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This study examines elements of the platinum group (PGE), primarily platinum and palladium, as geochemical indicators in the investigation of oil polygenesis. It has been found that, like other trace elements such as nickel, vanadium, and cobalt, platinum group elements and gold can occur in oil fields at both background levels and in elevated or even anomalously high concentrations. The objective of this research is to analyze PGE and trace elements as geochemical markers to identify the geological factors, including endogenous processes, responsible for these unusually high concentrations in oil. A comprehensive review of the literature on this subject was conducted, along with new data on the presence of precious metals in oils from Russia and globally. The study explores the geological mechanisms behind elevated PGE concentrations in oils, utilizing atomic absorption spectroscopy with atomization in the HGA-500 graphite furnace to measure PGE content. Previously, the tellurium co-deposition method (ISO 10478:1994) was used to isolate noble metals from associated elements. Possible geological origins of abnormally high concentrations of platinum metals in oils have been identified. These include endogenous factors such as the spatial proximity of oil fields to ultrabasic rock massifs, the effects of contact-metasomatic processes, and influences from mantle dynamics. Moreover, data concerning mantle elements can serve as indicators of the depth origins of certain hydrocarbon fluids, thus contributing to the study of oil polygenesis.

Abstract Background Epidemiological research on fractures in children under the age of two is of great importance to help understand differences between accidental and abusive trauma. Objective This systematic review aimed to evaluate studies reporting on the incidence of fractures in children under two years of age, excluding birth injuries. Secondary outcome measures included fracture location, mechanisms of injury and fracture characteristics. Methods A systematic literature review (1946 to February 7th 2024), including prospective and retrospective cohort studies and cross-sectional cohort studies, was performed. Studies including children from other age groups were included if the actual measures for those aged 0–2 years could be extracted. We also included studies restricted to infants. Annual incidence rates of fractures were extracted and reported as the main result. Critical appraisal of was performed using the Appraisal tool for Cross-Sectional Studies. Results Twelve moderate to good quality studies met eligibility criteria, of which seven were based on data from medical records and five were registry studies. Studies investigated different aspects of fractures, making comprehensive synthesis challenging. There was an overall annual fracture incidence rate of 5.3 to 9.5 per 1,000 children from 0–2 years of age; with commonest sites being the radius/ulna (25.2–40.0%), followed by tibia/fibula (17.3–27.6%) and the clavicle (14.6–14.8%) (location based on 3 studies with a total of 407 patients). In infants, the reported incidence ranged between 0.7 to 4.6 per 1,000 (based on 3 studies), with involvement of the clavicle in 22.2% and the distal humerus in 22.2% of cases (based on 1 study). Only a single metaphyseal lesion was reported (proximal humerus of an 11-month-old infant). Fracture mechanisms were detailed in four studies, with fall from chair, bed, table, own height or fall following indoor activities causing 50–60% of fractures. Conclusions There is a paucity of good quality data on fracture incidence in children under the age of two. Larger, prospective and unbiased studies would be helpful in determining normal pattern of injuries, so that differences from abusive trauma may be better understood.

Introduction: Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues. Methods: Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured. Results: Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01). Conclusion: ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.

IntroductionMigraines are the leading cause of disability in the United States, and the use of non-pharmaceutical treatments like osteopathic manipulative treatment (OMT) has shown promise. Despite its potential, the lack of mechanistic understanding has hindered widespread adoption. This study aims to investigate the efficacy of OMT in treating acute migraines and unravel its underlying mechanisms of action.MethodsFemale rats were subjected to a “two-hit” approach to induce migraine-like pain. This involved bilateral injections of Complete Freund's Adjuvant (CFA) into the trapezius muscle (1st hit) followed by exposure to Umbellulone, a human migraine trigger, on Day 6 post-CFA (2nd hit). Soft tissue and articulatory techniques were applied to the cervical region for acute abortive or repeated prophylactic treatment. Cutaneous allodynia and trigeminal system activation were assessed through behavioral tests and immunohistochemical staining.ResultsFollowing Umbellulone inhalation, CFA-primed rats exhibited periorbital and hind paw allodynia. Immediate application of OMT after Umbellulone inhalation as an abortive treatment partially alleviated cutaneous allodynia. With OMT applied thrice as a prophylactic measure, complete suppression of tactile hypersensitivity was observed. Prophylactic OMT also prevented the increase of c-fos signals in the trigeminal nucleus caudalis and the elevation of calcitonin gene-related peptide expression in trigeminal ganglia induced by CFA and Umbellulone exposure at 2 h post-inhalation.DiscussionThese findings provide mechanistic insights into OMT's migraine-relief potential and underscore its viability as a non-pharmacological avenue for managing migraines.

