Smurfness-based two-phase model of ageing helps deconvolve the ageing transcriptional signature.

Ageing is characterised at the molecular level by six transcriptional 'hallmarks of ageing', that are commonly described as progressively affected as time passes. By contrast, the 'Smurf' assay separates high-and-constant-mortality risk individuals from healthy, zero-mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non-Smurf individuals preceding the other five hallmarks of ageing that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro-longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing.

Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome.

INTRODUCTION: Ataxia telangiectasia (A-T) is a life-limiting autosomal recessive disease characterized by cerebellar degeneration, ocular telangiectasias, and sinopulmonary disease. Since there is no cure for A-T, the standard of care is primarily supportive. AREAS COVERED: We review clinical trials available in PubMed from 1990 to 2023 focused on lessening A-T disease burden. These approaches include genetic interventions, such as antisense oligonucleotides, designed to ameliorate disease progression in patients with select mutations. These approaches also include pharmacologic treatments that target oxidative stress, inflammation, and mitochondrial exhaustion, to attenuate neurological progression in A-T. Finally, we discuss the use of biological immunotherapies for the treatment of malignancies and granulomatous disease, along with other supportive therapies being used for the treatment of pulmonary disease and metabolic syndrome. EXPERT OPINION: Barriers to successful genetic and pharmacologic interventions in A-T include the need for personalized treatment approaches based on patient-specific ATM mutations and phenotypes, lack of an animal model for the neurologic phenotype, and extreme rarity of disease making large-scale randomized trials difficult to perform. Ongoing efforts are needed to diagnose patients earlier, discover more effective therapies, and include more individuals in clinical trials, with the goal to lessen disease burden and to find a cure for patients with A-T.

Intervenciones genéticas de Aedes aegypti para el control de arbovirosis / Genetic interventions of Aedes aegypti for the control of arboviruses

La ineficacia de las estrategias actuales para el control químico de los mosquitos vectores plantea la necesidad de desarrollar enfoques novedosos, entre estos están las estrategias genéticas para reducir las poblaciones de mosquitos vectores o sustituirlos por aquellos que no son capaces de transmitir patógenos, esto se logra a través de herramientas moleculares que permiten la manipulación y transgénesis de genes. Las secuencias del genoma de los mosquitos y las bases de datos de marcadores de secuencias expresadas asociadas permiten investigaciones a gran escala para proporcionar nuevos conocimientos sobre las vías evolutivas, bioquímicas, genéticas, metabólicas y fisiológicas. Además, la genómica comparativa revela las bases de los mecanismos evolutivos con especial atención a las interacciones específicas entre vectores y patógenos. Se ha desarrollado tecnología de transgénesis para el mosquito de la fiebre amarilla y dengue, Aedes aegypti. Se ha logrado integración exitosa de ADN exógeno en la línea germinal de este mosquito con los elementos transponibles. La disponibilidad de múltiples elementos y genes marcadores proporciona un poderoso conjunto de herramientas para investigar las propiedades biológicas básicas de este insecto vector, así como los materiales para desarrollar nuevas estrategias de control genético de poblaciones de mosquitos basadas en la técnica del insecto estéril. Una de estas estrategias consiste en liberar a la población machos esterilizados por radiación; otro, de integrar un gen letal dominante bajo el control de un promotor específico en hembras inmaduras. El uso de esta técnica de modificación genética constituirá una herramienta importante para el manejo integrado de vectores(AU)

The ineffectiveness of current strategies for the chemical control of vector mosquitoes raises the need to develop novel approaches, among these are genetic strategies to reduce populations of vector mosquitoes or replace them with those that are not capable of transmitting pathogens, this is achieved through molecular tools that allow the manipulation and transgenesis of genes. Mosquito genome sequences and associated expressed sequence marker databases enable large-scale investigations to provide new insights into evolutionary, biochemical, genetic, metabolic, and physiological pathways. Furthermore, comparative genomics reveals the basis of evolutionary mechanisms with special attention to the specific interactions between vectors and pathogens. Transgenesis technology has been developed for the yellow fever and dengue mosquito, Aedes aegypti. Successful integration of exogenous DNA into the germ line of this mosquito with the transposable elements has been achieved. The availability of multiple elements and marker genes provides a powerful set of tools to investigate the basic biological properties of this insect vector, as well as the materials to develop new strategies for genetic control of mosquito populations based on the sterile insect technique. One of this strategy is to release radiation-sterilized males into the population; another, to integrate a dominant lethal gene under the control of a specific promoter in immature females. The use of this genetic modification technique will constitute an important tool for the integrated management of vectors(AU)

TypiCal but DeliCate Ca++re: Dissecting the Essence of Calcium Signaling Network as a Robust Response Coordinator of Versatile Abiotic and Biotic Stimuli in Plants.

