Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth (CMT) disease is classified considering the neurophysiological and histological findings, the inheritance pattern and the underlying genetic defect. In recent years, with the advent of next generation sequencing, genetic complexity has increased exponentially, expanding the knowledge about disease pathways, and having an impact in clinical management. The aim of this guide is to offer recommendations for the diagnosis, prognosis, monitoring and treatment of this disease in Spain. MATERIAL AND METHODS: This consensus guideline has been developed by a multidisciplinary panel encompassing a broad group of professionals including neurologists, neuropediatricians, geneticists, rehabilitators, and orthopaedic surgeons. RECOMMENDATIONS: The diagnosis is based in the clinical characterization, usually presenting with a common phenotype. It should be followed by an appropriate neurophysiological study that allows for a correct classification, specific recommendations are established for the parameters that should be included. Genetic diagnosis must be approached in sequentially, once the PMP22 duplication has been ruled out if appropriate, a next generation sequencing should be considered taking into account the limitations of the available techniques. To date, there is no pharmacological treatment that modifies the course of the disease, but symptomatic management is important, as are the rehabilitation and orthopaedic considerations. The latter should be initiated early to identify and improve the patient's functional impairments, including individualised exercise guidelines, orthotic adaptation, and assessment of conservative surgeries such as tendon transpositions. The follow-up of patients with CMT is exclusively clinical, ancillary testing are not necessary in routine clinical practice.

Inherited SCN1A missense mutation in a Dravet Syndrome family: Neuropathological correlation, family screening and implications for adult carriers.

INTRODUCTION: Neuropathological findings in Dravet Syndrome (DS) are scarce, especially in adult patients, and often do not have a genetic confirmation. Additionally, the missense SCN1A pathogenic variant found has only been described as de novo mutation in previous literature. METHODS: We describe the clinical and genetic findings of a family (including three sisters and his father), using Sanger sequencing in the three sisters and in postmortem brain tissue in the father. The present study also shows the neuropathological findings of the father. RESULTS: Despite the presence of long term drug resistant epilepsy, starting with febrile seizures between 6 and 12 months of age, and intellectual disability (ID), the three sisters were diagnosed with DS in adulthood, identifying a missense SCN1A pathogenic variant in exon 20, previously described as de novo -p.Gly1332Glu (c .3995 G>A). The oldest sister had the most severe phenotype, with severe ID and wheel chair dependency, passing away at 52. The other two sisters had a moderate phenotype, being at the present seizure free, but with significant comorbidities, such as crouch gait and parkinsonism. Several relatives from the paternal path (including the father) presented epilepsy, but without ID. The father was diagnosed with Alzheimer´s Disease (AD) at 60, and because he donated his brain, the same variant was confirmed in postmortem study. Neither the MRI nor the histopathology showed specific morphological changes for DS, consistent with previous studies. CONCLUSIONS: This work supports the need to review the clinical and genetic spectra of DS in adults with epilepsy and unknown ID. The clinical consequences of this syndrome seem to have a functional rather than a structural basis, supported by the absence of specific neuropathological findings.

Tuberculosis in Spain: An opinion paper.

This document is the result of the deliberations of the Committee on Emerging Pathogens and COVID-19 of the Illustrious Official College of Physicians of Madrid (ICOMEM) regarding the current situation of tuberculosis, particularly in Spain. We have reviewed aspects such as the evolution of its incidence, the populations currently most exposed and the health care circuits for the care of these patients in Spain. We have also discussed latent tuberculosis, the reality of extrapulmonary disease in the XXI century and the means available in daily practice for the diagnosis of both latent and active forms. The contribution of molecular biology, which has changed the perspective of this disease, was another topic of discussion. The paper tries to put into perspective both the classical drugs and their resistance figures and the availability and indications of the new ones. In addition, the reality of direct observation in the administration of antituberculosis drugs has been discussed. All this revolution is making it possible to shorten the treatment time for tuberculosis, a subject that has also been reviewed. If everything is done well, the risk of relapse of tuberculosis is small but it exists. On the other hand, many special situations have been discussed in this paper, such as tuberculosis in pediatric age and tuberculosis as a cause for concern in surgery and intensive care. The status of the BCG vaccine and its present indications as well as the future of new vaccines to achieve the old dream of eradicating this disease have been discussed. Finally, the ethical and medicolegal implications of this disease are not a minor issue and our situation in this regard has been reviewed.

