RESUMEN

Fusarium head blight (FHB) remains one of the most destructive diseases of wheat (Triticum aestivum L.), causing considerable losses in yield and end-use quality. Phenotyping of FHB resistance traits, Fusarium-damaged kernels (FDK), and deoxynivalenol (DON), is either prone to human biases or resource expensive, hindering the progress in breeding for FHB-resistant cultivars. Though genomic selection (GS) can be an effective way to select these traits, inaccurate phenotyping remains a hurdle in exploiting this approach. Here, we used an artificial intelligence (AI)-based precise FDK estimation that exhibits high heritability and correlation with DON. Further, GS using AI-based FDK (FDK_QVIS/FDK_QNIR) showed a two-fold increase in predictive ability (PA) compared to GS for traditionally estimated FDK (FDK_V). Next, the AI-based FDK was evaluated along with other traits in multi-trait (MT) GS models to predict DON. The inclusion of FDK_QNIR and FDK_QVIS with days to heading as covariates improved the PA for DON by 58% over the baseline single-trait GS model. We next used hyperspectral imaging of FHB-infected wheat kernels as a novel avenue to improve the MT GS for DON. The PA for DON using selected wavebands derived from hyperspectral imaging in MT GS models surpassed the single-trait GS model by around 40%. Finally, we evaluated phenomic prediction for DON by integrating hyperspectral imaging with deep learning to directly predict DON in FHB-infected wheat kernels and observed an accuracy (R2 = 0.45) comparable to best-performing MT GS models. This study demonstrates the potential application of AI and vision-based platforms to improve PA for FHB-related traits using genomic and phenomic selection.

RESUMEN

Human papillomavirus (HPV) is a group of alpha papillomaviruses that cause various illnesses, including cancer. There are more than 160 types of HPV, with many being "high-risk" types that have been clinically linked to cervical and other types of cancer. "Low-risk" types of HPV cause less severe conditions, such as genital warts. Over the past few decades, numerous studies have shed light on how HPV induces carcinogenesis. The HPV genome is a circular double-stranded DNA molecule that is approximately 8 kilobases in size. Replication of this genome is strictly regulated and requires two virus-encoded proteins, E1 and E2. E1 is a DNA helicase that is necessary for replisome assembly and replication of the HPV genome. On the other hand, E2 is responsible for initiating DNA replication and regulating the transcription of HPV-encoded genes, most importantly the E6 and E7 oncogenes. This article explores the genetic characteristics of high-risk HPV types, the roles of HPV-encoded proteins in HPV DNA replication, the regulation of transcription of E6 and E7 oncogenes, and the development of oncogenesis.

Asunto(s)

Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Virus del Papiloma Humano , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/genética , Neoplasias del Cuello Uterino/genética , ADN , Transformación Celular Neoplásica , Carcinogénesis/genética , Papillomaviridae/genética , Papillomaviridae/metabolismo , Replicación del ADN/genética

RESUMEN

Genetic dissection of yield component traits including spike and kernel characteristics is essential for the continuous improvement in wheat yield. Genome-wide association studies (GWAS) have been frequently used to identify genetic determinants for spike and kernel-related traits in wheat, though none have been employed in hard winter wheat (HWW) which represents a major class in US wheat acreage. Further, most of these studies relied on assembled diversity panels instead of adapted breeding lines, limiting the transferability of results to practical wheat breeding. Here we assembled a population of advanced/elite breeding lines and well-adapted cultivars and evaluated over four environments for phenotypic analysis of spike and kernel traits. GWAS identified 17 significant multi-environment marker-trait associations (MTAs) for various traits, representing 12 putative quantitative trait loci (QTLs), with five QTLs affecting multiple traits. Four of these QTLs mapped on three chromosomes 1A, 5B, and 7A for spike length, number of spikelets per spike (NSPS), and kernel length are likely novel. Further, a highly significant QTL was detected on chromosome 7AS that has not been previously associated with NSPS and putative candidate genes were identified in this region. The allelic frequencies of important quantitative trait nucleotides (QTNs) were deduced in a larger set of 1,124 accessions which revealed the importance of identified MTAs in the US HWW breeding programs. The results from this study could be directly used by the breeders to select the lines with favorable alleles for making crosses, and reported markers will facilitate marker-assisted selection of stable QTLs for yield components in wheat breeding.

