Except for Robust Outliers, Rapamycin Increases Lesion Burden in a Murine Model of Cerebral Cavernous Malformations.

Cerebral cavernous malformation (CCM) is a hemorrhagic cerebrovascular disease where lesions develop in the setting of endothelial mutations of CCM genes, with many cases also harboring somatic PIK3CA gain of function (GOF) mutations. Rapamycin, an mTORC1 inhibitor, inhibited progression of murine CCM lesions driven by Ccm gene loss and Pik3ca GOF, but it remains unknown if rapamycin is beneficial in the absence of induction of Pik3ca GOF. We investigated the effect of rapamycin at three clinically relevant doses on lesion development in the Ccm3-/-PDGFb-icreERPositive murine model of familial CCM disease, without induction of Pik3ca GOF. Lesion burden, attrition, and acute and chronic hemorrhaging were compared between placebo and rapamycin-treated mice. Plasma miRNome was compared to identify potential biomarkers of rapamycin response. Outlier, exceptionally large CCM lesions (> 2 SD above the mean lesion burden) were exclusively observed in the placebo group. Rapamycin, across all dosages, may have prevented the emergence of large outlier lesions. Yet rapamycin also appeared to exacerbate mean lesion burden of surviving mice when outliers were excluded, increased attrition, and did not alter hemorrhage. miR-30c-2-3p, decreased in rapamycin-treated mouse plasma, has gene targets in PI3K/AKT and mTOR signaling. Progression of outlier lesions in a familial CCM model may have been halted by rapamycin treatment, at the potential expense of increased mean lesion burden and increased attrition. If confirmed, this can have implications for potential rapamycin treatment of familial CCM disease, where lesion development may not be driven by PIK3CA GOF. Further studies are necessary to determine specific pathways that mediate potential beneficial and detrimental effects of rapamycin treatment, and whether somatic PIK3CA mutations drive particularly aggressive lesions.

Computational modeling of decision-making in substance abusers: testing Bechara's hypotheses.

One of the cognitive abilities most affected by substance abuse is decision-making. Behavioral tasks such as the Iowa Gambling Task (IGT) provide a means to measure the learning process involved in decision-making. To comprehend this process, three hypotheses have emerged: (1) participants prioritize gains over losses, (2) they exhibit insensitivity to losses, and (3) the capacity of operational storage or working memory comes into play. A dynamic model was developed to examine these hypotheses, simulating sensitivity to gains and losses. The Linear Operator model served as the learning rule, wherein net gains depend on the ratio of gains to losses, weighted by the sensitivity to both. The study further proposes a comparison between the performance of simulated agents and that of substance abusers (n = 20) and control adults (n = 20). The findings indicate that as the memory factor increases, along with high sensitivity to losses and low sensitivity to gains, agents prefer advantageous alternatives, particularly those with a lower frequency of punishments. Conversely, when sensitivity to gains increases and the memory factor decreases, agents prefer disadvantageous alternatives, especially those that result in larger losses. Human participants confirmed the agents' performance, particularly when contrasting optimal and sub-optimal outcomes. In conclusion, we emphasize the importance of evaluating the parameters of the linear operator model across diverse clinical and community samples.

Three-dimensional histology reveals dissociable human hippocampal long-axis gradients of Alzheimer's pathology.

INTRODUCTION: Three-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without a magnetic resonance imaging (MRI) reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer's disease. METHODS: Blockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space. RESULTS: Path2MR successfully registered histological sections to their anatomic position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, whereas amyloid-beta (Aß) displayed a quadratic anterior-posterior distribution. CONCLUSION: Path2MR, which enables 3D histology using any brain bank data set, revealed significant differences along the hippocampus between tau and Aß. HIGHLIGHTS: Path2MR enables three-dimensional (3D) brain reconstruction from blockface dissection photographs. This pipeline does not require dense specimen sampling or a subject-specific magnetic resonance (MR) image. Anatomically consistent mapping of hippocampal sections was obtained with Path2MR. Our analyses revealed an anterior-posterior gradient of hippocampal tau pathology. In contrast, the peak of amyloid-beta (Aß) deposition was closer to the hippocampal body.