Advantages and disadvantages of maintaining the mandatory use of masks in health centers and nursing homes in Spain. How and when is it justified to maintain it?

We address the advantages and disadvantages of maintaining the mandatory use of masks in health centers and nursing homes in the current epidemiological situation in Spain and after the declaration of the World Health Organization on May 5, 2023 of the end of COVID-19 as public health emergency. We advocate for prudence and flexibility, respecting the individual decision to wear a mask and emphasizing the need for its use when symptoms suggestive of a respiratory infection appear, in situations of special vulnerability (such as immunosuppression), or when caring for patients with those infections. At present, given the observed low risk of severe COVID-19 and the low transmission of other respiratory infections, we believe that it is disproportionate to maintain the mandatory use of masks in a general way in health centers and nursing homes. However, this could change depending on the results of epidemiological surveillance and it would be necessary to reconsider returning to the obligation in periods with a high incidence of respiratory infections.

Increased frequency of CD14+HLA-DR-/low cells in type 2 diabetes patients with poor glycemic control.

AIMS: Type 2 diabetes (T2DM) is associated with alterations of the immune response and T2DM patients have an increased risk for infections and certain sorts of cancers. Although CD14+HLA-DR-/low cells have emerged as important mediators of immunosuppression in several pathologies, including cancer and non-malignant diseases, the presence of these cells in T2DM is not fully characterized. METHODS: In this study, we evaluated the frequency of CD14+HLA-DR-/low cells in non-obese T2DM patients and their association with glycemic control. Peripheral blood mononuclear cells were isolated from healthy controls (HC, n = 24) and non-obese T2DM patients (n = 25), the population was evaluated by flow cytometry, and an analysis of correlation between cell frequencies and clinical variables was performed. RESULTS: CD14+HLA-DR-/low monocytes were expanded in patients with T2DM compared to HC regardless of weight. Among the subjects with T2DM, the frequency of CD14+HLA-DR-/low was higher in patients with poor glycemic control (HbA1c > 9%) compared to those with better glycemic control (HbA1c < 9%) and, positively correlated with the years since the diagnosis of T2DM, the age of the patients and the glycemic index. CONCLUSIONS: An increased frequency of CD14+HLA-DR-/low cells in the blood of T2DM patients was recorded. The influence of hyperglycemia seems to be independent of obesity, but related to glycemic control and age.

On the Thermal Models for Resistive Random Access Memory Circuit Simulation.

Resistive Random Access Memories (RRAMs) are based on resistive switching (RS) operation and exhibit a set of technological features that make them ideal candidates for applications related to non-volatile memories, neuromorphic computing and hardware cryptography. For the full industrial development of these devices different simulation tools and compact models are needed in order to allow computer-aided design, both at the device and circuit levels. Most of the different RRAM models presented so far in the literature deal with temperature effects since the physical mechanisms behind RS are thermally activated; therefore, an exhaustive description of these effects is essential. As far as we know, no revision papers on thermal models have been published yet; and that is why we deal with this issue here. Using the heat equation as the starting point, we describe the details of its numerical solution for a conventional RRAM structure and, later on, present models of different complexity to integrate thermal effects in complete compact models that account for the kinetics of the chemical reactions behind resistive switching and the current calculation. In particular, we have accounted for different conductive filament geometries, operation regimes, filament lateral heat losses, the use of several temperatures to characterize each conductive filament, among other issues. A 3D numerical solution of the heat equation within a complete RRAM simulator was also taken into account. A general memristor model is also formulated accounting for temperature as one of the state variables to describe electron device operation. In addition, to widen the view from different perspectives, we deal with a thermal model contextualized within the quantum point contact formalism. In this manner, the temperature can be accounted for the description of quantum effects in the RRAM charge transport mechanisms. Finally, the thermometry of conducting filaments and the corresponding models considering different dielectric materials are tackled in depth.