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Previously, the small molecule inhibitor of transcriptional enhanced associate domain (TEAD) MGH-CP1 has been described in stem cells. Here, the authors demonstrate the utility of MGH-CP1 in cancer therapy and find treatment to increase Akt pathway activation via TEAD-Vgll3 activation, presenting a rationale for combination with Akt inhibition.

To assess the possibility of selective disintegration and reduction of overgrinding of hard-to-reproduce ores, optical microscopic and X-ray microtomographic studies were carried out and quantitative characteristics of morphological parameters of disseminated and rich cuprous ore samples from Norilsk-type Oktyabrsky deposit were identified. Among quantitative morphological parameters the most informative are area, perimeter, edge roughness, sphericity, elongation and average grain spacing for disseminated copper-nickel ores; area, perimeter, edge roughness and elongation for rich cuprous ores. The studied parameters are characterized by increased values and dispersion in ore zones, which is especially important for fine-grained ores, which are difficult to diagnose by optical methods. Three-dimensional modelling of the internal structure of sulphide mineralisation samples was carried out using computed X-ray microtomography, which allows observation of quantitative parameters of grains, aggregates and their distribution in the total rock volume and interrelationship with each other. The evaluation of rock pore space by computer microtomography made it possible to compare the results obtained with the strength characteristics of rocks and ores, including those on different types of crushers. The obtained quantitative characteristics of structural-textural parameters and analysis of grain size distribution of ore minerals allow us to evaluate the possibility of applying selective crushing at various stages of ore preparation

ABSTRACT: Vagal indigestion (VI) is a digestive disorder characterized by the dysfunction of the vagus nerve. This disorder leads to changes in forestomach motility. The causes of VI are varied. Failure to transport digestive contents may occur due to mechanical obstruction or a neurogenic origin. There are few reports in the literature regarding this disease in mini-cattle. These cattle seem to be predisposed to the development of VI. The aim of the present study was to analyze the epidemiological, clinical, laboratory, and electrocardiographic aspects of mini-cattle diagnosed with VI. The medical records of nine mini-cattle diagnosed with VI were retrospectively reviewed. Mini-cattle were referred to the Large Animal Hospital in Botucatu, Brazil, from 2002 to 2021. It was observed that VI affected young mini-cattle. The predominant clinical manifestations were intermittent gas ruminoreticular tympanism with increased volume in the left paralumbar fossa and increased volume in the right ventral region (apple/pear aspect), hypomotility in ruminal auscultation and the presence of pasty stools. The mean heart rate of the animals was 75 beats per minute. In one case, bradycardia was observed by electrocardiogram and Holter monitor system. In this case, the predominance of parasympathetic activity of the autonomic nervous system was observed. The main hematological findings were leukocytosis and lymphocytosis. The therapeutic approach included ruminal fistulation and the implantation of a permanent rumen cannula. All animals undergoing the procedure were discharged with daily care instructions.

Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment. We hypothesized that inhibiting this complex with a DNA-PK inhibitor, Peposertib (M3814), would improve treatment response.We assessed pDNA-PK in a rectal cancer cell line and mouse model utilizing western blotting, viability assays, γH2AX staining, and treatment response. The three treatment groups were: standard of care (SOC) (5-fluorouracil (5FU) with radiation), M3814 with radiation, and M3814 with SOC.SOC treatment of rectal cancer cells increased pDNA-PK protein and increased γH2AX foci, but this was abrogated by the addition of M3814. Mice with CT26 tumors treated with M3814 with SOC did not differ in average tumor size but individual tumor response varied. The clinical complete response rate improved significantly with the addition of M3814 but pathological complete response did not. We investigated alterations in DNA repair and found that Kap1 and pATM are increased after M3814 addition suggesting this may mediate resistance.When the DNA-PK inhibitor, M3814, is combined with SOC treatment, response improved in some rectal cancer models but an increase in other repair mechanisms likely diminishes the effect. A clinical trial is ongoing to further explore the role of DNA-PK inhibition in rectal cancer treatment.

Animal movements among habitat patches or populations are important for maintaining long-term genetic and demographic viability, but connectivity may also facilitate disease spread and persistence. Understanding factors that influence animal movements is critical to understanding potential transmission risk and persistence of communicable disease in spatially structured systems. We evaluated effects of sex, age and Mycoplasma ovipneumoniae infection status at capture on intermountain movements and seasonal movement rates observed in desert bighorn sheep (Ovis canadensis nelsoni) using global positioning system collar data from 135 individuals (27 males, 108 females) in 14 populations between 2013 and 2018, following a pneumonia outbreak linked to the pathogen M. ovipneumoniae in the Mojave Desert, California, USA. Based on logistic regression analysis, intermountain movements were influenced by sex, age and most notably, infection status at capture: males, older animals and uninfected individuals were most likely to make such movements. Based on multiple linear regression analysis, females that tested positive for M. ovipneumoniae at capture also had lower mean daily movement rates that were further influenced by season. Our study provides empirical evidence of a pathogenic infection decreasing an individual's future mobility, presumably limiting that pathogen's ability to spread, and ultimately influencing transmission risk within a spatially structured system.