Asunto(s)

Estudio de Asociación del Genoma Completo , Triticum , Genómica , Nucleótidos , Fenotipo , Fitomejoramiento , Polimorfismo de Nucleótido Simple , Triticum/genética

RESUMEN

The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

Asunto(s)

Empalme Alternativo/fisiología , Trastorno del Espectro Autista/metabolismo , Canales de Calcio/metabolismo , Diferenciación Celular/fisiología , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Trastorno Autístico , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Calcio , Canales de Calcio/genética , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Exones , Regulación del Desarrollo de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de QT Prolongado , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Ratones , Modelos Animales , Mutación , Neurogénesis , Neuronas/citología , Neuronas/metabolismo , Empalme del ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Sindactilia , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo

RESUMEN

Store-operated Ca2+ entry (SOCE), the fundamental Ca2+ signaling mechanism in myogenesis, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and induces Ca2+ influx by activating Orai channels in the plasma membrane. Recently, STIM2ß, an eight-residue-inserted splice variant of STIM2, was found to act as an inhibitor of SOCE. Although a previous study demonstrated an increase in STIM2ß splicing during in vitro differentiation of skeletal muscle, the underlying mechanism and detailed function of STIM2ß in myogenesis remain unclear. In this study, we investigated the function of STIM2ß in myogenesis using the C2C12 cell line with RNA interference-mediated knockdown and CRISPR-Cas-mediated knockout approaches. Deletion of STIM2ß delayed myogenic differentiation through the MEF2C and NFAT4 pathway in C2C12 cells. Further, loss of STIM2ß increased cell proliferation by altering Ca2+ homeostasis and inhibited cell cycle arrest mediated by the cyclin D1-CDK4 degradation pathway. Thus, this study identified a previously unknown function of STIM2ß in myogenesis and improves the understanding of how cells effectively regulate the development process via alternative splicing.

Asunto(s)

Desarrollo de Músculos , Mioblastos/metabolismo , Factores de Transcripción NFATC/metabolismo , Molécula de Interacción Estromal 2/metabolismo , Animales , Señalización del Calcio , Diferenciación Celular , Línea Celular , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Ratones , Mioblastos/citología , Factores de Transcripción NFATC/genética , Proteína ORAI1/metabolismo , Empalme del ARN , Molécula de Interacción Estromal 2/genética

RESUMEN

Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca(2+)-dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2ß, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2ß does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2ß mutants and Orai1-STIM2ß chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals.

Asunto(s)

Empalme Alternativo/fisiología , Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Moléculas de Adhesión Celular/metabolismo , Multimerización de Proteína/fisiología , Canales de Calcio/genética , Moléculas de Adhesión Celular/genética , Células HEK293 , Humanos , Mutación , Proteína ORAI1 , Molécula de Interacción Estromal 2

RESUMEN

The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage-dependent calcium currents. Cav1.2(TS) acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.

Asunto(s)

Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Calcio/metabolismo , Folículo Piloso/citología , Células Madre/citología , Células Madre/metabolismo , Animales , Trastorno Autístico , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/genética , Señalización del Calcio/efectos de los fármacos , Proteínas Relacionadas con la Folistatina/biosíntesis , Proteínas Relacionadas con la Folistatina/metabolismo , Síndrome de QT Prolongado/metabolismo , Ratones , Células Madre/efectos de los fármacos , Sindactilia/metabolismo

RESUMEN

Understanding the complexity of neuronal biology requires the manipulation of cellular processes with high specificity and spatio-temporal precision. The recent development of synthetic photo-activatable proteins designed using the light-oxygen-voltage and phytochrome domains provides a new set of tools for genetically targeted optical control of cell signaling. Their modular design, functional diversity, precisely controlled activity and in vivo applicability offer many advantages for investigating neuronal function. Although designing these proteins is still a considerable challenge, future advances in rational protein design and a deeper understanding of their photoactivation mechanisms will allow the development of the next generation of optogenetic techniques.