Antimicrobial peptides in domestic animals and their applications in veterinary medicine.

Antimicrobial peptides (AMPs) are molecules with a broad-spectrum activity against bacteria, fungi, protozoa, and viruses. These peptides are widely distributed in insects, amphibians and mammals. Indeed, they are key molecules of the innate immune system with remarkable antimicrobial and immunomodulatory activity. Besides, these peptides have also shown regulatory activity for gut microbiota and have been considered inductors of growth performance. The current review describes the updated findings of antimicrobial peptides in domestic animals, such as bovines, goats, sheep, pigs, horses, canines and felines, analyzing the most relevant aspects of their use as potential therapeutics and their applications in Veterinary medicine.

Immune checkpoint inhibitors in endometrial cancer.

The incidence of endometrial cancer (EC) is increasing worldwide. The prognosis for patients diagnosed with early-stage remains good, whereas for patients with recurrent or metastatic disease, the prognosis is poor and treatment options, until recently, were limited. In 2017, pembrolizumab was approved by the US Food and Drug Administration (FDA) for those patients with mistmach repair deficiency (MMRd) or high microsatellite instability (MSI-H) tumors. However, only 20-30 % of EC have MSI, and just over half of these patients benefit from treatment. In 2019, the FDA granted breakthrough therapy designation to lenvatinib in combination with pembrolizumab for the potential treatment of patients with advanced microsatellite stable EC that has progressed after treatment with at least one previous systemic therapy. It appears clear that immune check-point inhibitors will have a definite place in the management of EC, both as single agent or in combination with other targeted agents. In this review, we summarize the current evidence of immune check point blockade and the identification of potential biomarkers, beyond MSI-H or MMRd, that could help to predict response to this agents in correlation with the genomic EC subtypes.

Age estimation in north east Brazilians by measurement of open apices.

Dental age (DA) estimation is an extensively investigated resource used by forensic science. This study aimed to evaluate the applicability of the Measurement of Open Apices for DA estimation in north east Brazilians. A total of 429 orthopantomographs of individuals aged 5 to 14.99 years were used. The sample was distributed according to the age groups 5-6.99, 7-8.99, 9-10.99, 11-12.99 and 13-14.99 years, and the data were analyzed descriptively and by linear regression (α= 5%). The majority of the radiographs were from females (n = 241; 56.2%), with an overall mean age of 12 years (± 2.12). A significant difference was observed between DA and chronological age (CA) in the total sample and specifically in females and males. The method underestimated CA by 0.31 year (total sample) and by 0.3 and 0.32 year in females and males, respectively. In contrast, the method overestimated CA in the groups 5-6.99 and 7-8.99 years, with a mean difference (MD) of 0.48 year (p = 0.007) and 0.17 year (p = 0.182), respectively. In the other groups, DA was predicted to be below CA, with a significant difference in the group 13-14.99 (0.75 year). Based on the regression analysis, a correction factor was proposed from the original formula for this population, thereby reaching a predictive power of approximately 80%. To conclude, this method is applicable to the study population aged 5 to 13 years as the estimates obtained did not exceed the error limit of ±1 year.

First record of the parasitoid wasp Lymeon sp. (Ichneumonidae: Cryptinae) associated with spider eggs-sac of Araneus vincibilis (Araneae: Araneidae) in Northeastern Brazil / Primeiro registro da vespa parasitóide Lymeon sp. (Ichneumonidae: Cryptinae) associada ao ovissaco da aranha Araneus vincibilis (Araneae: Araneidae) no Nordeste do Brasil

Abstract Lymeon Förster, 1869 is a very large genus of the Cryptinae (Ichneumonidae) with predominantly Neotropical distribution where females attack small cocoons of various groups of insects and spider eggs-sac. In the present study, we report the first record the interaction between the parasitoid wasp Lymeon sp. (Ichneumonidae), with eggs-sac of spider Araneus vincibilis (Araneidae) in Northeastern Brazil. We observed that although the female of A. vincibilis cares for the eggs that were attacked by Lymeon sp, the wasp larva consumed about 80% of spider eggs, indicating that both maternal care and the physical barrier offered by the eggs-sac may not provide absolute defense against predators.

