Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation.

Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.

Anomalous Transport Signatures in Weyl Semimetals with Point Defects.

We present the first theoretical study of transport properties of Weyl semimetals with point defects. Focusing on a class of time-reversal symmetric Weyl lattice models, we show that dilute lattice vacancies induce a finite density of quasilocalized states at and near the nodal energy, causing strong modifications to the low-energy spectrum. This generates novel transport effects, namely, (i) an oscillatory behavior of the dc conductivity with the charge carrier density in the absence of magnetic fields, and (ii) a plateau-shaped dissipative optical response for photon frequencies below the interband threshold, E_{F}≲ℏω≲2E_{F}. Our results provide a path to engineer unconventional quantum transport effects in Weyl semimetals by means of common point defects.

Platelet proteome reveals features of cell death, antiviral response and viral replication in covid-19.

Coronavirus disease 2019 (COVID-19) has affected over 400 million people worldwide, leading to 6 million deaths. Among the complex symptomatology of COVID-19, hypercoagulation and thrombosis have been described to directly contribute to lethality, pointing out platelets as an important SARS-CoV-2 target. In this work, we explored the platelet proteome of COVID-19 patients through a label-free shotgun proteomics approach to identify platelet responses to infection, as well as validation experiments in a larger patient cohort. Exclusively detected proteins (EPs) and differentially expressed proteins (DEPs) were identified in the proteomic dataset and thus classified into biological processes to map pathways correlated with pathogenesis. Significant changes in the expression of proteins related to platelet activation, cell death, and antiviral response through interferon type-I were found in all patients. Since the outcome of COVID-19 varies highly among individuals, we also performed a cross-comparison of proteins found in survivors and nonsurvivors. Proteins belonging to the translation pathway were strongly highlighted in the nonsurvivor group. Moreover, the SARS-CoV-2 genome was fully sequenced in platelets from five patients, indicating viral internalization and preprocessing, with CD147 as a potential entry route. In summary, platelets play a significant role in COVID-19 pathogenesis via platelet activation, antiviral response, and disease severity.

Human endogenous retrovirus K in the respiratory tract is associated with COVID-19 physiopathology.

BACKGROUND: Critically ill 2019 coronavirus disease (COVID-19) patients under invasive mechanical ventilation (IMV) are 10 to 40 times more likely to die than the general population. Although progression from mild to severe COVID-19 has been associated with hypoxia, uncontrolled inflammation, and coagulopathy, the mechanisms involved in the progression to severity are poorly understood. METHODS: The virome of tracheal aspirates (TA) from 25 COVID-19 patients under IMV was assessed through unbiased RNA sequencing (RNA-seq), and correlation analyses were conducted using available clinical data. Unbiased sequences from nasopharyngeal swabs (NS) from mild cases and TA from non-COVID patients were included in our study for further comparisons. RESULTS: We found higher levels and differential expression of human endogenous retrovirus K (HERV-K) genes in TA from critically ill and deceased patients when comparing nasopharyngeal swabs from mild cases to TA from non-COVID patients. In critically ill patients, higher HERV-K levels were associated with early mortality (within 14 days of diagnosis) in the intensive care unit. Increased HERV-K expression in deceased patients was associated with IL-17-related inflammation, monocyte activation, and an increased consumption of clotting/fibrinolysis factors. Moreover, increased HERV-K expression was detected in human primary monocytes from healthy donors after experimental SARS-CoV-2 infection in vitro. CONCLUSION: Our data implicate the levels of HERV-K transcripts in the physiopathology of COVID-19 in the respiratory tract of patients under invasive mechanical ventilation. Video abstract.

Basis-independent spectral methods for non-linear optical response in arbitrary tight-binding models.

In this paper, we developed a basis-independent perturbative method for calculating the non-linear optical response of arbitrary non-interacting tight-binding models. Our method is based on the non-equilibrium Keldysh formalism and allows an efficient numerical implementation within the framework of the kernel polynomial method for systems which are not required to be translation-invariant. Some proof-of-concept results of the second-order optical conductivity are presented for the special case of gapped graphene with vacancies and an on-site Anderson disordered potential.

The Perfect Appetizer: A Pharmacological Strategy for a Non-biting Mosquito.

New possibilities for vector-borne disease control are revealed by Duvall et al. (2019), who link host-seeking behavioral modulation in Aedes aegypti to neuropeptide Y (NPY)-like receptor 7. Small-molecule screening yields agonist compounds able to activate NPYLR7 and suppress attraction to hosts.