Abstract Sarcopenia, defined as a progressive loss of muscle mass and reduced muscle strength and functional capacity, is common among older adults. This study aimed to assess the proportion of people at risk of sarcopenia and probable sarcopenia among Chinese community-dwelling older adults living alone and to identify the associated factors. A total of 390 older adults were included in this study. Sarcopenia and probable sarcopenia were defined according to the criteria of the Asian Working Group for Sarcopenia 2019. Data on socio-demographic characteristics, health status, health behaviours and lifestyle characteristics, nutritional status, physical activity level, and depressive symptoms were collected. The association between these characteristics and sarcopenia risk was analysed using a multivariate ordinal logistic regression. The proportion of subjects at risk of sarcopenia and probable sarcopenia was found to be 57.7% and 30%, respectively. Older age, being malnourished and being at risk of malnutrition were significantly associated with sarcopenia risk. Being educated to secondary level or above, being overweight or obese and higher physical activity level were associated with decreased sarcopenia risk. Our results showed that older adults living alone were at high risk of developing sarcopenia and probable sarcopenia. These results emphasise the urgent need to initiate aggressive screening and holistic lifestyle therapeutic intervention strategies for this high-risk population.

Summary: Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB.

Abstract Potato virus Y (PVY) and zebra chip (ZC) disease are major threats to solanaceous crop production in North America. PVY can be spread by aphid vectors and through vegetative propagation in potatoes. ZC is associated with “Candidatus Liberibacter solanacearum” (Lso), which is transmitted by the tomato/potato psyllid, Bactericera cockerelli Šulc (Hemiptera: Triozidae). As these two pathosystems may co-occur, we studied whether the presence of one virus strain, PVY°, affected the host preference, oviposition, and egg hatch rate of Lso-free or Lso-carrying psyllids in tomato plants. We also examined whether PVY infection influenced Lso transmission success by psyllids, Lso titer and plant chemistry (amino acids, sugars, and phytohormones). Lso-carrying psyllids showed a preference toward healthy hosts, whereas the Lso-free psyllids preferentially settled on the PVY-infected tomatoes. Oviposition of the Lso-carrying psyllids was lower on PVY-infected than healthy tomatoes, but Lso transmission, titer, and psyllid egg hatch were not significantly affected by PVY. The induction of salicylic acid and its related responses, and not nutritional losses, may explain the reduced attractiveness of the PVY-infected host to the Lso-carrying psyllids. Although our study demonstrated that pre-existing PVY infection can reduce oviposition by the Lso-carrying vector, the preference of the Lso-carrying psyllids to settle on healthy hosts could contribute to Lso spread to healthy plants in the presence of PVY infection in a field.

Abstract Changing climate and land‐use practices have the potential to bring previously isolated populations of pest insects into new sympatry. This heightens the need to better understand how differing patterns of host–plant association, and unique endosymbionts, serve to promote genetic isolation or integration. We addressed these factors in populations of potato psyllid, Bactericera cockerelli (Šulc), a generalist herbivore that vectors a bacterial pathogen (Candidatus Liberibacter solanacearum, causal pathogen of zebra chip disease) of potato (Solanum tuberosum L.). Genome‐wide SNP data revealed two major genetic clusters—psyllids collected from potato crops were genetically similar to psyllids found on a common weed, Lycium spp., but dissimilar from those found on another common non‐crop host, Solanum dulcamara L. Most psyllids found on Lycium spp. and potato represented a single mitochondrial cytochrome oxidase I (COI) haplotype that has been suggested to not be native to the region, and whose arrival may have been concurrent with zebra chip disease first emerging. The putatively introduced COI haplotype usually co‐occurred with endosymbiotic Wolbachia, while the putatively resident COI haplotype generally did not. Genetic intermediates between the two genetic populations of insects were rare, consistent with recent sympatry or reproductive isolation, although admixture patterns of apparent hybrids were consistent with introgression of genes from introduced into resident populations. Our results suggest that both host–plant associations and endosymbionts are shaping the population genetic structure of sympatric psyllid populations associated with different non‐crop hosts. It is of future interest to explicitly examine vectorial capacity of the two populations and their potential hybrids, as population structure and hybridization might alter regional vector capacity and disease outbreaks.