Resumo Lymeon Förster, 1869 é um grande gênero de Cryptinae (Ichneumonidae) com distribuição predominantemente neotropical, onde fêmeas atacam pequenos casulos de vários grupos de insetos e ovissacos de aranha. No presente estudo, relatamos o primeiro registro da interação entre a vespa parasitoide Lymeon sp. (Ichneumonidae), com o ovissaco da aranha Araneus vincibilis (Araneidae) no Nordeste do Brasil. Observamos que, embora a fêmea de A. vincibilis cuide dos ovos que foram atacados por Lymeon sp, a larva da vespa consumiu cerca de 80% dos ovos da aranha, indicando que tanto o cuidado maternal quanto a barreira física oferecida pelo ovissaco não podem fornecer defesa absoluta contra predadores.

Type 2 diabetes mellitus metabolic control correlates with the phenotype of human monocytes and monocyte-derived macrophages.

AIMS: Monocytes and macrophages express cell-surface markers indicative of their inflammatory and activation status. In this study, we investigated whether these markers are affected or correlated in non-obese T2D subjects, or glycemic/metabolic control variables. METHODS: Clinical data was recorded, and peripheral blood drawn from T2D patients (n = 28) and control subjects (n = 27). Isolated monocytes were evaluated by flow cytometry for the expression of CD14, CD16, and the phenotypic markers for the different states of activation spectrum, such as pro-inflammatory (M1) (HLA-DR, CD86), anti-inflammatory/pro-resolving (M2) (CD163, CD206, MERTK, PD-L1) and metabolically-activated (MMe) (CD36, ABCA-1). From a subset of individuals, monocytes-derived macrophages (MDM) were obtained and evaluated for phenotypic markers. A correlation analysis was performed between the clinical variables and the marker expression. RESULTS: The frequency of CD14++CD16- monocytes was lower in T2D patients and it correlates negatively with poor control in glycemic and metabolic variables. T2D monocytes expressed lower levels of HLA-DR, CD86, PD-L1, and CD163, which correlated negatively with poor metabolic control. In MDM from T2D patients, HLA-DR, CD86 and CD163 expression was lower and it inversely correlated with deficient glycemic or metabolic control parameters. CONCLUSION: The glycemic/metabolic control associated with T2D influences monocyte and MDM phenotypes toward an immune-suppressive phenotype.

First record of the parasitoid wasp Lymeon sp. (Ichneumonidae: Cryptinae) associated with spider eggs-sac of Araneus vincibilis (Araneae: Araneidae) in Northeastern Brazil.

Lymeon Förster, 1869 is a very large genus of the Cryptinae (Ichneumonidae) with predominantly Neotropical distribution where females attack small cocoons of various groups of insects and spider eggs-sac. In the present study, we report the first record the interaction between the parasitoid wasp Lymeon sp. (Ichneumonidae), with eggs-sac of spider Araneus vincibilis (Araneidae) in Northeastern Brazil. We observed that although the female of A. vincibilis cares for the eggs that were attacked by Lymeon sp, the wasp larva consumed about 80% of spider eggs, indicating that both maternal care and the physical barrier offered by the eggs-sac may not provide absolute defense against predators.

Nicotine modulates molecules of the innate immune response in epithelial cells and macrophages during infection with M. tuberculosis.