Treating low back pain with combined cerebral and peripheral electrical stimulation: A randomized, double-blind, factorial clinical trial.

BACKGROUND: Recent evidence suggests that chronic low back pain is associated with plastic changes in the brain that can be modified by neuromodulation strategies. This study investigated the efficacy of transcranial direct current stimulation (tDCS) combined simultaneously with peripheral electrical stimulation (PES) for pain relief, disability and global perception in patients with chronic low back pain (CLBP). METHODS: Ninety-two patients with CLBP were randomized to receive 12 sessions on nonconsecutive days of anodal tDCS (primary motor cortex, M1), 100 Hz sensory PES (lumbar spine), tDCS + PES or sham tDCS + PES. Pain intensity (11-point numerical rating scale), disability and global perception were applied before treatment and four weeks, three months and six months post randomization. RESULTS: A two points reduction was achieved only by the tDCS + PES (mean reduction [MR] = -2.6, CI95% = -4.4 to -0.9) and PES alone (MR = -2.2, CI95% = -3.9 to -0.4) compared with the sham group, but not of tDCS alone (MR = -1.7, CI95% = -3.4 to -0.0). In addition to maintaining the analgesic effect for up to three months, tDCS + PES had a higher proportion of respondents in different cutoff points. Global perception was improved at four weeks and maintained three months after treatment only with tDCS + PES. None of the treatments improved disability and the affective aspect of pain consistently with pain reduction. CONCLUSION: The results suggest that tDCS + PES and PES alone are effective in relieving CLBP in the short term. However, only tDCS + PES induced a long-lasting analgesic effect. tDCS alone showed no clinical meaningful pain relief. SIGNIFICANCE: Transcranial direct current stimulation combined simultaneously with PES leads to a significant and clinical pain relief that can last up to three months in chronic low back pain patients. For this article, a commentary is available at the Wiley Online Library.

Efeitos de sessões educativas no uso das mochilas escolares em estudantes do ensino fundamental I / Effects of educational sessions on school backpack use among elementary school students

OBJETIVO: Avaliar a modificação na quantidade de carga transportada, o modelo e o modo de transportar mochilas escolares após sessões educativas. MÉTODOS: Estudo de uma série de casos, com 99 crianças de sete a 11 anos do ensino fundamental, em escola particular da cidade São Paulo, São Paulo. Foram avaliadas a massa corporal (kg) e estatura dos alunos (cm), quantidade de carga transportada nas mochilas (kg). Os modelos e os modos de transporte das mochilas foram avaliados por filmagem pré e pós-intervenção. Como medida de intervenção, os sujeitos (crianças, pais e professores) foram submetidos a uma sessão educativa, que consistiu de orientações teóricas sobre coluna vertebral e transporte de carga. Para os escolares foi adicionada orientação prática das posturas corretas no transporte de carga. Os escolares receberam um reforço prático mensal por três meses. Pais e professores receberam reforço em folheto informativo e orientações na homepage da escola. Os dados foram analisados pelos testes estatísticos de igualdade de duas proporções e Wilcoxon. O nível de significância adotado foi 5 por cento. RESULTADOS: O modelo de mochila modificou para duas alças de 46,5 por cento para 60,6 por cento (p=0,046), modo de transporte para ombro bilateral de 41,4 por cento para 55,6 por cento (p=0,047). A carga transportada nas mochilas diminuiu 2,66kg (p<0,001) e a relação massa corporal do sujeito e carga transportada nas mochilas diminuiu 7 por cento. Na modificação por categorias, o número de alunos do grupo inadequado (carga transportada>15 por cento da massa corporal do aluno) diminuiu (p<0,001). CONCLUSÕES: As sessões educativas promoveram mudanças na utilização de mochilas, revelando adesão satisfatória ao modelo de intervenção proposto entre os escolares e o importante papel da Fisioterapia na saúde escolar.

