An orthogonalized PYR1-based CID module with reprogrammable ligand-binding specificity.

Plants sense abscisic acid (ABA) using chemical-induced dimerization (CID) modules, including the receptor PYR1 and HAB1, a phosphatase inhibited by ligand-activated PYR1. This system is unique because of the relative ease with which ligand recognition can be reprogrammed. To expand the PYR1 system, we designed an orthogonal '*' module, which harbors a dimer interface salt bridge; X-ray crystallographic, biochemical and in vivo analyses confirm its orthogonality. We used this module to create PYR1*MANDI/HAB1* and PYR1*AZIN/HAB1*, which possess nanomolar sensitivities to their activating ligands mandipropamid and azinphos-ethyl. Experiments in Arabidopsis thaliana and Saccharomyces cerevisiae demonstrate the sensitive detection of banned organophosphate contaminants using living biosensors and the construction of multi-input/output genetic circuits. Our new modules enable ligand-programmable multi-channel CID systems for plant and eukaryotic synthetic biology that can empower new plant-based and microbe-based sensing modalities.

Sensory plastid-associated PsbP DOMAIN-CONTAINING PROTEIN 3 triggers plant growth- and defense-related epigenetic responses.

Sensory plastids are important in plant responses to environmental changes. Previous studies show that MutS HOMOLOG 1 (MSH1) perturbation in sensory plastids induces heritable epigenetic phenotype adjustment. Previously, the PsbP homolog DOMAIN-CONTAINING PROTEIN 3 (PPD3), a protein of unknown function, was postulated to be an interactor with MSH1. This study investigates the relationship of PPD3 with MSH1 and with plant environmental sensing. The ppd3 mutant displays a whole-plant phenotype variably altered in growth rate, flowering time, reactive oxygen species (ROS) modulation and response to salt, with effects on meristem growth. Present in both chloroplasts and sensory plastids, PPD3 colocalized with MSH1 in root tips but not in leaf tissues. The suppression or overexpression of PPD3 affected the plant growth rate and stress tolerance, and led to a heritable, heterogenous 'memory' state with both dwarfed and vigorous growth phenotypes. Gene expression and DNA methylome data sets from PPD3-OX and derived memory states showed enrichment in growth versus defense networks and meristem effects. Our results support a model of sensory plastid influence on nuclear epigenetic behavior and ppd3 as a second trigger, functioning within meristem plastids to recalibrate growth plasticity.

A Case of Dentatotomy for Pain and Spasticity and Systematic Review.

BACKGROUND: Surgical interventions for spasticity aim to improve motor function and pain in cases that are refractory to medical treatment. Ablation of the cerebellar dentate nucleus (dentatotomy) may be a useful alternative. CASE REPORT: A 55-year-old male patient with spasticity, secondary to a traumatic cervical spinal cord injury with quadriparesis, had bilateral lumbar DREZotomy with an improvement that lasted for 6 years. Ten years after the DREZotomy, a progressive increased spasticity manifested as spastic diplegia (Ashworth 4) and spontaneous muscle painful spasms (Penn 4), as well as spasticity in the upper extremities, predominantly on the right side (Ashworth 3). A right radio frequency dentatotomy was performed with intraoperative electrophysiological monitoring. Spasticity scales were applied at the following times: preoperative and at 1 and 8 months after surgery. During the first month, the patient presented a clear decrease in spasticity ipsilateral to the side of lesioning (Ashworth 1) and of painful spasms in the lower extremities (Penn 1). After 8 months, spasticity ipsilateral to the injury decreased even more to Ashworth (0), but a progressive increase in muscle spasms of lower extremities was observed (Penn 2). CONCLUSION: Stereotactic dentatotomy may be an effective surgical alternative for management of spasticity associated with painful spasms in selected patients.

Graph-based data integration from bioactive peptide databases of pharmaceutical interest: toward an organized collection enabling visual network analysis.

