Prediction of physical realizations of the coordinated universal time with gated recurrent unit.

Coordinated Universal Time (UTC), produced by the Bureau International des Poids et Mesures (BIPM), is the official worldwide time reference. Given that there is no physical signal associated with UTC, physical realizations of the UTC, called UTC(k), are very important for demanding applications such as global navigation satellite systems, communication networks, and national defense and security, among others. Therefore, the prediction of the time differences UTC-UTC(k) is important to maintain the accuracy and stability of the UTC(k) timescales. In this paper, we report for the first time the use of a deep learning (DL) technique called Gated Recurrent Unit (GRU) to predict a sequence of H futures values of the time differences UTC-UTC(k) for ten different UTC(k) timescales. UTC-UTC(k) time differences published on the monthly Circular T document of the BIPM are used as training samples. We utilize a multiple-input, multiple-output prediction strategy. After a training process where about 300 past values of the difference UTC-UTC(k) are used, H (H = 6) values of the Circular T can be predicted using p (typically p = 6) past values. The model has been tested with data from ten different UTC(k) timescales. When comparing GRU results with other standard DL algorithms, we found that the GRU approximation has a good performance in predicting UTC(k) timescales. According to our results, the GRU error in predicting UTC-UTC(k) values is typically 1 ns. The frequency instability of the UTC(k) timescale is the main limitation in reducing the GRU error in the time difference prediction.

Securing access to a comprehensive diagnostic panel for children with suspected acute lymphoblastic leukemia: Results from the Mexico in Alliance with St. Jude "Bridge Project".

Background: The "Bridge Project" is a Mexico in Alliance with St. Jude (MAS) initiative developed in 2019 to improve access, accuracy, and timeliness of specialized diagnostic studies for patients with suspected acute lymphoblastic leukemia (ALL). The project strategy relies on service centralization to improve service delivery, biological characterization, risk-group classification, and support proper treatment allocation. Methods: This is an ongoing prospective multisite intersectoral quality improvement (QI) project available to all patients 0-18 years of age presenting with suspected ALL to the 14 actively participating institutions in 12 Mexican states. Institutions send specimens to one centralized laboratory. From a clinical standpoint, the project secures access to a consensus-derived comprehensive diagnostic panel. From a service delivery standpoint, we assess equity, timeliness, effectiveness, and patient-centeredness. From an implementation science standpoint, we document feasibility, utility, and appropriateness of the diagnostic panel and centralized approach. This analysis spans from July 2019 to June 2023. Results: 612 patients have accessed the project. The median age was 6 years (IQR 3-11), and 53% were males. 94% of the specimens arrived within 48 hours, which documents the feasibility of the centralized model, and 100% of the patients received precise and timely diagnostic results, which documents the effectiveness of the approach. Of 505 (82.5%) patients with confirmed ALL, 463/505 (91.6%) had B-cell ALL, and 42/505 (8.3%) had T-cell ALL. High-hyperdiploidy was detected by DNA index in 36.6% and hypodiploidy in 1.6%. 76.6% of the patients had conclusive karyotype results. FISH studies showed t(12;21) in 15%, iAMP21 in 8.5%, t(1;19) in 7.5%, t(4;11) in 4.2%, t(9;22) in 3.2%, del(9)(p21) in 1.8%, and TRA/D (14)(q11.2) rearrangement in 2.4%. Among B-cell ALL patients, 344/403 (85.1%) had Day 15 MRD<1% and 261/305 (85.6%) Day 84 MRD<0.01. For T-cell ALL patients 20/28 (71.4%) had Day 29 MRD<0.01% and 19/22 (86.4%) Day 84 MRD<0.01%. Conclusions: By securing access to a standardized consensus-derived diagnostic panel, the Bridge Project has allowed better characterization of childhood ALL in Mexico while producing unprecedented service improvements and documenting key implementation outcomes. We are using these results to inform iterative changes to the diagnostic panel and an associated treatment guideline (MAS-ALL18).