OBJECTIVE: To evaluate the changes in loads carried, in the model of backpack used and in the way of carrying school backpacks after the implementation of an educational program. METHODS: This study was performed on 99 children aged seven to 11 years at elementary school level in a private school in São Paulo, São Paulo, Brazil. The subjects' body mass (kg) and height (cm) and the loads carried in their backpacks (kg) were evaluated. The backpack models and the ways of carrying them were evaluated by filming before and after the intervention. The intervention program consisted of educational sessions offered to the children, parents and teachers. The sessions involved lectures about the spine and about the principles of load carrying. The children also received practical guidance relating to correct postures for load carrying. The children received monthly practical reinforcement for three months. The parents and teachers received reinforcement by means of information flyers and guidance on the school's home page. The data were analyzed by means of two-proportion equality and Wilcoxon statistical tests. The significance level was considered as α=0.05. RESULTS: The use of a two-strap backpack model increased from 46.5 percent to 60.6 percent (p=0.046) and carrying it on two shoulders increased from 41.4 percent to 55.6 percent (p=0.047). The load carried in the backpacks decreased by 2.66kg (p<0.001) and the ratio between the subject's body mass and the load carried in the backpacks decreased by 7 percent. With regard to change per category, the number of subjects in the inappropriate group (load carried>15 percent of the subject's body mass) decreased (p<0.001). CONCLUSIONS: The educational sessions promoted changes in backpack use and it was observed a satisfactory adherence to the intervention program proposed. These results demonstrate the importance of Physical Therapy educational programs in schoolchildren's health.

Qualitative postural analysis among boys and girls of seven to ten years of age / Análise postural qualitativa entre meninos e meninas de sete a dez anos de idade

BACKGROUND: Postural abnormalities are often found in children. At this stage of life, posture undergoes many adjustments and adaptations due to body changes. Objective: To qualitatively identify the postural abnormalities which occur most frequently among children aged OBJECTIVE: Reven and ten years, comparing boys and girls, and to evaluate these subjects' lumbar flexibility. METHODS: One hundred and ninety-one children were photographed in the sagittal and frontal planes. The variables analyzed were: ankle (valgus and varus), tibiotarsal angle (opened and closed), knee (hyperextension and semiflexion, valgus and varus), pelvis (anteversion and retroversion; lateral pelvic inclination), trunk (antepulsion and retropulsion), lumbar spine (hyperlordosis and rectification), thoracic spine (hyperkyphosis and rectification), cervical spine (hyperlordosis and rectification), scoliosis, shoulder (imbalance and protraction), scapula (winged, abducted and adducted) and head (tilt and protraction). The lumbar flexibility was assessed using Schõber's index. RESULTS: The boys had greater incidence of winged scapula, shoulder imbalance, protraction of shoulders and head and cervical hyperlordosis than the girls did. Conversely, the girls had greater incidence of head tilt and larger Schõber index values. CONCLUSIONS: There were abnormalities in children's postural development that are probably related to muscle, skeletal and flexibility differences between the genders. These differences may influence each child's postural pattern during growth.

CONTEXTUALIZAÇÃO: Alterações posturais são freqüentemente encontradas em crianças. Nessa fase, a postura sofre uma série de ajustes e adaptações às mudanças no próprio corpo. OBJETIVO: Identificar, de maneira qualitativa, quais as alterações posturais mais freqüentes em crianças entre sete e dez anos, comparando meninos e meninas, e avaliar a flexibilidade lombar desses sujeitos. MATERIAIS E MÉTODOS: Cento e noventa e uma crianças foram fotografadas nos planos frontal e sagital. As variáveis analisadas foram: tornozelo (valgo e varo), ângulo tíbio-társico (aberto e fechado), joelho (hiperextensão e semiflexão, valgo e varo), pelve (anteversão e retroversão, inclinação pélvica lateral), tronco (antepulsão e retropulsão), lombar (hiperlordose e retificação), torácica (hipercifose e retificação), cervical (hiperlordose e retificação), escoliose, ombro (desnível e protração), escápula (alada, abduzida e aduzida) e cabeça (inclinada e protraída). A flexibilidade da coluna lombar foi avaliada pelo índice de Schõber. RESULTADOS: Os meninos mostraram maior incidência de escápula alada, desnível de ombros, protração de ombros e cabeça e hiperlordose cervical do que as meninas. Por sua vez, as meninas apresentaram maior incidência de inclinação de cabeça e maior valor para o índice de Schõber. CONCLUSÕES: Existem alterações no desenvolvimento postural das crianças que podem estar relacionadas a diferenças, entre os sexos, no sistema muscular, esquelético e na flexibilidade. Estas diferenças podem influenciar o padrão postural do indivíduo durante o crescimento.