MOTIVATION: Bioactive peptides have gained great attention in the academy and pharmaceutical industry since they play an important role in human health. However, the increasing number of bioactive peptide databases is causing the problem of data redundancy and duplicated efforts. Even worse is the fact that the available data is non-standardized and often dirty with data entry errors. Therefore, there is a need for a unified view that enables a more comprehensive analysis of the information on this topic residing at different sites. RESULTS: After collecting web pages from a large variety of bioactive peptide databases, we organized the web content into an integrated graph database (starPepDB) that holds a total of 71 310 nodes and 348 505 relationships. In this graph structure, there are 45 120 nodes representing peptides, and the rest of the nodes are connected to peptides for describing metadata. Additionally, to facilitate a better understanding of the integrated data, a software tool (starPep toolbox) has been developed for supporting visual network analysis in a user-friendly way; providing several functionalities such as peptide retrieval and filtering, network construction and visualization, interactive exploration and exporting data options. AVAILABILITY AND IMPLEMENTATION: Both starPepDB and starPep toolbox are freely available at http://mobiosd-hub.com/starpep/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

What is the Evidence of Lymphoma in Patients with Prostheses Other Than Breast Implants?

INTRODUCTION: Medical devices such as hip, knee, breast, vascular prostheses, among others, are very useful in different pathologies. We cannot doubt that their use is a great tool, besides being an advance in medicine; they provide a change in the quality of life of many patients; however, they are not exempt from adverse reactions and events. METHODS: We conduct a systematic review about lymphoma in the presences of prostheses other than breast implants. RESULTS: We selected 21 publications with a total of 24 patients. The largest number of prostheses was related to long bones in a total of 13 prostheses. The most frequent symptoms were: pain (52%), inflammation (24%), visible or palpable mass 20%. The most frequent type of lymphoma was non-Hodgkin B cell lymphoma in 14 cases. DISCUSSION: The presence of microparticles make biological degradation and wear of the implants, with macrophage and lymphocyte activation and the consequent production of proinflammatory cytokines such as tumor necrosis factor α, interleukin-1ß, interleukin-6, and prostaglandin 2 (PGE2). CONCLUSION: Lymphoma is not a common disease in patients with prostheses, and more data are needed to identify risk factors and make proper diagnoses. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Specialized Plastids Trigger Tissue-Specific Signaling for Systemic Stress Response in Plants.

Plastids comprise a complex set of organelles in plants that can undergo distinctive patterns of differentiation and redifferentiation during their lifespan. Plastids localized to the epidermis and vascular parenchyma are distinctive in size, structural features, and functions. These plastids are termed "sensory" plastids, and here we show their proteome to be distinct from chloroplasts, with specialized stress-associated features. The distinctive sensory plastid proteome in Arabidopsis (Arabidopsis thaliana) derives from spatiotemporal regulation of nuclear genes encoding plastid-targeted proteins. Perturbation caused by depletion of the sensory plastid-specific protein MutS HOMOLOG1 conditioned local, programmed changes in gene networks controlling chromatin, stress-related phytohormone, and circadian clock behavior and producing a global, systemic stress response in the plant. We posit that the sensory plastid participates in sensing environmental stress, integrating this sensory function with epigenetic and gene expression circuitry to condition heritable stress memory.

Optimal selection of molecular descriptors for antimicrobial peptides classification: an evolutionary feature weighting approach.

BACKGROUND: Antimicrobial peptides are a promising alternative for combating pathogens resistant to conventional antibiotics. Computer-assisted peptide discovery strategies are necessary to automatically assess a significant amount of data by generating models that efficiently classify what an antimicrobial peptide is, before its evaluation in the wet lab. Model's performance depends on the selection of molecular descriptors for which an efficient and effective approach has recently been proposed. Unfortunately, how to adapt this method to the selection of molecular descriptors for the classification of antimicrobial peptides and the performance it can achieve, have only preliminary been explored. RESULTS: We propose an adaptation of this successful feature selection approach for the weighting of molecular descriptors and assess its performance. The evaluation is conducted on six high-quality benchmark datasets that have previously been used for the empirical evaluation of state-of-art antimicrobial prediction tools in an unbiased manner. The results indicate that our approach substantially reduces the number of required molecular descriptors, improving, at the same time, the performance of classification with respect to using all molecular descriptors. Our models also outperform state-of-art prediction tools for the classification of antimicrobial and antibacterial peptides. CONCLUSIONS: The proposed methodology is an efficient approach for the development of models to classify antimicrobial peptides. Particularly in the generation of models for discrimination against a specific antimicrobial activity, such as antibacterial. One of our future directions is aimed at using the obtained classifier to search for antimicrobial peptides in various transcriptomes.