Asunto(s)

Proteínas Luminiscentes/metabolismo , Neuronas/metabolismo , Fotoquímica/métodos , Transducción de Señal/fisiología , Coloración y Etiquetado/métodos , Animales , Marcación de Gen/métodos , Marcación de Gen/tendencias , Humanos , Proteínas Luminiscentes/química , Proteínas Luminiscentes/genética , Neuronas/química , Neuronas/fisiología , Fotoquímica/tendencias , Rodopsinas Microbianas/química , Rodopsinas Microbianas/genética , Rodopsinas Microbianas/metabolismo , Transducción de Señal/efectos de la radiación

RESUMEN

Functional role of cellular prion protein (PrPc) has been hypothesized to be in metal homeostasis and providing cells with a superoxide dismutase (SOD)-like activity to escape damage by reactive oxygen species (ROS). PrPc interacts with a range of divalent metal ions and undergoes Cu2+ as well as Zn2+-associated endocytosis, thereby maintaining homeostasis of these and other metal ions. Conformational change to a beta-sheet rich, protease resistant entity, reminiscent of the disease-associated scrapie form called PrPsc, has been found to be induced by interaction of PrPc with metal ions like Cu2+, Zn2+, Mn2+ and Fe2+. This review compiles data from various experimental studies of the interaction of metals with PrPc. The effect of metal ions on the expression and conformation of the prion protein is described in detail with emphasis on their possible physiological and pathogenic role. Further, a hypothesis is presented where attainment of altered conformation by metal-bound PrPc has been viewed as a deleterious consequence of efforts made by cells to maintain metal homeostasis. Thus, PrPc presumably sacrifices itself by converting into PrPsc form in an attempt to protect cells from the toxicity of metal imbalance. Finally, possible reasons for contradictions reported in the literature on the subject are explored and experimental approaches to resolve the same are suggested.

Asunto(s)

Metales/metabolismo , Proteínas PrPC/fisiología , Enfermedades por Prión/fisiopatología , Animales , Cationes Bivalentes , Humanos , Proteínas PrPC/química , Proteínas PrPC/metabolismo , Unión Proteica

RESUMEN

Obsessive compulsive disorder (OCD) is a common psychiatric disorder which is easily recognized. However, sometimes patients of OCD present in such an atypical or bizarre way that their problem comes to notice as being a psychiatric disorder after multiple consultations in different specialties. We are reporting a case of a man who had first sought opinion in the Department of Ear, Nose and Throat (ENT) for hearing impairment. He was then referred to a neurologist and a general physician for evaluation of neurological cause of his symptom. As no pathology related to ENT or neurology could be detected, he was referred to the Department of Psychiatry. The patient's chief complaints were difficulty in hearing and inability to understand at once. He could be diagnosed as a case of OCD after meticulous evaluation and studying his response to treatment. There was significant improvement in all the presenting symptoms over a period of 6 weeks on 60 mg of fluoxetine.

RESUMEN

Amyloids are typically characterized by extensive aggregation of proteins where the participating polypeptides are involved in formation of intermolecular cross beta-sheet structures. Alternate structure attainment and amyloid formation has been hypothesized to be a generic property of a polypeptide, the propensities of which vary widely depending on the polypeptide involved and the physicochemical conditions it encounters. Many proteins that exist in the normal form in-vivo have been shown to form amyloid when incubated in partially denaturing conditions. The protein bovine carbonic anhydrase II (BCA II) when incubated in mildly denaturing conditions showed that the partially unfolded conformers assemble together and form ordered amyloid aggregates. The properties of these aggregates were tested using the traditional Congo-Red (CR) and Thioflavin-T (ThT) assays along with fluorescence microscopy, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. The aggregates were found to possess most of the characteristics ascribed to amyloid fibers. Thus, we report here that the single-domain globular protein, BCA II, is capable of forming amyloid fibrils. The primary sequence of BCA II was also analyzed using recurrence quantification analysis in order to suggest the probable residues responsible for amyloid formation.

Asunto(s)

Amiloide/química , Anhidrasa Carbónica II/química , Amiloide/metabolismo , Amiloide/ultraestructura , Animales , Benzotiazoles , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica II/ultraestructura , Bovinos , Dicroismo Circular , Rojo Congo/química , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Modelos Biológicos , Pliegue de Proteína , Tiazoles/química