Caracterização postural da jovem praticante de ginástica olímpica / Postural characterization of young participants in Olympic gymnastics

OBJETIVO: Identificar as alterações posturais em crianças praticantes de ginástica olímpica, com idade entre 8 e 12 anos. MÉTODOS: Foram avaliadas 84 estudantes, 38 praticantes de ginástica olímpica e 46 não praticantes, com idade entre 8 e 12 anos. Foram realizadas fotografias de cada criança nos planos frontal anterior e posterior e plano sagital. As fotos foram analisadas através do software Corel Draw, v. 11.0, utilizando as ferramentas linhas-guia e dimensão (dimensão angular, dimensão vertical e dimensão horizontal), visando determinar os parâmetros das 19 variáveis qualitativas e 5 variáveis quantitativas. RESULTADOS: Ao comparar os sujeitos do grupo teste (GT) com os sujeitos do grupo controle (GC), observa-se diferença estatisticamente significante nas variáveis rotação medial de fêmur (GC 56,52 por cento; GT 39,47 por cento), antepulsão de pelve (GC 43,48 por cento; GT 76,32 por cento) e rotação de tronco (GC 67,39 por cento; GT 23,68 por cento). Observa-se também diferença significante em relação às medidas de valgo de joelho (GC 4,06 ± 2,32 cm; GT 3,14 ± 1,49cm), desnível de pelve (GC 0,69 ± 0,39 cm; GT 0,53 ± 0,33cm) e ângulo tíbio-társico (GC 86,93 ± 2,90 cm; GT 87,11 ± 4,17 cm). CONCLUSÃO: Ao analisar os resultados, nota-se uma tendência ao melhor alinhamento dos membros inferiores no grupo teste quando comparado ao grupo controle. Há um aumento da inclinação pélvica anterior e uma tendência ao aumento da hiperlordose lombar no grupo teste, fatores que podem predispor a praticante de ginástica olímpica a um desalinhamento sobre as estruturas esqueléticas, levando a quadros dolorosos, limitando a sua vida esportiva.

OBJECTIVE: To identify the postural alterations among children aged 8 to 12 years who perform Olympic gymnastics. METHOD: Eighty-four students aged 8 to 12 years were assessed: 38 who were participating in Olympic gymnastics and 46 who were not. Each child was photographed in the anterior and posterior frontal planes and in the sagittal plane. The photos were analyzed using the CorelDraw v. 11.0 software. The line-guide and dimension tools (angular, vertical and horizontal dimensions) were used to determine the parameters of the nineteen qualitative and five quantitative variables. RESULTS: Comparison between the test group subjects (TG) and control group subjects (CG) showed significant differences in the variables of medial rotation of the femur (CG 56.52 percent; TG 39.47 percent), antepulsion of the pelvis (CG 43.48 percent; TG 76.32 percent) and trunk rotation (CG 67.39 percent; TG 23.68 percent). There were also found significant differences in the measurements of knee valgism (CG 4.06 ± 2.32 cm; TG 3.14 ± 1.49 cm), pelvic inclination (CG 0.69 ± 0.39 cm; TG 0.53 ± 0.33 cm) and tibiotarsal angle (CG 86.93 ± 2.90 cm; TG 87.11 ± 4.17 cm). CONCLUSION: Analysis of the results showed a tendency towards better alignment of the lower limbs in the test group than in the control group. There was greater anterior pelvic inclination and a tendency towards lumbar hyperlordosis in the test group. These factors may predispose individuals participating in Olympic gymnastics to misalignment of skeletal structures, thereby leading to painful conditions that may limit their sports activities.

Avaliação das perdas sensório-motoras do pé e tornozelo decorrentes da neuropatia diabética / Assessment of motor sensory losses in the foot and ankle due to diabetic neuropathy