Smoking increases susceptibility to becoming infected with and developing tuberculosis. Among the components of cigarette smoke, nicotine has been identified as the main immunomodulatory molecule; however, its effect on the innate immune system is unknown. In the present study, the effect of nicotine on molecules of the innate immune system was evaluated. Lung epithelial cells and macrophages were infected with Mycobacterium tuberculosis (Mtb) and/or treated with nicotine. The results show that nicotine alone decreases the expression of the Toll-like receptors (TLR)-2, TLR-4 and NOD-2 in all three cell types, as well as the production of the SP-D surfactant protein in type II pneumocytes. Moreover, it was observed that nicotine decreases the production of interleukin (IL)-6 and C-C chemokine ligand (CCL)5 during Mtb infection in epithelial cells (EpCs), whereas in macrophages derived from human monocytes (MDMs) there is a decrease in IL-8, IL-6, tumor necrosis factor (TNF)-α, IL-10, CCL2, C-X-C chemokine ligand (CXCL)9 and CXCL10 only during infection with Mtb. Although modulation of the expression of cytokines and chemokines appears to be partially mediated by the nicotinic acetylcholine receptor α7, blocking this receptor found no effect on the expression of receptors and SP-D. In summary, it was found that nicotine modulates the expression of innate immunity molecules necessary for the defense against tuberculosis.

Cheiloscopy in individuals with Down syndrome and their nonsyndromic biological siblings.

The study aimed to carry out a comparative analysis between the lip print patterns in individuals with Down Syndrome and their nonsyndromic biological siblings. This was a cross-sectional blind study using an inductive approach and extensive direct observation procedures. A total of 68 cheiloscopic charts, named cheilograms, were divided into two groups (n=34), as follows: G1, including Down Syndrome individuals; and G2, including their nonsyndromic siblinggs. The convenience sample was selected in the city of João Pessoa, PB, Brazil. The following features were evaluated in eight labial regions called sub-quadrants: oral commissures (downturned, horizontal and upturned); lip thickness (thin, medium, thick and mixed); and labial grooves (I - complete vertical; I '- incomplete vertical; II - bifurcated; III - criss-cross; IV - reticular; or V - undefined). The data were analyzed by paired Student's t test and McNemar's Chi-square, with a 5% significance level. Most Down Syndrome individuals were found to have downturned oral commissures in 73.5% of cases, while their siblings showed a predominance of horizontal commissures in 73.5% of cases (p=0.009). There was no statistically significant difference for lip thickness between groups. In the analysis of labial groove patterns, Down Syndrome individuals (G1) showed a significant prevalence of the type I pattern (52.2%) as compared to their nonsyndromic siblings (30.1%) (p =< 0.001). Due to the tendency of having vertical labial groove patterns and downturned commissures, Down Syndrome individuals present cheiloscopic differences in relation to their nonsyndromic biological siblings, which suggests that syndromic genetics influences the development of these features. However, this may imply in a reduced potential of cheiloscopic identification due to the low divergence of labial phenotypes among Down Syndrome individuals.

Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates and humans.

Targeting genes to specific neuronal or glial cell types is valuable for both understanding and repairing brain circuits. Adeno-associated viruses (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is an unsolved problem. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that a number of these AAVs specifically target expression to neuronal and glial cell types in the mouse and non-human primate retina in vivo and in the human retina in vitro. We demonstrate applications for recording and stimulation, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.

Diferenciar la apendicitis con o sin fecalito ¿puede cambiar el enfoqueterapéutico?: Resultados preliminares / Differentiating between appendicitis with or without fecalith to change the therapeutic approach: Preliminary results

Antecedentes: el manejo de los pacientes con apendicitis aguda fue clásicamente quirúrgico. En la era de los antibióticos se plantean nuevos paradigmas terapéuticos. La diferencia en el origen de la apendicitis podría establecer el tratamiento por elegir. Objetivo: analizar si la presencia de fecalito en una apendicitis puede condicionar un tratamiento quirúrgico o solo con antibióticos. Material y métodos: análisis descriptivo observacional de las diferencias intraoperatorias y anatomopatológicas de los pacientes operados por apendicitis aguda, divididos en 2 grupos según presentaran fecalito o hiperplasia linfoidea como causa de origen. Se utilizó la prueba de Chi2 para la comparación de ambos grupos, tomando un valor de p<0,05. Resultados: el grupo de apendicitis por fecalito presentó un estadio más avanzado de la enfermedad, con líquido libre con más frecuencia (el 67% de los pacientes con apendicitis aguda por fecalito vs. el 18% en el grupo de apendicitis aguda por hiperplasia), en más de una localización (solo el grupo con fecalito presentó líquido en el fondo de saco de Douglas o en el resto del abdomen, en el 50% y 16,7% respectivamente), con características que variaron entre seroso y purulento y anatomopatológicamente presentaron mayor afectación de las capas histológicas (en el grupo hiperplasia la afectación hasta la mucosa fue 63,6% vs. 16,7%, mientras que en el grupo fecalito fue más frecuente la afectación hasta la serosa 66,6% vs. 27,3%). Conclusiones: los pacientes con apendicitis aguda por hiperplasia linfoidea tendrían menos complicaciones intraabdominales en el posoperatorio y podrían ser buenos candidatos a tratamiento médico solo con antibióticos, evitando la cirugía.