Plant growth, development, and ultimately crop productivity are largely impacted by the interaction of plants with different abiotic and biotic factors throughout their life cycle. Perception of different abiotic stresses, such as salt, cold, drought, heat, and heavy metals, and interaction with beneficial and harmful biotic agents by plants lead to transient, sustained, or oscillatory changes of [calcium ion, Ca2+]cyt within the cell. Significant progress has been made in the decoding of Ca2+ signatures into downstream responses to modulate differential developmental and physiological responses in the whole plant. Ca2+ sensor proteins, mainly calmodulins (CaMs), calmodulin-like proteins (CMLs), and others, such as Ca2+-dependent protein kinases (CDPKs), calcineurin B-like proteins (CBLs), and calmodulin-binding transcription activators (CAMTAs) have played critical roles in coupling the specific stress stimulus with an appropriate response. This review summarizes the current understanding of the Ca2+ influx and efflux system in plant cells and various Ca2+ binding protein-mediated signal transduction pathways that are delicately orchestrated to mitigate abiotic and biotic stresses. The probable interactions of different components of Ca2+ sensor relays and Ca2+ sensor responders in response to various external stimuli have been described diagrammatically focusing on established pathways and latest developments. Present comprehensive insight into key components of the Ca2+ signaling toolkit in plants can provide an innovative framework for biotechnological manipulations toward crop improvability in near future.

Iron Homeostasis Disorder and Alzheimer's Disease.

Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer's disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.

Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the "dying back" phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.

Pathogenic Mitochondria DNA Mutations: Current Detection Tools and Interventions.

Mitochondria are best known for their role in energy production, and they are the only mammalian organelles that contain their own genomes. The mitochondrial genome mutation rate is reported to be 10-17 times higher compared to nuclear genomes as a result of oxidative damage caused by reactive oxygen species during oxidative phosphorylation. Pathogenic mitochondrial DNA mutations result in mitochondrial DNA disorders, which are among the most common inherited human diseases. Interventions of mitochondrial DNA disorders involve either the transfer of viable isolated mitochondria to recipient cells or genetically modifying the mitochondrial genome to improve therapeutic outcome. This review outlines the common mitochondrial DNA disorders and the key advances in the past decade necessary to improve the current knowledge on mitochondrial disease intervention. Although it is now 31 years since the first description of patients with pathogenic mitochondrial DNA was reported, the treatment for mitochondrial disease is often inadequate and mostly palliative. Advancements in diagnostic technology improved the molecular diagnosis of previously unresolved cases, and they provide new insight into the pathogenesis and genetic changes in mitochondrial DNA diseases.

Engineering of tomato for the sustainable production of ketocarotenoids and its evaluation in aquaculture feed.

Ketocarotenoids are high-value pigments used commercially across multiple industrial sectors as colorants and supplements. Chemical synthesis using petrochemical-derived precursors remains the production method of choice. Aquaculture is an example where ketocarotenoid supplementation of feed is necessary to achieve product viability. The biosynthesis of ketocarotenoids, such as canthaxanthin, phoenicoxanthin, or astaxanthin in plants is rare. In the present study, complex engineering of the carotenoid pathway has been performed to produce high-value ketocarotenoids in tomato fruit (3.0 mg/g dry weight). The strategy adopted involved pathway extension beyond ß-carotene through the expression of the ß-carotene hydroxylase (CrtZ) and oxyxgenase (CrtW) from Brevundimonas sp. in tomato fruit, followed by ß-carotene enhancement through the introgression of a lycopene ß-cyclase (ß-Cyc) allele from a Solanum galapagense background. Detailed biochemical analysis, carried out using chromatographic, UV/VIS, and MS approaches, identified the predominant carotenoid as fatty acid (C14:0 and C16:0) esters of phoenicoxanthin, present in the S stereoisomer configuration. Under a field-like environment with low resource input, scalability was shown with the potential to deliver 23 kg of ketocarotenoid/hectare. To illustrate the potential of this "generally recognized as safe" material with minimal, low-energy bioprocessing, two independent aquaculture trials were performed. The plant-based feeds developed were more efficient than the synthetic feed to color trout flesh (up to twofold increase in the retention of the main ketocarotenoids in the fish fillets). This achievement has the potential to create a new paradigm in the renewable production of economically competitive feed additives for the aquaculture industry and beyond.

Standardized management of thalassemia / 中华实用儿科临床杂志

Thalassemia is inherited hemolytic anemia caused by globin production disorder,clinically known as beta thalassemia and alpha thalassemia resulted from beta and alpha chain synthesis disorder.Significant anemic clinical manifestations are observed in intermediate -level and severe -level patients with the 2 types of anemia, affecting greatly the growth and life quality of children patients who need blood transfusion to stay alive.The incidence rate of thalassemia is as high as 7% -20% in South China,so the prevention and standaridized treatment of thalasse-mia and the management over target population draw more attention.This paper is a review on the latest development of blood transfusion,chelation therapy,health education,birth intervention for thalassemia.