OBJETIVOS: Identificar déficits sensório-motores de pés de pacientes diabéticos neuropatas e comparar os déficits do grupo neuropata com um grupo de sujeitos saudáveis. MÉTODO: 49 diabéticos neuropatas (GD) e 22 controles foram submetidos a um protocolo de três estágios: (1) entrevista por meio de questionário, que caracterizou a neuropatia e sintomas, (2) avaliação da função muscular, amplitude de movimentos e testes funcionais dos pés e tornozelos, (3) avaliação da sensibilidade tátil e térmica. Os grupos foram comparados por meio dos testes Qui-quadrado, Mann-Withney e Teste T (p<0,05). RESULTADOS: O GD mostrou perda significativa das sensibilidades tátil e térmica em comparação ao grupo controle, principalmente nos calcanhares (49,0 por cento no GD e 97,3 por cento no GC). A função muscular está diminuída no GD, com predomínio da perda do grau 5. Os músculos mais afetados são os interósseos (23,4 por cento), extensor do hálux (42,5 por cento) e tríceps sural (43,2 por cento), enquanto que o GC teve todos os músculos preservados. Todas as ADMs do GD estão diminuídas em relação ao GC. O GD apresentou os testes funcionais de tornozelo diminuídos em 50 por cento. CONCLUSÃO: Houve diferenças significativas entre os grupos quanto às perdas sensitivas, de função muscular, amplitude de movimento e funcionais. Essas diferenças podem ser atribuídas à neuropatia diabética.

OBJECTIVE: To identify motor sensory deficits in the feet of neuropathic diabetic patients and compare their deficits with a group of healthy subjects. METHOD: 49 neuropathic diabetics (group NG) and 22 controls (group CG) underwent a three-stage protocol: (1) an interview using a questionnaire to characterize the neuropathy and symptoms; (2) assessment of muscle function and range of motion, and functional tests on the feet and ankles; (3) assessment of tactile and thermal sensitivity. The groups were compared using the chi-squared, Mann-Whitney and Student t tests (p<0.05). RESULTS: NG presented significant losses of tactile and thermal sensitivity in comparison with CG, especially in the heels (49.0 percent of NG and 97.3 percent of CG). Muscle function was decreased in NG, with predominance of loss of grade 5. The muscles most affected were the interossei (23.4 percent), extensor hallucis (42.5 percent) and triceps surae (43.2 percent), while all muscle function was preserved in CG. All ranges of motion in NG were reduced in comparison with CG. The functional tests on the ankles in NG presented a decrease of around 50 percent. CONCLUSION: There were significant differences between the groups with regard to sensitivity, muscle function, range of motion and functional losses. These differences can be attributed to the diabetic neuropathy.

The biological clock of an hematophagous insect: locomotor activity rhythms, circadian expression and downregulation after a blood meal.

Despite the importance of circadian rhythms in vector-borne disease transmission, very little is known about its molecular control in hematophagous insect vectors. In Drosophila melanogaster, a negative feedback loop of gene expression has been shown to contribute to the clock mechanism. Here, we describe some features of the circadian clock of the sandfly Lutzomyia longipalpis, a vector of visceral leishmaniasis. Compared to D. melanogaster, sandfly period and timeless, two negative elements of the feedback loop, show similar peaks of mRNA abundance. On the other hand, the expression of Clock (a positive transcription factor) differs between the two species, raising the possibility that the different phases of Clock expression could be associated with the observed differences in circadian activity rhythms. In addition, we show a reduction in locomotor activity after a blood meal, which is correlated with downregulation of period and timeless expression levels. Our results suggest that the circadian pacemaker and its control over the activity rhythms in this hematophagous insect are modulated by blood intake.

Pain evaluation of patients with fibromyalgia, osteoarthritis, and low back pain.

UNLABELLED: The purpose of this study was to evaluate and compare pain as reported by outpatients with fibromyalgia, osteoarthritis, and low back pain, in view of designing more adequate physical therapy treatment. PATIENTS AND METHODS: A Portuguese version of the McGill Pain Questionnaire - where subjects are asked to choose, from lists of pre-categorized words, one or none that best describes what they feel - was used to assess pain intensity and quality of 64 patients, of which 24 had fibromyalgia, 22 had osteoarthritis, and 18 had low back pain. The pre-categorized words were organized into 4 major classes - sensory, affective, evaluative, and miscellaneous. RESULTS: Patients with fibromyalgia reported, comparatively, more intense pain through their choice of pain descriptors, both sensory and affective; they also chose a higher number of words from these classes than patients in the other groups and were the only ones to choose specific affective descriptors such as "vicious", "wretched", "exhausting", "blinding". CONCLUSION: Assuming that each disease presents unique qualities of pain experience, and that these can be pointed out by means of this questionnaire by patients' choice of specific groups of words, the findings suggest that fibromyalgia include not only a physical component, but also a psycho-emotional component, indicating that they require both emotional/affective and physical care.