Abstract Background Although many musicians perceive music performance anxiety (MPA) as a significant problem, studies about the psychobiological and performance-related concomitants of MPA are limited. Using the biopsychosocial model of challenge and threat as theoretical framework, we aim to investigate whether musicians’ changes in their psychobiological responses and performance quality from a private to a public performance are moderated by their general MPA level. According to the challenge and threat framework, individuals are in a threat state when the perceived demands of a performance situation outweigh the perceived resources, whereas they are in a challenge state when the perceived resources outweigh the perceived demands. The resources-demands differential (resources minus demands) and the cardiovascular challenge-threat index (sum of cardiac output and reverse scored total peripheral resistance) are the main indices of these states. We postulate that the relationship between general MPA level and performance quality is mediated by these challenge and threat measures. Methods We will test 100 university music students reporting general MPA levels ranging from low to high. They will perform privately (i.e., without audience) and publicly (i.e., with an audience) on two separate days in counterbalanced order. During each performance session, we will record their cardiovascular and respiratory activity and collect saliva samples and self-reported measures. Measures of primary interest are self-reported anxiety, the resources-demands differential, the cardiovascular challenge-threat index, sigh rate, total respiratory variability, partial pressure of end-tidal carbon dioxide and the salivary biomarkers cortisol, dehydroepiandrosterone, and alpha-amylase. Both, the participants and anonymous experts will evaluate the performance quality from audio recordings. Discussion The results of the planned project are expected to contribute to a more comprehensive understanding of the psychobiology of MPA and of the processes that influence musicians’ individual reactions to performance situations. We also anticipate the findings of this project to have important implications for the development and implementation of theory-based interventions aimed at managing musicians’ anxiety and improving performance quality. Thanks to the use of multimethod approaches incorporating psychobiology, it might be possible to better assess the progress and success of interventions and ultimately improve musicians’ chance to have a successful professional career. Trial registration Not applicable.

ABSTRACT: Patients with chronic kidney disease (CKD) have paradoxical hemostatic potential because they have bleeding episodes but are also prone to thrombosis. Few studies have evaluated blood viscoelastic properties in dogs with kidney disease; on the other hand, hypercoagulability has been observed in these patients. It is also emphasized that the platelet function and its participation in this process have not yet been fully understood. The objective of this study was to evaluate and compare the Thrombin Generation Test (TGT) and also viscoelastic properties of the blood measured by thromboelastometry (TEM) in dogs with proteinuria in CKD. Twenty healthy dogs (Control Group) and 19 dogs with CKD in stage III or IV, classified according to International Renal Interest Society - IRIS, were selected, and the reference test of urine protein:creatinine ratio (UPCR) should be greater than one (CKD group). Blood samples for TEM, thrombin generation, Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), and fibrinogen concentration was collected at a single time for both groups after inclusion criteria being confirmed. Statistical analysis was performed according to the distribution of variables at 5% significance level. Differences were observed between healthy dogs and those with proteinuria in CKD noted in TEM. The TGT was unable to differentiate between sick and healthy groups. However, when the nephropathy was stratified, increases in TTP and peak thrombin concentration by TGT were observed in females and dogs over 30 days of diagnosis of CKD. Both tests signaled a discrete state of hypercoagulability. In fact, TEM is more sensitive to detect hypercoagulability in dogs with CKD. However, the TGT has potential clinical application by allowing long-term sample storage.

ABSTRACT: Equine leukoencephalomalacia (LEM) is a disease caused by the ingestion of food, especially corn, contaminated by fumonisin, a Fusarium verticillioides (synonymous with F. moniliforme) metabolite. The clinical signs of brain injuries have an acute onset and rapid evolution. This study aimed to describe the clinical findings in 11 animals diagnosed with LEM, including cerebrospinal fluid (CSF) analysis. Of these animals, 91% (10/11) were horses, and only 9% (1/11) were asinine. The clinical localization of the lesions was 64% (7/10) cerebral, manifested mainly by altered mental state and behavioral disturbance, and 36% (4/11) were brainstem lesions, manifested by incoordination, head tilt, nystagmus, facial hypoalgesia, difficulty in apprehension, chewing, and swallowing food. Postmortem findings revealed that 82% (9/11) of the lesions were in the cerebrum and 18% (2/11) in the brainstem. CSF findings, such as xanthochromia (43%, 3/7), hyperproteinorrachia (50%, 3/6), and pleocytosis (43%, 3/7) were observed. The affected animals showed neurological signs that were compatible with cerebral and/or brainstem injuries. The CSF from animals with LEM may present with xanthochromia, hyperproteinorrachia, and pleocytosis, reinforcing the fact that this disease should be included in the differential diagnosis of encephalomyelopathies.

Background and purpose — The optimal cementing technique for primary total knee arthroplasty (TKA) remains unclear. We therefore performed a scoping review based on available studies regarding cementation technique in primary TKA and unicondylar knee arthroplasty (UKA). Patients and methods — A search in 3 databases identified 1,554 studies. The inclusion criteria were literature that studied cementing technique in primary TKA or UKA. This included cement application methods, full or surface cementing, applying cement to the bone and/or prosthesis, stabilization of the implant during curing phase, bone irrigation technique, drilling holes in the bone, use of suction, and the timing of cementation. 57 studies met the inclusion criteria. Results — The evidence was unanimously in favor of pulsatile lavage irrigation, drying the bone, and drilling holes into the tibia during a TKA. All studies concerning suction recommended it during TKA cementation. 7 out of 11 studies favored the use of a cement gun and no studies showed that finger packing was statistically significantly better than using a cement gun. There is evidence that full cementation should be used if metal-backed tibial components are used. Applying the cement to both implant and bone seems to give better cement penetration. Interpretation — There are still many knowledge gaps regarding cementing technique in primary TKA. There seems to be sufficient evidence to recommend pulsatile lavage irrigation of the bone, drilling multiple holes, and drying the bone before cementing and implant insertion, and applying cement to both implant and on the bone.

Abstract Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome‐wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.

Music performance anxiety (MPA) is a major problem for music students. It is largely unknown whether music students who experience high or low anxiety differ in their respiratory responses to performance situations and whether these co-vary with self-reported anxiety, tension, and breathing symptoms. Affective processes influence dynamic respiratory regulation in ways that are reflected in measures of respiratory variability and sighing. This study had two goals. First, we determined how measures of respiratory variability, sighing, self-reported anxiety, tension, and breathing symptoms vary as a function of the performance situation (practice vs. public performance), performance phase (pre-performance vs. post-performance), and the general MPA level of music students. Second, we analyzed to what extent self-reported anxiety, tension, and breathing symptoms co-vary with the respiratory responses. The participants were 65 university music students. We assessed their anxiety, tension, and breathing symptoms with Likert scales and recorded their respiration with the LifeShirt system during a practice performance and a public performance. For the 10-min periods before and after each performance, we computed number of sighs, coefficients of variation (CVs, a measure of total variability), autocorrelations at one breath lag (ARs(1), a measure of non-random variability) and means of minute ventilation (V’E), tidal volume (VT), inspiration time (TI), and expiration time (TE). CVs and sighing were greater whereas AR(1) of V’E was lower in the public session than in the practice session. The effect of the performance situation on CVs and sighing was larger for high-MPA than for low-MPA participants. Higher MPA levels were associated with lower CVs. At the within-individual level, anxiety, tension, and breathing symptoms were associated with deeper and slower breathing, greater CVs, lower AR(1) of V’E, and more sighing. We conclude that respiratory variability and sighing are sensitive to the performance situation and to musicians’ general MPA level. Moreover, anxiety, tension, breathing symptoms, and respiratory responses co-vary significantly in the context of music performance situations. Respiratory monitoring can add an important dimension to the understanding of music performance situations and MPA and to the diagnostic and intervention outcome assessments of MPA.

This Special Issue was focused on advancing our understanding of the long-term consequences of pediatric viral infections [...]

Summary: KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3′ kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Potato psyllid (Bactericera cockerelli Sulc)-transmitted "Candidatus Liberibacter solanacearum" (Lso) has been negatively impacting the potato industry in the United States as well as other potato-producing countries. Lso has been linked to a condition known as zebra chip (ZC) that affects yield and quality of potato tubers. Efforts to find sources of resistance to ZC have primarily focused on greenhouse evaluations based on a single inoculation time prior to harvest. Plant response to infection, however, could be influenced by the developmental stage of the host plant, and ZC may continue to develop after harvest. The objectives of this study were to quantify Lso inoculation success, Lso titer, ZC severity and Lso development during storage in eight potato genotypes. These evaluations were conducted on plants infested with Lso-positive psyllids at 77, 12, and 4 days before vine removal (DBVR). The evaluated genotypes were categorized according to their relative resistance to Lso and tolerance to ZC symptoms. Lso inoculation success in the genotype family A07781, derived from Solanum chacoense, was lower than that of the susceptible control ('Russet Burbank'). A07781-4LB and A07781-3LB genotypes were characterized relatively resistant to the pathogen and highly tolerant to ZC symptoms, while A07781-10LB was categorized as susceptible to Lso but relatively tolerant to symptom expression. In stored potatoes, increase in Lso concentrations was observed for all infestation times. However, significantly higher Lso titer was detected in tubers infested 12 DBVR and the effect was similar across genotypes. Overall, the A07781 family can be considered as a promising source of resistance or tolerance to ZC.