Background: Surgery is the traditional approach for patients with acute appendicitis. In the antibiotic era, new therapeutic paradigms are being proposed. The difference in the cause of appendicitis could establish the treatment of choice. Objective: to analyze if the presence of fecalith in an appendicitis can condition a surgical treatment or only with antibiotics. Material and methods: This observational analysis describes the intraoperative and pathological differences between patients undergoing surgery for acute appendicitis, divided into two groups according to the presence of fecalith or lymphoid hyperplasia as cause of the condition. The chi square test was used to compare the fecalith group versus the lymphoid hyperplasia group using a p value < 0.05. Results: The presence of fecaliths was more commonly associated with advanced stage of inflammation, presence of free peritoneal fluid (67% vs. 18% in the lymphoid hyperlasia group) and in more than one site (50% in the Douglas' pouch and 16.7% in the rest of the abdominal cavity). In this group, peritoneal fluid varied between serous and purulent and more appendiceal layers were involved (63.6% of mucous layer involvement in the lymphoid hyperplasia group vs. 16.7%, while serous compromise was more common in the fecalith group: 66.6% vs. 27.3%). Conclusions: Patients with acute appendicitis due to lymphoid hyperplasia could have lower rate of post-operative complications or could be good candidates for medical treatment with antibiotics alone, avoiding surgery.

Gastric carcinoid tumor after laparoscopic gastric banding: Case report of a patient with weight regain.

INTRODUCTION: Although carcinoid tumours are a rare gastrointestinal neoplasm with an incidence rate of 1-2.5 cases per 100 000 inhabitants, they are the most common neuroendocrine tumour of the stomach. PRESENTATION OF CASE: A 70-year-old-man consulted for epigastric pain and dyspepsia symptoms. His past medical and surgical history included obesity (BMI: 53.9 kg/m2), hypertension, hyperlipidemia, diabetes mellitus type 2, cardiac failure and a surgical treatment with laparoscopic gastric banding. For the analysis and control of the gastric banding an upper gastrointestinal endoscopy was performed evidencing many small polyps in the gastric antrum, body and fundus. The histopathological examination of the resected specimen revealed a well differentiated carcinoid. Laparoscopic surgery for the removal of the gastric banding and the subtotal gastrectomy leaving a small gastric remnant of approximately 2-cm in size similar to the pouch of a bypass was done. Twelve months after surgery the patient presented a body mass index of 36.6 kg /m2. DISCUSSION: Gastric carcinoid increased incidence among the obese population, although the causing mechanisms are not clear, yet it is likely that metabolic and hormonal effects of the obesity play a role. The resection may be performed either endoscopically when the lesions are small, or surgically according to the tumor type and size. CONCLUSION: The resective gastric bypass or gastrectomy with anastomosis by Roux- en- Y bypass may be considered as a treatment of choice for patients who after bariatric surgery were diagnosed with gastric carcinoid and weight regain.

Clinical implication of FMR1 intermediate alleles in a Spanish population.

FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X-associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA ≥ 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA ≥ 50CGGs remains to be further elucidated.

A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.

To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.

Causal evidence for retina-dependent and -independent visual motion computations in mouse cortex.

How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex.