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The etiology of Alzheimer's disease (AD) remains under active debate. In this perspective, we explore the hypothesis that a primarily infection-caused chronic dysregulation and weakening of human innate immunity via the underexpression, degradation, and inactivation of innate immune proteins necessary for direct antimicrobial effects and regulation of host defense and autophagy could lead to AD. Key evidence relates to the fact that important innate immune proteins such as LL-37-which can bind Aβ and block amyloid formation-as well as Apolipoprotein E, antiviral interferons, and TNF-α can be degraded and deactivated by enzymes produced by the common oral anaerobic pathogen Porphyromonas gingivalis (Pg). Pg produces numerous virulence factors; of particular importance for AD are Pg's gingipain cysteine proteases. Deleterious effects of chronic Pg infection and gingipains include a systemic downregulation and paralysis of the interferon response, particularly the antiviral interferon-lambda response, which enables replication of endemic herpesviruses. The result is a chronic, low-level viral infectious assault on gut, nerves, and brain causing the production of Aβ antimicrobial peptides, accumulation of Aβ plaques, phosphorylation of Tau, progressive neuroinflammation, and neurodegeneration. The resultant innate immune system dysregulation, as an AD etiology, ties together the well-known amyloid cascade hypothesis and the infectious theory of AD into a unified explanation of the pathology and cause of AD. If this theory holds true, it suggests preventative approaches: (1) test for and eradicate Pg from oral flora, and/or directly deactivate the gingipains; and (2) reduce Herpesvirus exacerbations by the use of antiviral drugs and/or vaccines (e.g., Bacillus Calmette-Guérin).

A plethora of cellular signaling pathways are dysregulated in cancer cells, promoting carcinogenesis and migration. Cholesterol has recently been linked to cancer by several subcellular mechanisms, especially by its involvement in the formation of lipid rafts, which promote oncogenic signaling and cancer cell invasion. Squalene synthase (SQS), a pivotal enzyme in the cholesterol biosynthetic pathway downstream of the molecular target of statins, has drawn attention as a potential therapeutic target in cancer. Being the first enzyme in the pathway solely responsible for sterol formation, SQS presents an appealing approach for studying the explicit role of cholesterol in cancer. In recent years, research has re-focused on SQS inhibitors, which modulate cellular cholesterol levels, ultimately regulating crucial processes for cancer progression. However, the mechanisms through which they exert anticancer activity have not been fully elucidated to date. In this review, we examine the roles of cholesterol, lipid rafts, and SQS in cancer and metastasis, and the potential therapeutic implications of SQS inhibitors.

The development of commercially available porometers has allowed for higher throughput measurement of stomatal conductance, but a body of evidence has suggested a persistent positive bias in their measurements relative to "reference" measurements from instrumentation based on infra-red gas analysis. We compiled a data set comprised of 25 angiosperm species, across a range of field conditions and found that the LI-COR LI-600, an open flow-through porometer, produced an exponentially increasing bias relative to the LI-COR LI-6800 infra-red gas analyser-based instrument in response to increasing stomatal conductance and decreasing relative humidity. This bias was minimal at lower stomatal conductance (below roughly 0.25 mol m ${}^{-2}$ s ${}^{-1}$ ), but was pronounced for larger values. We hypothesised that this bias is the result of the assumption of a constant air temperature throughout the flow stream used by the instrument software to estimate stomatal conductance from raw sensor measurements. We relaxed this assumption, and applied psychrometrics to augment the typical gas exchange equations with an additional energy balance constraint to solve for the temperature change throughout the air flow stream. We found that including this temperature difference corrects the computed transpiration and stomatal conductance values, and brings the porometer measurement into agreement with that of the infra-red gas analysis-based system. Software is provided to apply the correction to LI-600 output files. For future instrument design iterations, explicit measurement of temperature variation in the flow stream provides a potential opportunity for improvement in measurement accuracy at high stomatal conductance.