A single rapid heat stress episode does not result in prolonged elevations in salivary cortisol and C-reactive protein production in firefighters.

In the present experiment, we evaluated the impact of rapid heat stress (RHS) on salivary cortisol and C-reactive protein production pre-RHS, post-RHS, and 24 and 48 h post-RHS exposure among firefighters. Previous research has demonstrated that RHS increases salivary cortisol during RHS and immediately post-RHS exposure. However, no research has evaluated the duration necessary to return to baseline cortisol levels following RHS. Additionally, no studies have analyzed the impact of RHS on inflammatory biomarkers, such as C-reactive protein. This study hypothesized that salivary cortisol and C-reactive protein levels would increase following RHS and then return to pre-RHS levels within 24 h post-exposure. Twenty-four participants performed a steady-state treadmill protocol in an environmental chamber (35 °C; 45% humidity) in full firefighter personal protective equipment until reaching either a core temperature (Tc) of 39 °C or a volitional maximum. The subjects had their saliva collected via the passive drool protocol pre-RHS, post-RHS, and 24 and 48 h post-RHS. Pre-RHS of 0.23 ± 0.03 µg/dL increased post-RHS to 0.51 ± 0.06 µg/dL (p < 0.001). This finding supports previous literature demonstrating the immediate impact of RHS. There were no changes in C-reactive protein. The novel finding of this study is that salivary cortisol levels return to baseline in the 24 h post-RHS exposure. This indicates that 24 h is recommended to recover from RHS and should be applied to prevent the chronic stress response.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Video Abstract.

Barley MLA3 recognizes the host-specificity effector Pwl2 from Magnaporthe oryzae.

Plant nucleotide-binding leucine-rich repeat (NLRs) immune receptors directly or indirectly recognize pathogen-secreted effector molecules to initiate plant defense. Recognition of multiple pathogens by a single NLR is rare and usually occurs via monitoring for changes to host proteins; few characterized NLRs have been shown to recognize multiple effectors. The barley (Hordeum vulgare) NLR gene Mildew locus a (Mla) has undergone functional diversification, and the proteins encoded by different Mla alleles recognize host-adapted isolates of barley powdery mildew (Blumeria graminis f. sp. hordei [Bgh]). Here, we show that Mla3 also confers resistance to the rice blast fungus Magnaporthe oryzae in a dosage-dependent manner. Using a forward genetic screen, we discovered that the recognized effector from M. oryzae is Pathogenicity toward Weeping Lovegrass 2 (Pwl2), a host range determinant factor that prevents M. oryzae from infecting weeping lovegrass (Eragrostis curvula). Mla3 has therefore convergently evolved the capacity to recognize effectors from diverse pathogens.

Impulsivity and sexual addiction: factor structure and criterion-related validity of the sexual addiction screening test in Mexican adults.

Sexual addiction is associated with serious health problems. Due to that fact, it is quite important to perform a comprehensive assessment. The Sex Addiction Screening Test (SAST-R) is a self-administered questionnaire with good psychometric properties used in several countries. Our study conducts a cross-cultural adaptation of the SAST-R on the Mexican population. The original version of the SAST-R was translated into Mexican Spanish, and we performed a pilot with 23 participants to be sure that the participants understood the meaning of the items. The final version was administered to 370 adults who completed the SAST-R, and measures of impulsivity (the Kirby questionnaire), reward/punishment responsivity (BIS-BAS scale), personality (BIG-Five), and psychological distress (SCL-90). The confirmatory factor analysis (CFA) with a five-factor model with one second-order factor model had the best fit. Reliability analysis suggests acceptable internal consistency (α = 0.80). The SAST-R scores exhibited significant correlations with several variables. Specifically, they showed a positive correlation with the neuroticism scale (r = 0.11, p < 0.05), a negative correlation with the conscientiousness scale (r = -0.21, p < 0.01), a negative correlation with the BIS scale (r = -0.11, p < 0.05), and a positive correlation with psychological distress (r = 0.34, p < 0.01). Notably, there were no significant correlations observed with variables that we initially expected to have a substantial association, such as impulsivity (r = -0.004, p > 0.05) and the three BAS subscales (p > 0.05). We found with an algorithm that psychological distress, impulsivity, neuroticism, and agreeableness were the good predictors to identify high scores of hypersexuality. Our results confirmed that the Mexican Spanish version of the SAST-R has good psychometric properties to be used in future research.

