morphology modulators, the crystal surface orientation can be precisely tuned to a controlled percentage of {111} facets. The photocatalytic overall water splitting activity increases with the exposure percentage of {111} facets. Owing to the outstanding crystallinity and favorable anisotropic surface structure, the SrTiO3 single crystals with 36.6% of {111} facets lead to a 3-fold enhancement of photocatalytic hydrogen evolution rates up to 1.55 mmol·h-1 in a stoichiometric ratio of 2:1 than thermodynamically stable SrTiO3 enclosed with isotropic {100} facets.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

A Defective Disc-Like Cu1.96 S Anode Material with the Efficient Cu Vacancies for High-Performance Sodium-Ion Storage.

Due to their significant capacity and reliable reversibility, transition metal sulphides (TMSs) have received attention as potential anode materials for sodium-ion batteries (SIBs). Nonetheless, a prevalent challenge with TMSs lies in their significant volume expansion and sluggish kinetics, impeding their capacity for rapid and enduring Na+ storage. Herein, a Cu1.96 S@NC nanodisc material enriched with copper vacancies is synthesised via a hydrothermal and annealing procedure. Density functional theory (DFT) calculations reveal that the incorporation of copper vacancies significantly boosts electrical conductivity by reducing the energy barrier for ion diffusion, thereby promoting efficient electron/ion transport. Moreover, the presence of copper vacancies creates ample active sites for the integration of sodium ions, streamlines charge transfer, boosts electronic conductivity, and, ultimately, significantly enhances the overall performance of SIBs. This novel anode material, Cu1.96 S@NC, demonstrates a reversible capacity of 339 mAh g-1 after 2000 cycles at a rate of 5 A g-1 . In addition, it maintains a noteworthy reversible capacity of 314 mAh g-1 with an exceptional capacity retention of 96% even after 2000 cycles at 20 A g-1 . The results demonstrate that creating cationic vacancies is a highly effective strategy for engineering anode materials with high capacity and rapid reactivity.

Synthesis of FeOOH/Zn(OH)2/CoS Ferromagnetic Nanocomposites and the Enhanced Mechanism of Magnetic Field for Their Electrochemical Performances.

The FeOOH/Zn(OH)2/CoS (FZC) nanocomposites are synthesized and show the outstanding electrochemical properties in both supercapacitor and catalytic hydrogen production. The specific area capacitance reaches 17.04 F cm-2, which is more than ten times higher than that of FeOOH/Zn(OH)2 (FZ) substrate: 1.58 F cm-2). FZC nanocomposites also exhibit the excellent cycling stability with an initial capacity retention rate of 93.6% after 10 000 long-term cycles. The electrolytic cell (FZC//FZC) assembled with FZC as both anode and cathode in the UOR (urea oxidation reaction)|| HER (hydrogen evolution reaction) coupled system requires a cell voltage of only 1.453 V to drive a current density of 10 mA cm-2. Especially, the electrochemical performances of FZC nanocomposites are enhanced in magnetic field, and the mechanism is proposed based on Stern double layer model at electrode-electrolyte interface (EEI). More electrolyte ions reach the surface of FZC electrode material under Kelvin force, moreover, the warburg impedance of FZC nanocomposites decrease under magnetic field action, which results in the enhanced behaviors for both the energy storage and urea oxidation reaction .

High-robustness autofocusing method in the microscope with laser-based arrayed spots.

Accurate and rapid autofocus technology plays a crucial role in various fields, including automatic optical inspection technology, bio-chips scanning, and semiconductor manufacturing. The current photoelectric autofocus methods have limitations because of detecting the focal plane solely at the center of the microscope field of view. In the application of Stereo-seq the risk of autofocus errors will be increased, which have reduced the robustness of the system, like when the surface of the tested samples are wrinkling and inconsistent thickness, or the detection spot is at the edge of the sample. To enhance the robustness of the autofocus system and mitigate the constraints of the photoelectric autofocus methods, the laser-based arrayed spots photoelectric autofocus method has been proposed. To achieve the uniform light splitting, a 2D-Dammann grating is incorporated into the optical path of the autofocus system, resulting in the formation of an n × n arrayed spots on the surface of the sample. Through experimental verification, it has been demonstrated that this method can achieve the autofocus range of ±100µm and the autofocus accuracy of ±1/4 DOF when applied to a microscope equipped with a 10× objective lens, thereby satisfying the requirements for microscopic focusing. The arrayed light autofocus method devised in this study presents what we believe is a novel research concept for active autofocus detection and holds significant application value.

Thermal stability of triple-junction gallium arsenide cells.

Laser wireless power transmission (LWPT) systems have significant applications in the field of wireless energy transmission, including spacecraft sensor networks, satellite-to-satellite communication, and remote power supply. However, continuous laser exposure increases the temperature of the photovoltaic (PV) cells in the LWPT system, thus decreasing the electrical output performance. This work, which we believe is a new approach, is on the basis of a notch film designed by a combined merit function proposed to maintain the electrical output performance while under 1064-nm continuous laser irradiation. Moreover, the thermal stability of PV cells under laser irradiation was investigated, which revealed the recoverability of the open-circuit voltage (Voc) of the cells at different temperatures, and the thermal damage to cells was a gradual process. This process began with the vaporization of the encapsulation adhesive, followed by a decline in, but still recoverable and functional, electrical performance, and finally, the cell was completely damaged. The thermal stability of the PV cells coated with the notch film increased ten-fold compared to those without it. Furthermore, the correlation between the minimum Voc and maximum temperature of the cells with notch films of different performances was established. These investigations serve as references for further optimization of LWPT.

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Genome analysis of a newly isolated Bacillus velezensis-YW01 for biodegrading acetaldehyde.

Acetaldehyde (AL), a primary carcinogen, not only pollutes the environment, but also endangers human health after drinking alcohol. Here a promising bacterial strain was successfully isolated from a white wine cellar pool in the province of Shandong, China, and identified as Bacillus velezensis-YW01 with 16 S rDNA sequence. Using AL as sole carbon source, initial AL of 1 g/L could be completely biodegraded by YW01 within 84 h and the cell-free extracts of YW01 has also been detected to biodegrade the AL, which indicate that YW01 is a high-potential strain for the biodegradation of AL. The optimal culture conditions and the biodegradation of AL of YW01 are at pH 7.0 and 38 °C, respectively. To further analyze the biodegradation mechanism of AL, the whole genome of YW01 was sequenced. Genes ORF1040, ORF1814 and ORF0127 were revealed in KEGG, which encode for acetaldehyde dehydrogenase. Furthermore, ORF0881 and ORF052 encode for ethanol dehydrogenase. This work provides valuable information for exploring metabolic pathway of converting ethanol to AL and subsequently converting AL to carboxylic acid compounds, which opened up potential pathways for the development of microbial catalyst against AL.

A chaotic map with two-dimensional offset boosting.

A chaotic map with two-dimensional offset boosting is exhaustively studied, which is derived from the Lozi map and shows the controllability of amplitude control. The mechanism of two-dimensional offset boosting is revealed based on the cancelation of offset-involved feedback terms. Furthermore, the coexistence of homogeneous multistability and heterogeneous multistability is disclosed when the offset boosting turns to the initial condition. It is also found that the independent constant term rescales the amplitude of all the sequences without changing the Lyapunov exponents. More strikingly, the parameters for amplitude control and offset boosting are bound together introducing hybrid control. The circuit implementation based on the microcontroller unit is used to validate the theoretical analysis and numerical simulations. This chaotic map is applied for particle swarm optimization showing its stronger performance and robustness in solving optimization problems.

Offset boosting in a discrete system.

Offset boosting plays an important role in chaos application in electronic engineering. A direct variable substitution typically will destroy the dynamics of a discrete map even though the initial condition is well considered. The internal fundamental reason is that the left-hand side of a discrete system does not have the dimension of variable differentiation (DVD) like the one of a continuous system. When the key property of DVD is completely preserved, the offset boosting based on a parameter or the initial condition can be reasonably achieved like in a differential system. Consequently, by the initial condition-oriented offset boosting, flexible multistability like attractor self-reproducing or attractor doubling can be further realized. A circuit experiment is completed for the verification of reliable offset boosting. The systematic exploration of offset boosting in a map will cast a new light on chaos regulation and attractor transportation in a discrete map. As a simple case, a two-dimensional Hénon map is taken as the example demonstrating the achievement of offset boosting via the parameter or initial condition.

Quality Evaluation of Asparagus officinalis by Profile of Amino Acids and Mineral Elements in Different Parts Combined with Chemometrics Methods.

Asparagus officinalis has a homologous value in medicine and vegetables. Its immature stem, commonly called asparagus, is a central edible part. Asparagus skin and leaf also contain rich nutrients. However, these parts are often discarded. This study investigated amino acid and mineral elements in immature stem, skinless asparagus, asparagus skin, and leaf. Their quality was further evaluated by chemometrics methods such as principal component analysis and neural network analysis. The results showed amino acid content was high in immature stem and skinless asparagus and low in leaf, whereas the mineral elements were in four parts. Quality evaluation results showed four parts were divided into three grades. Immature stem and skinless asparagus were grouped into cluster 1 with the best quality as high-quality raw materials in food and health-care products. Meanwhile, three AA (Cys, His, Arg) and two mineral elements (Na, Cr) were identified as quality evaluation iconic substances.

Advancements and Prospects of Genome-Wide Association Studies (GWAS) in Maize.

Genome-wide association studies (GWAS) have emerged as a powerful tool for unraveling intricate genotype-phenotype association across various species. Maize (Zea mays L.), renowned for its extensive genetic diversity and rapid linkage disequilibrium (LD), stands as an exemplary candidate for GWAS. In maize, GWAS has made significant advancements by pinpointing numerous genetic loci and potential genes associated with complex traits, including responses to both abiotic and biotic stress. These discoveries hold the promise of enhancing adaptability and yield through effective breeding strategies. Nevertheless, the impact of environmental stress on crop growth and yield is evident in various agronomic traits. Therefore, understanding the complex genetic basis of these traits becomes paramount. This review delves into current and future prospectives aimed at yield, quality, and environmental stress resilience in maize and also addresses the challenges encountered during genomic selection and molecular breeding, all facilitated by the utilization of GWAS. Furthermore, the integration of omics, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, and phenomics has enriched our understanding of intricate traits in maize, thereby enhancing environmental stress tolerance and boosting maize production. Collectively, these insights not only advance our understanding of the genetic mechanism regulating complex traits but also propel the utilization of marker-assisted selection in maize molecular breeding programs, where GWAS plays a pivotal role. Therefore, GWAS provides robust support for delving into the genetic mechanism underlying complex traits in maize and enhancing breeding strategies.