Control of carotenoid biosynthesis through a heme-based cis-trans isomerase.

Plants synthesize carotenoids, which are essential for plant development and survival. These metabolites also serve as essential nutrients for human health. The biosynthetic pathway for all plant carotenoids occurs in chloroplasts and other plastids and requires 15-cis-ζ-carotene isomerase (Z-ISO). It was not known whether Z-ISO catalyzes isomerization alone or in combination with other enzymes. Here we show that Z-ISO is a bona fide enzyme and integral membrane protein. Z-ISO independently catalyzes the cis-trans isomerization of the 15-15' carbon-carbon double bond in 9,15,9'-cis-ζ-carotene to produce the substrate required by the subsequent biosynthetic-pathway enzyme. We discovered that isomerization depends upon a ferrous heme b cofactor that undergoes redox-regulated ligand switching between the heme iron and alternate Z-ISO amino acid residues. Heme b-dependent isomerization of a large hydrophobic compound in a membrane was previously undescribed. As an isomerase, Z-ISO represents a new prototype for heme b proteins and potentially uses a new chemical mechanism.

Evidence of Epigenetic Mechanisms Affecting Carotenoids.

Epigenetic mechanisms are able to regulate plant development by generating non-Mendelian allelic interactions. An example of these are the responses to environmenal stimuli that result in phenotypic variability and transgression amongst important crop traits. The need to predict phenotypes from genotypes to understand the molecular basis of the genotype-by-environment interaction is a research priority. Today, with the recent discoveries in the field of epigenetics, this challenge goes beyond analyzing how DNA sequences change. Here we review examples of epigenetic regulation of genes involved in carotenoid synthesis and degradation, cases in which histone- and/or DNA-methylation, and RNA silencing at the posttranscriptional level affect carotenoids in plants.

Systematic Identification of Machine-Learning Models Aimed to Classify Critical Residues for Protein Function from Protein Structure.

Protein structure and protein function should be related, yet the nature of this relationship remains unsolved. Mapping the critical residues for protein function with protein structure features represents an opportunity to explore this relationship, yet two important limitations have precluded a proper analysis of the structure-function relationship of proteins: (i) the lack of a formal definition of what critical residues are and (ii) the lack of a systematic evaluation of methods and protein structure features. To address this problem, here we introduce an index to quantify the protein-function criticality of a residue based on experimental data and a strategy aimed to optimize both, descriptors of protein structure (physicochemical and centrality descriptors) and machine learning algorithms, to minimize the error in the classification of critical residues. We observed that both physicochemical and centrality descriptors of residues effectively relate protein structure and protein function, and that physicochemical descriptors better describe critical residues. We also show that critical residues are better classified when residue criticality is considered as a binary attribute (i.e., residues are considered critical or not critical). Using this binary annotation for critical residues 8 models rendered accurate and non-overlapping classification of critical residues, confirming the multi-factorial character of the structure-function relationship of proteins.

[Tetanus, a current disease in pediatric population: Case report]. / Tétanos, una enfermedad vigente en población pediátrica: Reporte de un caso.

INTRODUCTION: Tetanus is an acute disease caused by a toxin produced by Clostridium tetanii. The disease can affect people of any age, and the fatality rate is high. Thanks to immunization the number of cases of the disease has decreased, although they are still present in isolation in countries with social and economic backwardness. OBJECTIVE: To describe a case of a pediatric patient with generalized tetanus to reinforce the relevance of prophylaxis and early detection. CASE REPORT: 6 years old female patient, with only one dose of pentavalent vaccine, 10 days after sharps injury by wood chips, starts with fever, muscle pain and generalized contractions, Tetanus was diagnosed by clinical symptoms and history. The management was based on the latest recommendations of the World Health Organization (WHO): Penicillin-Metronidazole antibiotic regimen, tetanus toxoid and tetanus high-dose gammaglobulin. After 2 years of follow-up under physiotherapy support, slight motor sequelae were observed. CONCLUSION: Tetanus is still presented in the pediatric population, associated with lack of vaccination. It is necessary to know the disease to provide proper diagnosis and management according to international lineaments.

Validation of the FRAIL scale in Mexican elderly: results from the Mexican Health and Aging Study.

BACKGROUND: The aging population in Latin America is characterized by not optimal conditions for good health, experiencing high burden of comorbidity, which contribute to increase the frequency of frailty; thus, identification should be a priority, to classify patients at high risk to develop its negative consequences. AIM: The objective of this analysis was to validate the FRAIL instrument to measure frailty in Mexican elderly population, from the database of the Mexican Health and Aging Study (MHAS). MATERIALS AND METHODS: Prospective, population study in Mexico, that included subjects of 60 years and older who were evaluated for the variables of frailty during the year 2001 (first wave of the study). Frailty was measured with the five-item FRAIL scale (fatigue, resistance, ambulation, illnesses, and weight loss). The robust, pre-frail or intermediate, and the frail group were considered when they had zero, one, and at least two components, respectively. Mortality, hospitalizations, falls, and functional dependency were evaluated during 2003 (second wave of the study). Relative risk was calculated for each complications, as well as hazard ratio (for mortality) through Cox regression model and odds ratio with logistic regression (for the rest of the outcomes), adjusted for covariates. RESULTS: The state of frailty was independently associated with mortality, hospitalizations, functional dependency, and falls. The pre-frailty state was only independently associated with hospitalizations, functional dependency, and falls. CONCLUSIONS: Frailty measured through the FRAIL scale, is associated with an increase in the rate of mortality, hospitalizations, dependency in activities of daily life, and falls.

[Pioglitazone hydrochloride a instrumental analytical perspective by Raman spectroscopy and HPLC]. / Clorhidrato de pioglitazona: una perspectiva analítico-instrumental por espectroscopia Raman y HPLC.

INTRODUCTION: The thiazolidinediones (pioglitazone) increases the action of insulin and produces the glycemic control in the patients with type 2 diabetes mellitus. Also, the pharmacological effect may be affected by the purity and pioglitazone plasma concentration. Therefore, the instrumental techniques offer a tool for characterization, identification and/or quantification of the pioglitazone; Raman spectroscopy offers several advantages due to its easy application methodology and structural analysis and the HPLC technique is the gold standard vs. other qualitative and quantitative techniques. OBJECTIVE: The aim of this work is to develop and validate analytical techniques for the characterization of pioglitazone hydrochloride by Raman spectroscopy and quantitative analysis in human plasma by HPLC. MATERIAL AND METHODS: The pioglitazone hydrochloride was analyzed by Raman spectroscopy with a 678 mW power and 3 integration time seconds. The analytical method for quantification by HPLC was validated with the guidelines of the NOM-177SSAl-1998. RESULTS: The Raman technique allowed us to elucidate the functional groups of the pioglitazone hydrochloride and the HPLC technique was linear, accurate, precise, specific and sensitive in the range of 30 to 2000 ng/mL under the chromatographic conditions specified. CONCLUSIONS: The structure analysis by Raman spectroscopy allowed us a complete characterization of the functional groups of pioglitazone hydrochloride effectively and non-destructively. Likewise, the analytical technique for the pioglitazone hydrochloride quantification by HPLC was linear, accurate, precise and sensitive in the range of 30 to 2000 ng/mL under the guidelines.

Synthetic reprogramming of plant developmental and biochemical pathways.

Plant synthetic biology (Plant SynBio) is an emerging field with the potential to enhance agriculture, human health, and sustainability. Integrating genetic tools and engineering principles, Plant SynBio aims to manipulate cellular functions and construct novel biochemical pathways to develop plants with new phenotypic traits, enhanced yield, and be able to produce natural products and pharmaceuticals. This review compiles research efforts in reprogramming plant developmental and biochemical pathways. We highlight studies leveraging new gene expression toolkits to alter plant architecture for improved performance in model and crop systems and to produce useful metabolites in plant tissues. Furthermore, we provide insights into the challenges and opportunities associated with the adoption of Plant SynBio in addressing complex issues impacting agriculture and human health.