Ammonium (NH₄ ⁺) is a crucial nitrogen (N) form for plant growth. The functions of ammonium transporters (AMTs) in mycorrhizal plants and their role in mediating ammonium uptake and regulating N metabolism in blueberry are not fully understood. In this study, 19 VcAMT genes were identified in blueberry. Tissue-specific expression analysis revealed that nine VcAMT members exhibited root-predominant expression patterns, with significant upregulation following inoculation with the O. maius BL01. Notably, VcAMT14 was specifically upregulated during mycorrhizal symbiosis and under N regulation, and subcellular localisation analysis confirmed its protein is located at the plasma membrane. Functional analysis in yeast demonstrated that VcAMT14 mediates NH₄⁺ transport activity. Furthermore, inoculation with O. maius BL01 enhanced rhizosphere soil sucrase activity, soil urease activity, soil phosphatase activity, N content, GS/GOGAT enzyme activity, and the expression levels of related genes in blueberry plants, while simultaneously reducing soil pH. Conversely, VcAMT14 silencing resulted in significantly reduced NH₄⁺ content, GS/GOGAT enzyme activities, and the expression of related genes, along with an increase in the pH of the hydroponic nutrient solution. These findings suggest that VcAMT14 plays a crucial role in regulating N response in blueberry under ERMF symbiosis, providing important insights into the mycorrhiza-mediated N uptake mechanism.

Transpiration restriction under high vapour pressure deficit (VPD), measured indoors with individual plants, increases water use efficiency (WUE). However, VPD is not the only factor driving transpiration, individual plants in a field rapidly become a canopy, and reports on the transpiration restriction versus WUE are scant. We analyzed the transpiration response to the evaporative demand (Penman-Monteith reference evapotranspiration, ET_ref) and WUE in sorghum canopies outdoors. These responses showed no plateau at high ET_ref in 47 genotypes. The slope of the resulting linear relationship over the whole range of ET_ref showed a large genetic variability. Unexpectedly, this slope was positively correlated with WUE in experiments with high ET_ref. Conversely, a (classical) negative correlation was observed under low ET_ref. Genotypes with high WUE and response to ET_ref allowed maximum light penetration into the canopy, via more erect leaf orientation. VPD in the canopy was also lower than in open air when the leaf area index reached 2.5-3. We interpret that higher WUE related to a larger proportion of plant photosynthesis being contributed by lower level leaves that received light and faced lower VPD than leaves exposed to air VPD. This study opens new opportunities, agronomic and genetic, to improve WUE.

Gene therapy is emerging as a groundbreaking strategy for treating epilepsy, offering new hope to patients who do not respond to conventional medications. Despite advancements in anti-seizure treatments, nearly 30%-40% of individuals with epilepsy continue to experience uncontrolled seizures, highlighting the urgent need for more effective and long-lasting solutions. By addressing the underlying causes of epilepsy at the genetic level, gene therapy represents a paradigm shift in treatment. Two key approaches are being explored: (1) activating or supplementing beneficial genes to suppress seizures and (2) silencing harmful genes or pathways that contribute to epilepsy. To achieve these objectives, viral vectors, such as adeno-associated viruses and lentiviruses, have shown promise in delivering targeted genetic interventions. In parallel, cutting-edge techniques such as optogenetics, chemogenetics, and clustered regularly interspaced short palindromic repeat-based gene editing are enhancing the precision of these therapies, enabling greater control over neuronal activity. However, significant challenges exist, including ensuring safe and efficient gene delivery, maintaining long-term therapeutic effects, and mitigating potential side effects. This review examines recent developments in gene therapy for epilepsy, assessing its potential to deliver targeted, long-lasting treatments for drug-resistant epilepsy. By examining current strategies, therapeutic targets, and emerging technologies, it provides insights into the promising future of gene therapy as a transformative tool in epilepsy treatment and summarizes current clinical trials utilizing gene and cell therapy technologies for epilepsy.

Background: Liver disease is on the increase worldwide, with cirrhosis and liver cancer accounting for around 3.5% of all deaths.

Objectives: Investigate the prognostic utility of three non-invasive liver fibrosis markers in the Welsh primary care population for identification of those at risk of cirrhosis or hepatocellular carcinoma (HCC).

Methods: Using the Secure Anonymised Information Linkage (SAIL) Databank at Swansea University (2000-2017), we identified people with liver blood tests allowing calculation of three commonly used liver fibrosis markers: aspartate transaminase to alanine transaminase (AST/ALT) ratio, AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4). We modelled 10-year risk of cirrhosis/HCC across a range of thresholds using competing risk survival analysis and compared their prognostic value using decision curve analysis (DCA).