Síndrome de Morquio, una afección infrecuente / Morquio syndrome, a rare condition

Introducción: el síndrome de Morquio es una rara enfermedad hereditaria autosómica recesiva, caracterizada por la presencia de un trastorno del metabolismo de los glúcidos, generando dismi- nución de la calidad de vida. Caso clínico: recién nacido a término de 37.6 semanas con APGAR 7-9, que minutos después de nacido muestra signos de cianosis distal y bucal, acompañado de disminución en la saturación de oxígeno al 70%. Posteriormente, se identificaron características fenotípicas y manifestaciones clínicas que permitieron la sospecha diagnóstica de esta enferme- dad, lo que se corroboró mediante estudio genético. Conclusiones: El diagnóstico de síndrome de Morquio se logró establecer en los primeros momentos del nacimiento, las manifestaciones observadas en el caso que se presenta fueron las clásicas que informa la literatura médica, el estudio genético confirmó el diagnóstico.

Introduction: Morquio syndrome is a rare autosomal recessive hereditary disease, characterized by the presence of a carbohydrate metabolism disorder, generating a decrease in the quality of life. Clinical case: newborn of 37.6 weeks with APGAR 7-9, who shows signs of distal and oral cyanosis, accompanied by a decrease in oxygen saturation to 70% minutes after birth. Subse- quently, the diagnostic suspicion of this disease was identified due to the phenotypic characteris- tics and clinical manifestations, which was corroborated by genetic study. Conclusions: The diagnosis of Morquio syndrome was established in the first moments of birth, the manifestations observed in the case presented were the classic ones reported in the medical literature, the gene- tic study confirmed the diagnosis

Variants in ARID5B gene are associated with the development of acute lymphoblastic leukemia in Mexican children.

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.

Profile of genetically modified plants authorized in Mexico.

Mexico is a center of origin for several economically important plants including maize, cotton, and cocoa. Maize represents more than a food crop, has been declared a biological, cultural, agricultural and economic patrimony, and is linked to the national identity of Mexicans. In this review, we describe the historic and current use of genetically modified plants in Mexico and factors that contributed to the development of the biosafety regulation. We developed a database containing all permit applications received by the government to release genetically modified plants. A temporal and geographical analysis identified the plant species that have been authorized for experimental purposes, pilot programs, or commercial production, the geographic areas where they have been released, and the traits that have been introduced. Results show that Mexico has faced a dual challenge: accepting the benefits of genetically modified plants and their products, while protecting native plant biodiversity.

Mechanisms, applications, and perspectives of antiviral RNA silencing in plants.

Viral diseases of plants cause important economic losses due to reduction in crop quality and quantity to the point of threatening food security in some countries. Given the reduced availability of natural sources, genetic resistance to viruses has been successfully engineered for some plant-virus combinations. A sound understanding of the basic mechanisms governing plant-virus interactions, including antiviral RNA silencing, is the foundation to design better management strategies and biotechnological approaches to engineer and implement antiviral resistance in plants. In this review, we present current molecular models to explain antiviral RNA silencing and its application in basic plant research, biotechnology and genetic engineering.

Roles and programming of Arabidopsis ARGONAUTE proteins during Turnip mosaic virus infection.

In eukaryotes, ARGONAUTE proteins (AGOs) associate with microRNAs (miRNAs), short interfering RNAs (siRNAs), and other classes of small RNAs to regulate target RNA or target loci. Viral infection in plants induces a potent and highly specific antiviral RNA silencing response characterized by the formation of virus-derived siRNAs. Arabidopsis thaliana has ten AGO genes of which AGO1, AGO2, and AGO7 have been shown to play roles in antiviral defense. A genetic analysis was used to identify and characterize the roles of AGO proteins in antiviral defense against Turnip mosaic virus (TuMV) in Arabidopsis. AGO1, AGO2 and AGO10 promoted anti-TuMV defense in a modular way in various organs, with AGO2 providing a prominent antiviral role in leaves. AGO5, AGO7 and AGO10 had minor effects in leaves. AGO1 and AGO10 had overlapping antiviral functions in inflorescence tissues after systemic movement of the virus, although the roles of AGO1 and AGO10 accounted for only a minor amount of the overall antiviral activity. By combining AGO protein immunoprecipitation with high-throughput sequencing of associated small RNAs, AGO2, AGO10, and to a lesser extent AGO1 were shown to associate with siRNAs derived from silencing suppressor (HC-Pro)-deficient TuMV-AS9, but not with siRNAs derived from wild-type TuMV. Co-immunoprecipitation and small RNA sequencing revealed that viral siRNAs broadly associated with wild-type HC-Pro during TuMV infection. These results support the hypothesis that suppression of antiviral silencing during TuMV infection, at least in part, occurs through sequestration of virus-derived siRNAs away from antiviral AGO proteins by HC-Pro. These findings indicate that distinct AGO proteins function as antiviral modules, and provide a molecular explanation for the silencing suppressor activity of HC-Pro.