Alveolar morphometry in young adults with and without agenesis of the upper lateral incisor: A retrospective study.

INTRODUCTION: We aimed to compare alveolar morphometry in young adults with agenesis of the upper lateral incisor versus the side without agenesis and versus matched controls. MATERIAL AND METHODS: In this observational retrospective study, cone beam computed tomography scans were obtained of 36 upper hemiarches from young adults aged 15 to 30 years. The hemiarches were distributed into three groups: group 1: 12 upper hemiarches presenting agenesis of the upper lateral incisor; group 2: 12 upper hemiarches from the opposite side without agenesis of the upper lateral incisor (control group 1); and group 3: 12 upper hemiarches without agenesis of the upper lateral incisor matched for age and sex with respect to the affected group (control group 2). A trained and calibrated investigator performed all the alveolar measurements at two different times, including sagittal, coronal and axial slices of each hemiarch. Paired Student's t-tests, Chi-square and repeated measures ANOVA with Bonferroni correction were used, (P<0.05). RESULTS: Apical mesial evaluation of group 1 (4.22±1.19mm) was significantly lower (P<0.001) than that of groups 2 (6.72±1.17mm) and 3 (7.58±1.67mm). Apical distal evaluation also showed differences (P<0.001) among the three groups, with the dimension being smaller in group 1 with agenesis (4.53±1.14mm), followed by group 2 without agenesis (6.23±1.55mm) and the healthy control group 3 (7.73±1.71mm). CONCLUSIONS: Lateral incisor agenesis significantly reduces the alveolar dimensions of the affected area. In cases of unilateral agenesis, the unaffected side also shows sequelae, with decreased dimensions compared to cases without agenesis. This condition should be taken into account when making therapeutic decisions regarding rehabilitation with implants or canine replacement.

Synergistic interactions between carotene ring hydroxylases drive lutein formation in plant carotenoid biosynthesis.

Plant carotenoids play essential roles in photosynthesis, photoprotection, and as precursors to apocarotenoids. The plastid-localized carotenoid biosynthetic pathway is mediated by well-defined nucleus-encoded enzymes. However, there is a major gap in understanding the nature of protein interactions and pathway complexes needed to mediate carotenogenesis. In this study, we focused on carotene ring hydroxylation, which is performed by two structurally distinct classes of enzymes, the P450 CYP97A and CYP97C hydroxylases and the nonheme diiron HYD enzymes. The CYP97A and HYD enzymes both function in the hydroxylation of ß-rings in carotenes, but we show that they are not functionally interchangeable. The formation of lutein, which involves hydroxylation of both ß- and ε-rings, was shown to require the coexpression of CYP97A and CYP97C enzymes. These enzymes were also demonstrated to interact in vivo and in vitro, as determined using bimolecular fluorescence complementation and a pull-down assay, respectively. We discuss the role of specific hydroxylase enzyme interactions in promoting pathway flux and preventing the formation of pathway dead ends. These findings will facilitate efforts to manipulate carotenoid content and composition for improving plant adaptation to climate change and/or for enhancing nutritionally important carotenoids in food crops.

Provitamin A accumulation in cassava (Manihot esculenta) roots driven by a single nucleotide polymorphism in a phytoene synthase gene.

Cassava (Manihot esculenta) is an important staple crop, especially in the arid tropics. Because roots of commercial cassava cultivars contain a limited amount of provitamin A carotenoids, both conventional breeding and genetic modification are being applied to increase their production and accumulation to fight vitamin A deficiency disorders. We show here that an allelic polymorphism in one of the two expressed phytoene synthase (PSY) genes is capable of enhancing the flux of carbon through carotenogenesis, thus leading to the accumulation of colored provitamin A carotenoids in storage roots. A single nucleotide polymorphism present only in yellow-rooted cultivars cosegregates with colored roots in a breeding pedigree. The resulting amino acid exchange in a highly conserved region of PSY provides increased catalytic activity in vitro and is able to increase carotenoid production in recombinant yeast and Escherichia coli cells. Consequently, cassava plants overexpressing a PSY transgene produce yellow-fleshed, high-carotenoid roots. This newly characterized PSY allele provides means to improve cassava provitamin A content in cassava roots through both breeding and genetic modification.