Resumo: A anemia hemolítica imuno-mediada (AHIM) é a causa mais comum dentre as anemias hemolíticas e a doença imuno-mediada de maior prevalência em cães, incluindo causas primárias e secundárias. As AHIM tem sido associadas a estados de hipercoagulabilidade, sendo o tromboembolismo a complicação mais comum. Este estudo teve como objetivo correlacionar as possíveis alterações hemostáticas e o risco tromboembólico nas AHIM e nas anemias por outras etiologias. Para tanto, foram selecionados 76 cães anêmicos (hematócrito ≤ 20%) somados ao menos um sinal clínico comumente associado à AHIM ou possuir pré-disposição racial. Foram realizados os seguintes testes para os animais selecionados: teste de citometria de fluxo e avaliação do perfil hemostático (contagem de plaquetas, TP, TTPA, TT, AT, PDF e Dímeros D); além de hemograma com contagem de reticulócitos, pesquisa de hematozoários em sangue periférico, PCR para Ehrlichia sp. e sorologia para leptospirose. 59 cães foram positivos para AHIM. O estado tromboembólico foi caracterizado pela presença de alteração em três ou mais testes do perfil hemostático. 74,6% casos de AHIM foram atribuídos às doenças infecciosas, sendo em sua maioria associados à Ehrlichia sp. (88,6%). 72,1% apresentaram trombocitopenia e 57,6% apresentaram anemia regenerativa com valores significativamente maiores de metarrubrícitos e contagem de reticulócitos. Não houve diferença estatística entre os grupos de cães anêmicos (positivos e negativos para AHIM). Os cães anêmicos apresentaram valores médios maiores de TTPA e menores de AT e contagem de plaquetas quando comparados aos cães saudáveis (p < 0,05). 25 cães positivos e sete negativos apresentaram estado tromboembólico. A especificidade de PDF foi menor (30,2%) quando comparada outros estudos. A escolha da classe de Ig não interfere no diagnóstico de AHIM. Não houve correlação entre a presença de anticorpos ligados às hemácias e as variáveis hemostáticas, porém houve uma fraca correlação (p

Abstract: The present paper reports blood gas analysis, hematologic and micro bacteriologic information on four female Red-billed curassows, rescued from illegal wild animal trading, that were undergoing habilitation for reintroduction into the wild through Projeto Centrofauna/Botucatu-SP. There is a lack of physiological data on this species, endemic to the region of Atlantic Forest (Mata Atlântica), now under threat of extinction. This lack of information makes the clinical evaluation of these birds very difficult and has a direct and adverse effect on any of these birds received for medical treatment in hospitals, veterinary clinics and centers for research and conservation, as well as in reintroduction centers.

Necroptosis is a lytic programmed cell death mediated by the RIPK1-RIPK3-MLKL pathway. The loss of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression and necroptotic potential have been previously reported in several cancer cell lines; however, the extent of this loss across cancer types, as well as its mutational drivers, were unknown. Here, we show that RIPK3 expression loss occurs progressively during tumor growth both in patient tumor biopsies and tumor xenograft models. Using a cell-based necroptosis sensitivity screen of 941 cancer cell lines, we find that escape from necroptosis is prevalent across cancer types, with an incidence rate of 83%. Genome-wide bioinformatics analysis of this differential necroptosis sensitivity data in the context of differential gene expression and mutation data across the cell lines identified various factors that correlate with resistance to necroptosis and loss of RIPK3 expression, including oncogenes BRAF and AXL. Inhibition of these oncogenes can rescue the RIPK3 expression loss and regain of necroptosis sensitivity. This genome-wide analysis also identifies that the loss of RIPK3 expression is the primary factor correlating with escape from necroptosis. Thus, we conclude that necroptosis resistance of cancer cells is common and is oncogene driven, suggesting that escape from necroptosis could be a potential hallmark of cancer, similar to escape from apoptosis.

Since microRNAs (miRNAs, miRs) have been implicated in oncogenesis, many of them have been identified as therapeutic targets. Previously we have demonstrated that miRNA-10b acts as a master regulator of the viability of metastatic tumor cells and represents a target for therapeutic intervention. We designed and synthesized an inhibitor of miR-10b, termed MN-anti-miR10b. We showed that treatment with MN-anti-miR10b led to durable regression/elimination of established metastases in murine models of metastatic breast cancer. Since miRNA-10b has been associated with various metastatic and non-metastatic cancers, in the present study, we investigated the effect of MN-anti-miR10b in a panel of over 600 cell lines derived from a variety of human malignancies. We observed an effect on the viability of multiple cell lines within each cancer type and a mostly dichotomous response with cell lines either strongly responsive to MN-anti-miR10b or not at all even at maximum dose tested, suggesting a very high specificity of the effect. Genomic modeling of the drug response showed enrichment of genes associated with the proto-oncogene, c-Jun.

Rakhi Karwa and colleagues discuss a program in which peer navigators support care for people with HIV at a Kenyan hospital.

O estudo tem o objetivo de identificar efeitos indesejáveis da ribavirina, prednisona e DMSO em cães naturalmente infectados com o vírus da cinomose. Foram utilizados 60 cães apresentando quadro neurológico da cinomose com evolução de 10 dias. Os animais foram internados e receberam tratamento de suporte; foram avaliados diariamente e realizados hemograma, dosagem bioquímica e exame de urina tipo I. Os grupos 1 e 2 foram tratados com ribavirina e sua associação com DMSO; os grupos 3 e 4 com DMSO e prednisona e o grupos 5 com ribavirina e prednisona e o grupo 6 com ribavirina, prednisona e DMSO. Os animais foram anestesiados para a colheita de líquor, medula óssea e sangue, antes do tratamento para diagnóstico através da RT-PCR. As amostras negativas foram analisadas pela técnica de hn-PCR. Todos os animais apresentaram resultado positivo em pelo menos uma das duas reações. O efeito adverso da ribavirina e a sua associação com a prednisona foi a anemia hemolítica, que foi confirmada pela observação de bilirrubina na urina apenas dos cães tratados com ribavirina.

O presente estudo teve como objetivo a avaliação do leucograma e do metabolismo oxidativo de neutrófilos em fêmeas caprinas da raça Saanen, nos períodos de gestação, parto e pós-parto. Amostras de sangue foram colhidas de 20 fêmeas nulíparas da raça Saanen, clinicamente sadias por venipunção jugular aos 49 (M1), 42 (M2), 35 (M3), 28 (M4), 21 (M5), 14 (M6), sete (M7), três (M8) dias antes do parto, no dia do parto (M9), três (M10) e sete (M11) dias após o parto, para a realização do leucograma e dosagens séricas de cortisol, estradiol e progesterona. A partir de 28 dias (M4) antes do parto até sete dias do pós-parto (M11) foram colhidas amostras de sangue para a avaliação do metabolismo oxidativo de neutrófilos por meio do teste de redução do tetrazólio nitroazul (NBT). Os resultados demonstraram que no dia do parto houve aumento nas concentrações séricas de cortisol e estradiol, e diminuição da progesterona, leucocitose por neutrofilia e desvio à esquerda leve, diminuição dos linfócitos, aumento da relação neutrófilo:linfócito, eosinopenia, monocitose e basofilia. No sétimo dia do pós-parto houve leucocitose por neutrofilia e aumento da relação neutrófilo:linfócito. Não houve nos períodos de gestação, parto e pós-parto alterações significativas no metabolismo oxidativo dos neutrófilos. Conclui-se que o parto determina elevação da concentração sérica de cortisol e estradiol, e diminuição da progesterona determinando quadro de leucocitose por neutrofilia e desvio à esquerda leve, com diminuição dos linfócitos, aumento da relação neutróflo:linfócito, eosinopenia, monocitose e basofilia. Ao sétimo dia do pós-parto há leucocitose por neutrofilia, aumento da relação neutrófilo:linfócito e do fibrinogênio. A gestação, o parto e o período do pós-parto não alteram o metabolismo oxidativo de neutrófilos avaliado por meio do teste de redução do NBT.

A presente pesquisa foi realizada com o objetivo de desenvolver e adaptar técnicas diagnósticas em neurologia para primatas não humanos, da espécie Alouatta guariba Geoffroy Saint-Hilaire, 1812 (bugio-ruivo) saudáveis e mantidos em cativeiro. Foram realizadas análises físico-químicas e citológicas do líquido cefalorraquidiano obtido na cisterna magna de oito bugios-ruivos. Para realização dos exames, todos os animais foram contidos quimicamente com associação de cetamina, xilazina e midazolam e anestesia inalatória com isoflurano. Os resultados das análises do líquido cefalorraquidiano demonstraram valores médios de proteína: 16,92mg/dL±9,84; glicose: 131,25mg/dL±106,7; pH: 8,37±0,69; células nucleadas: 0,5/mm³±0,75; hemácias: 49,37/mm³±111,76 e pressão: 7,37cm H2O±1,77. O trabalho demonstrou a segurança e a eficácia da colheita do líquido cefalorraquidiano na cisterna magna de Alouatta guariba e os valores de referência para a espécie.