Separation of PEGylated variants of ribonuclease A and apo-α-lactalbumin via reversed phase chromatography.

The covalent attachment of polyethylene glycol (PEG) molecules to pharmaceutical proteins, "PEGylation", often results in a population of conjugate species that includes differing numbers and locations of attached PEG chains. As some portion of this population may be biologically inactive, a challenging separation problem arises. An interesting alternative to the size-based resolution of these conjugates involves the use of reversed phase chromatography (RPC), treating the PEG moieties as hydrophobic purification tags. The use of RPC raises concerns about protein denaturation in the mobile and on the stationary phase. Here, the potential dual role of conjugated PEG chains as both group-specific separation tags and as steric or structural stabilizers in RPC was explored. In this work, RPC with C18-based media was used to resolve PEGylation number variants of ribonuclease A (RNase A) and apo-α-lactalbumin (apo-αLac) in a neutral pH mobile phase. While the attachment of 20kDa PEG molecules did not modify the structures of RNase A and apo-αLac, as confirmed by structural analysis using circular dichroism, exposure to the mobile phase modifier, acetonitrile, and to the C18 media during separation resulted in perturbations to both the secondary and tertiary structures of all species studied. RNase A experienced small perturbations that were mediated to some extent by PEGylation; these results were consistent with activity assays which showed that PEGylated RNase A species retained native-like activity after RPC separation. Apo-αLac, a more hydrophobic and less stable protein than RNase A, experienced extensive structural perturbations regardless of PEGylation state. The temperature of the mobile phase was found to strongly influence chromatographic separation of PEG-conjugates with conjugate species becoming more strongly retained with increasing temperature. This work shows that it is feasible to employ RPC with neutral pH mobile phases to resolve PEG conjugate number heterogeneity.

Rotavirus-like particles primary recovery from insect cells in aqueous two-phase systems.

Virus-like particles have a wide range of applications, including vaccination, gene therapy, and even as nanomaterials. Their successful utilization depends on the availability of selective and scalable methods of product recovery and purification that integrate effectively with upstream operations. In this work, a strategy based on aqueous two phase system (ATPS) was developed for the recovery of double-layered rotavirus-like particles (dlRLP) produced by the insect cell-baculovirus expression system. Polyethylene glycol (PEG) molecular mass, PEG and salt concentrations, and volume ratio (Vr, volume of top phase/volume of bottom phase) were evaluated in order to determine the conditions where dlRLP and contaminants concentrated to opposite phases. Two-stage ATPS consisting of PEG 400-phosphate with a Vr of 13.0 and a tie-line length (TLL) of 35% (w/w) at pH 7.0 provided the best conditions for processing highly concentrated crude extract from disrupted cells (dlRLP concentration of 5 microg/mL). In such conditions intracellular dlRLP accumulated in the top phase (recovery of 90%), whereas cell debris remained in the interface. Furthermore, dlRLP from culture supernatants accumulated preferentially in the interface (recovery of 82%) using ATPS with a Vr of 1.0, pH of 7.0, PEG 3350 (10.1%, w/w) and phosphate (10.9%, w/w). The purity of dlRLP from culture supernatant increased up to 55 times after ATPS. The use of ATPS resulted in a recovery process that produced dlRLP with a purity between 6 and 11% and an overall product yield of 85% (w/w), considering purification from intracellular and extracellular dlRLP. Overall, the strategy proposed in this study is simpler than traditional methods for recovering dlRLP, and represents a scalable and economically viable alternative for production processes of vaccines against rotavirus infection with significant scope for generic commercial application.