Results: Blood tests enabling calculation of FIB-4, APRI and AST/ALT were available for 203,005 people. At commonly utilized cut-points to detect advanced fibrosis/cirrhosis of 3.25, 1.5 and 1.0 for FIB-4, APRI and AST/ALT, respectively, the 10-year risks of cirrhosis/HCC were 4.7%, 16% and <1%. DCA demonstrated the APRI has the greatest net benefit for estimating cirrhosis/HCC risk over 10 years, in a general population compared to AST/ALT or FIB-4. In higher risk subgroups, a greater proportion of at-risk patients were captured for fewer referrals. This was also observed in groups with combinations of risk factors.

Conclusion: At risk thresholds often used for referral, liver fibrosis markers had prohibitively high false positive rates unless restricted to subgroups at increased risk of developing severe liver disease.

Cyclophilins are a family of enzymes with peptidyl-prolyl isomerase activity found in all cells of all organisms. To date, 17 cyclophilin isoforms have been identified in the human body, participating in diverse biological processes. Consequently, cyclophilins have emerged as promising targets for drug development to address a wide array of human diseases. This review describes the structural characteristics of individual cyclophilin isoforms and explores the roles that they play in human health and diseases, such as in viral infections, Alzheimer's disease, Parkinson's disease, cardiovascular diseases, or cancer. Additionally, the review addresses inhibition of cyclophilins, particularly focusing on the development of selective small-molecule inhibitors of individual cyclophilins, which possess a significant potential as novel therapeutics.

Flowering is essential for plants to reach the survival of species and flowering is influenced by many environmental factors. However, trithorax group (TrxG) mediated epigenetic modification mechanisms of Physalis grisea under low temperature on flowering remain largely unknown. Here, we report that TrxG core member ULTRAPETALA1 (PgULT1) inhibits flowering in P. grisea by interacting with Polycomb Group (PcG) member LIKE-HETEROCHROMATIN-PROTEIN 1 (PgLHP1) and transcription factor DNA-BINDING-ONE-FINGER 3.4 (PgDOF3.4) to regulate H3K4me3 and H3K27me3. PgULT1 overexpression delayed flowering, yet flowering was relatively promoted under low temperatures. Similarly, PgDOF3.4 confers delayed flowering by transcribing PgULT1, PgLHP1, and FLOWERING LOCUS C (PgFLC). Protein interaction assays indicated that PgULT1, PgDOF3.4 and PgLHP1 can interact with each other, enhance PgFLC transcription and suppress FLOWERING LOCUS T (PgFT) transcription. Genetic evidence demonstrated that PgULT1 and PgLHP1 inhibit flowering by depositing H3K4me3 and H3K27me3 at the PgFLC and PgFT transcription start sites, respectively. PgULT1, PgDOF3.4 and PgLHP1 expression are suppressed under low temperatures, leading to reduced H3K4me3 and H3K27me3 modifications on PgFLC and PgFT promoters, thereby promoting flowering. Collectively, the functional interactions between epigenetic modifiers and transcription factors reveal a cooperative mechanism between TrxG and PcG to respond to low temperatures and promote flowering in P. grisea.

Leaf intrinsic water use efficiency (iWUE) quantifies the trade-off between carbon assimilation and water loss in plants, and is constrained by leaf traits such as maximum carboxylation capacity (V_c,max) and stomatal conductance. Yet, the potential links of iWUE with leaf elementomes across different forest types remain unclear. Here, we analyzed iWUE (estimated by leaf carbon isotopes) variability and its associations with V_c,max, stomatal conductance (estimated by ¹⁸O enrichment in leaf dry matter above source water, Δ¹⁸O), and leaf elementomes across 82 tree species from temperate, subtropical and tropical forests, and evaluated the effectiveness of leaf reflectance spectroscopy as an indicator of iWUE variability and trait-iWUE associations. Across species, V_c,max, Δ¹⁸O, leaf mass per area (LMA) and leaf iron, nitrogen, sodium and manganese concentrations were the traits most strongly associated with cross-site iWUE variability. Furthermore, climatic factors (mean annual precipitation, mean annual temperature and climate moisture index) shaped trait-iWUE covariation by negatively linking leaf elements and positively with LMA, which affected iWUE more directly than indirectly via V_c,max and Δ¹⁸O. Leaf reflectance spectroscopy accurately predicted iWUE (R² = 0.83), and the trait-iWUE relationships derived from spectral modelling were consistent with those obtained through field measurements. These findings reveal strong linkages between the leaf elementomes and iWUE, and highlight the potential of reflectance spectroscopy for characterizing iWUE variability and trait-iWUE relationships, thereby improving process modelling of forest carbon and water cycles.