Three-dimensional histology reveals dissociable human hippocampal long axis gradients of Alzheimer's pathology.

INTRODUCTION: Three-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without an MRI reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer's Disease. METHODS: Blockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space. RESULTS: Path2MR successfully registered histological sections to their anatomical position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, while amyloid-ß displayed a quadratic anterior-posterior distribution. CONCLUSION: Path2MR, which enables 3D histology using any brain bank dataset, revealed significant differences along the hippocampus between tau and amyloid-ß.

Localized T3 production modifies the transcriptome and promotes the hepatocyte-like lineage in iPSC-derived hepatic organoids.

Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we studied human induced pluripotent stem cell-derived (iPSC-derived) hepatic organoids and identified a robust induction of DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in DIO2-T3 (the deiodinase that activates thyroxine [T4] to triiodothyronine [T3]) persists until the hepatoblasts differentiate into hepatocyte- or cholangiocyte-like cells, neither of which expresses DIO2. Preventing the induction of the DIO2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in DIO2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.

To produce or not to produce? Contrasting the effect of substance abuse in social decision-making situations.

Substance use disorders (SUD) have been related to high criminal justice costs, expensive healthcare, social impairment, and decision-making deficits. In non-social decision-making tasks, people with SUD tend to take more risks and choose small immediate rewards than controls. However, few studies have explored how people with SUD behave in social decision-making situations where the resources and profits depend directly on participants' real-time interaction, i.e., social foraging situations. To fulfill this gap, we developed a real-time interaction task to (a) compare the proportion of producers (individuals who tend to search for food sources) and scroungers (individuals who tend to steal or join previously discovered food sources) among participants with SUD and controls with respect to the optimal behavior predicted by the Rate Maximization Model, and (b) explore the relationship between social foraging strategies, prosocial behavior, and impulsivity. Here participants with SUD (n = 20) and a non-user control group (n = 20) were exposed to the Guaymas Foraging task (GFT), the Social Discounting task (SD), and the Delay Discounting task (DD). We found that participants in the control group tended to produce more and obtain higher profits in contrast to substance abuser groups. Additionally, SD and DD rates were higher for scroungers than producers regardless of the group. Our results suggest that producers tend to be more altruistic and less impulsive than scroungers. Knowing more about social strategies and producers' characteristics could help develop substance abuse prevention programs.

Efectividad antimicrobiana de los sistemas adhesivos. Una alternativa eficaz: revisión bibliográfica / Antimicrobial effectiveness of adhesive systems. An effective alternative: literature review / Eficácia antimicrobiana dos sistemas adesivos. Uma alternativa eficaz: revisão da literatura

RESUMEN Los sistemas adhesivos se utilizan en la práctica clínica diaria; sin embargo, su principal desventaja es la contracción por polimerización que podría ocasionar la aparición de microfiltraciones, acumulo de placa, caries secundaria e hipersensibilidad. Por este motivo, se han venido incorporando agentes antimicrobianos, como el metacrilato de amonio cuaternario fotopolimerizable, los rellenos de vidrio que liberan iones de flúor, el pirogalol y las nanopartículas de plata, calcio y grafeno fluorado. En los últimos años, algunos de estos han demostrado tener una buena efectividad antimicrobiana, que, a su vez, no interfieren con la adhesión en las restauraciones. De tal manera, estos sistemas adhesivos antimicrobianos podrían favorecer a obtener mejores resultados a largo plazo. Las nanopartículas que presentaron mejores resultados fueron el fosfato de calcio amorfo y las compuestas de plata.

ABSTRACT Adhesive systems are used in daily clinical practice; however, the main disadvantage is polymerization shrinkage, which could lead to microleakage, plaque accumulation, secondary caries, and hypersensitivity. For this reason, antimicrobial agents have been incorporated, such as light-curing quaternary ammonium methacrylate, fluoride ion-releasing glass fillers, pyrogallol, and nanoparticles of silver, calcium, and fluorinated graphene. In recent years, some of these have been shown to have good antimicrobial effectiveness and, in turn, do not interfere with adhesion in restorations. Thus, these antimicrobial adhesive systems could contribute to better long-term results. The best-performing nanoparticles were amorphous calcium phosphate and silver nanoparticles.

RESUMO Os sistemas adesivos são utilizados na prática clínica diária; no entanto, a principal desvantagem é a contração da polimerização, que pode levar a microinfiltração, acumulação de placa, cáries secundárias e hipersensibilidade. Por este motivo, foram incorporados agentes antimicrobianos, como o metacrilato de amónio quaternário fotopolimerizável, cargas de vidro que libertam iões de flúor, pirogalol e nanopartículas de prata, cálcio e grafeno fluorado. Nos últimos anos, algumas destas substâncias demonstraram ter uma boa eficácia antimicrobiana e não interferem com a adesão nas restaurações. Assim, estes sistemas adesivos antimicrobianos poderiam conduzir a melhores resultados a longo prazo. As nanopartículas com melhor desempenho foram o fosfato de cálcio amorfo e as nanopartículas de prata.

Optimism, Resilience, and Infertility-Specific Stress during Assisted Reproductive Technology / El optimismo, la resiliencia y el estrés especifico por infertilidad en la aplicación de las técnicas de reproducción asistida

Background: Infertility generates high levels of stress to women. The aim was to explore optimism and resilience among women undergoing assisted reproductive technology (ART). Method: Participants were recruited in a private fertility clinic. The sample consisted of 229 women under medical treatment for fertility who completed the following self-report instruments: a sociodemographic and clinical questionnaire, Resilience Scale (RS), Life Orientation Test (LOT-R), Perceived Stress Scale (PSS), and STAI State and STAI Trait. Results: Our data revealed that high resilience levels were associated with a reduced psychological stress (β = .02, p < .001, 95% CI [.34, .13]). A significant negative correlation between perceived stress and resilience (r = -.320, p = .001) was found. Conclusion: The findings highlight the protective mediating role of resilience when women are confronted with the negative effects of infertility diagnosis and assisted reproductive technology (ART), and therefore the potential utility of resilience to reduce infertility-specific stress. (AU)

Antecedentes: La infertilidad genera un nivel de estrés elevado en la mujer. El objetivo era explorar el optimismo y la resiliencia en las mujeres que se someten a técnicas de reproducción asistida (TRA). Método: Los participantes fueron reclutados en una clínica de fertilidad privada. La muestra estuvo conformada por 229 mujeres en tratamiento médico para de fertilidad que cumplimentaron los siguientes instrumentos de autoinforme: cuestionario sociodemográfico y clínico, Escala de Resiliencia (RS), Test de Orientación a la Vida (LOT-R), Escala de Estrés Percibido (PSS) y STAI Estado y Rasgo. Resultados: Los datos revelaron que un nivel elevado de resiliencia se asociaba con menos estrés psicológico (β = .02, p < .001, IC del 95 % [.34, .13]). Se obtuvo una correlación negativa significativa entre estrés percibido y resiliencia (r = -.320, p = .001). Conclusión: Los hallazgos resaltan el papel mediador protector de la resiliencia cuando las mujeres se enfrentan a los efectos negativos del diagnóstico de infertilidad y las técnicas de reproducción asistida (TRA) y, por lo tanto, la utilidad potencial de la resiliencia para reducir el estrés específico de la infertilidad. (AU)

Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically-defined features is unknown. We investigated pre-mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia-associated pathologies. METHODS: We analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow-up and post-mortem neuropathological evaluation, including HS assessment in the hippocampal head and body. RESULTS: Significant HS-associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy. DISCUSSION: HS-associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD. HIGHLIGHTS: Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre-mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.

Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically-defined features is unknown. We investigated pre-mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia-associated pathologies. METHODS: We analyzed hippocampal volumes from MRI segmentations in 64 dementia patients with longitudinal MRI follow-up and post-mortem neuropathological evaluation, including HS assessment in the hippocampal head and body. RESULTS: Significant HS-associated hippocampal volume changes were observed thoughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer’s Disease (AD) burden, and specifically driven by CA1 and subiculum. AD burden, but not HS, significantly associated with the rate of hippocampal atrophy. DISCUSSION: HS-associated volume changes are detectable on MRI earlier than 10 years before death. These findings could contribute to the derivation of volumetric cut-offs for in vivo differentiation between HS and AD.

A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. METHODS: We studied 159 brain donations from the multimodal Vallecas Alzheimer's Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data. RESULTS: Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. DISCUSSION: The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS. HIGHLIGHTS: The definition of hippocampal sclerosis of aging (HS) is currently limited to an end-stage pathological fingerprint. We characterize early HS histological features to define a complete staging system. The proposed staging displays a parallel but not identical progression to limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). The proposed staging also reflects the expected demographic and cognitive differences associated with HS. In vivo magnetic resonance imaging (MRI) showed focal hippocampal gray matter loss as a function of HS staging.

Versatilidad del colgajo nasogeniano basado en perforantes de la arteria facial en reconstrucción facial / Versatility of the nasolabial flap based on facial artery perforators in facial reconstruction

Se conocen varios colgajos locales basados en la arteria facial al momento de reconstruir unidades estéticas faciales. Levantar estos colgajos basados en las ramas perforantes de la arteria facial, los hace más finos, móviles, fiables, y adaptables, y la posibilidad de realizarlos en un solo tiempo quirúrgico. El propósito de este estudio es demostrar nuestra experiencia con el colgajo perforante de la arteria facial en reconstrucciones faciales de defectos hasta tamaño de 5x4cm, utilizando su pedículo superior o su pedículo inferior. Método. Realizamos un estudio longitudinal retrospectivo con 15 pacientes de ambos sexos, con edades comprendidas entre 40 a 60 años, a quienes se realizó el colgajo perforante facial en un solo tiempo quirúrgico. Los defectos faciales tratados fueron de tamaño pequeño a mediano, localizados en subunidades de la mejilla, nariz, pliegue nasolabial, labios superior e inferior. Resultados. De los 15 pacientes de nuestro estudio, 13 evolucionaron sin complicaciones (84.6%); 1 paciente concurrió con leve dehiscencia de herida (7.7%) y 1 paciente al que se le realizó un colgajo de 5x4cm concurrió con una mínima necrosis en la parte distal del colgajo (7.7%). Estas complicaciones fueron leves y con resolución ambulatoria, sin requerir otro tiempo quirúrgico. Conclusiones: Gracias a su libertad de movimiento, este colgajo nos permite reconstruir varias unidades estéticas, y por su delgado espesor, mínimas complicaciones y una cicatriz de la zona dadora que se camufla en el surco nasogeniano, los resultados tanto funcionales como estéticos son superiores comparados con los tradicionales colgajos locales miocutáneos nasolabiales.

Several local flaps based on the facial artery are well known when reconstructing facial aesthetic units. Making these flaps based on the perforating branches of the facial artery makes them thinner, more mobile, reliable, and adaptable, and the possibility of performing them in a single surgical time. The purpose of this study is to demonstrate our experience with the perforating vessel of the facial artery flap, in facial reconstructions of defects up to a size of 5x4 cm, using its upper or lower pedicle. Method. We carried out a retrospective longitudinal study with 15 patients of both sexes, aged between 40 and 60 years, who underwent the facial artery perforator flap in a single surgical time. The facial defects treated were small to medium in size, located in subunits of the cheek, nose, nasolabial fold, upper and lower lips. Results. The complications that we obtained when doing this flap were hematoma, partial dehiscence of the suture and slight venous congestion. All of these were mild and with outpatient resolution, without requiring another surgical time. Conclusions. Due to its freedom of movement, this flap allows us to reconstruct several aesthetic units, and due to its thin thickness and with minimal complications, both functional and aesthetic results are superior compared to traditional nasolabial myocutaneous flaps.

Digital Pregnancy Test Powered by an Air-Breathing Paper-Based Microfluidic Fuel Cell Stack Using Human Urine as Fuel.

The direct integration of paper-based microfluidic fuel cells (µFC's) toward creating autonomous lateral flow assays has attracted attention. Here, we show that an air-breathing paper-based µFC could be used as a power supply in pregnancy tests by oxidizing the human urine used for the diagnosis. We present an air-breathing paper-based µFC connected to a pregnancy test, and for the first time, as far as we know, it is powered by human urine without needing any external electrolyte. It uses TiO2-Ni as anode and Pt/C as cathode; the performance shows a maximum value of voltage and current and power densities of ∼0.96 V, 1.00 mA cm-2, and 0.23 mW cm-2, respectively. Furthermore, we present a simple design of a paper-based µFC's stack powered with urine that shows a maximum voltage and maximum current and power densities of ∼1.89 V, 2.77 mA cm-2 and 1.38 mW cm-2, respectively, which powers the display of a pregnancy test allowing to see the analysis results.

Targeted therapy for breast cancer: An overview of drug classes and outcomes.

The last 25 years have seen significant growth in new therapeutic options for breast cancer, termed targeted therapies based on their ability to block specific pathways known to drive breast tumor growth and survival. Introduction of these drugs has been made possible through advances in the understanding of breast cancer biology. While the promise of targeted therapy for breast cancer has been clear for some time, the experience of the clinical use of multiple drugs and drug classes allows us to now present a summary and perspective as to the success and impact of this endeavor. Here we will review breast cancer targeted therapeutics in clinical use. We will provide the rationale for their indications and summarize clinical data in patients with different breast cancer subtypes, their impact on breast cancer progression and survival and their major adverse effects. The focus of this review will be on the development that has occurred within classes of targeted therapies and subsequent impact on breast cancer patient outcomes. We will conclude with a perspective on the role of targeted therapy in breast cancer treatment and highlight future areas of development.

The barley leaf rust resistance gene Rph3 encodes a predicted membrane protein and is induced upon infection by avirulent pathotypes of Puccinia hordei.

Leaf rust, caused by Puccinia hordei, is an economically significant disease of barley, but only a few major resistance genes to P. hordei (Rph) have been cloned. In this study, gene Rph3 was isolated by positional cloning and confirmed by mutational analysis and transgenic complementation. The Rph3 gene, which originated from wild barley and was first introgressed into cultivated Egyptian germplasm, encodes a unique predicted transmembrane resistance protein that differs from all known plant disease resistance proteins at the amino acid sequence level. Genetic profiles of diverse accessions indicated limited genetic diversity in Rph3 in domesticated germplasm, and higher diversity in wild barley from the Eastern Mediterranean region. The Rph3 gene was expressed only in interactions with Rph3-avirulent P. hordei isolates, a phenomenon also observed for transcription activator-like effector-dependent genes known as executors conferring resistance to Xanthomonas spp. Like known transmembrane executors such as Bs3 and Xa7, heterologous expression of Rph3 in N. benthamiana induced a cell death response. The isolation of Rph3 highlights convergent evolutionary processes in diverse plant-pathogen interaction systems, where similar defence mechanisms evolved independently in monocots and dicots.