Prognostic factors of unilateral prelemniscal radiations radiofrequency lesions: A surgical technique for the treatment of Parkinson's disease motor symptoms.

OBJECTIVE: A group of patients with Parkinson's disease (PD) were managed with unilateral prelemniscal radiation radiofrequency lesions (U-Raprl). The current study aims to evaluate prognostic factors that could influence clinical response. METHODS: Patients previously diagnosed with PD managed with U-Raprl were included in the study, classifying them into two groups according to their percentage of clinical response ( 1.5), Age (p < 0.0001, ∆ = 2.38), Evolution (p < 0.0001, ∆ = 2.38), and post-operative UPDRS (p < 0.01, ∆ = 1.38). The qualitative analysis of the distribution regarding the responder group shows that those patients with an age under 58 years, an evolution fewer than 7 years, and a preoperative HYS score smaller than 2, showed a response ≥ 50% according to the UPDRS-III in all cases. CONCLUSION: U-Raprl is a highly effective procedure with a 5-year persistence of improvement. The most relevant prognostic factors to consider for a clinical response according to UPDRS-III greater than 50% are age under 58 years, less than 7 years of PD evolution, and HYS less or equal to 3.

High-Performance Cannabinoid Sensor Empowered by Plant Hormone Receptors and Antifouling Magnetic Nanorods.

The misuse of cannabinoids and their synthetic variants poses significant threats to public health, necessitating the development of advanced techniques for detection of these compounds in biological or environmental samples. Existing methods face challenges like lengthy sample pretreatment and laborious antifouling steps. Herein, we present a novel sensing platform using magnetic nanorods coated with zwitterionic polymers for the simple, rapid, and sensitive detection of cannabinoids in biofluids. Our technique utilizes the engineered derivatives of the plant hormone receptor Pyrabactin Resistance 1 (PYR1) as drug recognition elements and employs the chemical-induced dimerization (CID) mechanism for signal development. Additionally, the magnetic nanorods facilitate efficient target capture and reduce the assay duration. Moreover, the zwitterionic polymer coating exhibits excellent antifouling capability, preserving excellent sensor performance in complex biofluids. Our sensors detect cannabinoids in undiluted biofluids like serum, saliva, and urine with a low limit of detection (0.002 pM in saliva and few pM in urine and serum) and dynamic ranges spanning up to 9 orders of magnitude. Moreover, the PYR1 derivatives demonstrate high specificity even in the presence of multiple interfering compounds. This work opens new opportunities for sensor development, showcasing the excellent performance of antifouling magnetic nanorods that can be compatible with different recognition units, including receptors and antibodies, for detecting a variety of targets.

Innovative perspectives in limbic surgery using deep brain stimulation.

Limbic surgery is one of the most attractive and retaken fields of functional neurosurgery in the last two decades. Psychiatric surgery emerged from the incipient work of Moniz and Lima lesioning the prefrontal cortex in agitated patients. Since the onset of stereotactic and functional neurosurgery with Spiegel and Wycis, the treatment of mental diseases gave attention to refractory illnesses mainly with the use of thalamotomies. Neurosis and some psychotic symptoms were treated by them. Several indications when lesioning the brain were included: obsessive-compulsive disorder, depression, and aggressiveness among others with a diversity of targets. The indiscriminately use of anatomical sites without enough scientific evidence, and uncertainly defined criteria for selecting patients merged with a deficiency in ethical aspects, brought a lack of procedures for a long time: only select clinics allowed this surgery around the world from 1950 to the 1990s. In 1999, Nuttin et al. began a new chapter in limbic surgery with the use of Deep Brain Stimulation, based on the experience of pain, Parkinson's disease, and epilepsy. The efforts were focused on different targets to treat depression and obsessive-compulsive disorders. Nevertheless, other diseases were added to use neuromodulation. The goal of this article is to show the new opportunities to treat neuropsychiatric diseases.