O objetivo do presente estudo foi à monitoração dos parâmetros laboratoriais como hemograma, enzimas hepáticas alanina aminotransferase (ALT) e gama-glutamiltransferase (GGT), glicemia e proteinograma sérico, e avaliar o efeito da idade em gatos sem raça definida durante a fase neonatal. Vinte gatos machos e fêmeas foram utilizados a partir do terceiro dia de vida até o 38º dia de idade. As amostras de sangue foram colhidas semanalmente e as análises laboratoriais (hemograma, enzimas hepáticas, glicemia e proteinograma sérico) realizadas no 3º, 10º, 17º, 24º, 31º e 38º dia de idade. Os resultados exibiram efeito significativo da idade sobre a contagem total de eritrócitos, concentração de hemoglobina, volume globular, volume corpuscular médio, concentração de hemoglobina corpuscular média, leucócitos totais, neutrófilos, eosinófilos e basófilos. Nenhum efeito foi observado em células como linfócitos, monócitos ou na concentração sérica de glicose. A análise das modificações ocorridas nos parâmetros laboratoriais durante a fase neonatal reflete o desenvolvimento fisiológico do filhote e contribui para o conhecimento do processo adaptativo em gatos neonatos durante o primeiro mês de vida, sendo útil para a avaliação clínica, diagnóstico e tratamento das doenças neonatais.The purpose of the study was to evaluate the effects of age on blood count, liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), glycemia and on protein profile in mixed-breed cats during the neonatal phase. Twenty male and female cats were used from 3 to 38 days after birth. Weekly blood samples were obtained and laboratory analyses (blood count, liver enzymes, glycemia and protein profile) were performed on the 3rd, 10th, 17th, 24th, 31st and 38th day of age. The results exhibited significant effect of age on total red blood cell count, hemoglobin concentration, packed cell volume, mean cell volume, mean cell hemoglobin concentration, total leukocyte count, mean segmented neutrophils, eosinophils and basophils. No effect was observed in lymphocyte, monocyte and glucose concentration. The analysis of changes in laboratory parameters which occurred during the neonatal period reflects the physiological development of the kitten and contributes to knowledge of the adaptive process in neonates cats during the first month of life, and is useful for clinical assessment, diagnosis and treatment of neonatal diseases.

The importance of studies with hematological, serum biochemistry and urinary values of Crab-eating Fox (Cerdocyon thous) is based on the need for health care and maintenance of those populations. This paper has the objective to investigate hematological, serum biochemistry and urinary physiological parameters of the Crab-eating fox, comparing gender and age differences. Blood samples were collected in 2003 from 52 animals of different Zoos in São Paulo state, Brazil; 7mL of blood was used to obtain a complete blood cell count (CBC) and the profile of the serum biochemistry. Moreover, 5mL of urine were collected for analysis. There was no difference in values for male and female animals, as for the CBC and serum biochemistry. Some hematological and serum biochemical parameters were influenced by age, showing significant differences. Urinalysis results were just demonstrated in a descriptive form. The studied values were, RBC 4.35±0.73 x 10(6) /µL, WBC 7.72±3.66 x 10³ /µL (predominance of segmented neutrophils), platelets 227.06±111.58 x 10³ /µL, urea 43.06±14.28mg/dL and creatinine 1.03±0.24mg/dL. Hematological, serum biochemistry and urinary values obtained in this study can be used as physiological values of the captive Crab-eating Fox. It is possible to conclude that wild species need their own reference values, differentiating animals in captivity from free-ranging animals.

Estudou-se a broncopneumonia de ocorrência natural em bezerros e a influência da administração de acetato de DL-α-tocoferol na profilaxia e tratamento desta enfermidade. Foram avaliados 60 bezerros machos, com idade máxima de 10 dias, divididos em dois grupos experimentais: GSV (grupo sem vitamina) e GCV (grupo com vitamina). A suplementação com dose única de 4.500 UI de acetato de DL-α-tocoferol por via intramuscular (IM) foi precedida por exame físico, perfil hematológico, determinação de proteínas séricas, globulinas, gamaglutamiltransferase e citologia do lavado traqueobrônquico (D0) para verificar a sanidade e homogeinização dos grupos. Os bezerros foram mantidos em bezerreiro e distribuídos aleatoriamente, 2 a 2 em baias individuais de 2,40m², onde permaneceram até o 21º dia (D0 ao D21). Foram avaliados por exame físico diário e, na presença de sinais clínicos indicativos de broncopneumonia (DX), retirados do bezerreiro, avaliados por hemograma e citologia do lavado traqueobrônquico, e tratados com enrofloxacina (5mg/kg, IM). Durante o tratamento, o exame físico foi realizado diariamente, e o hemograma e a citologia do lavado traqueobrônquico repetidos uma semana após seu término (DY). Nos bezerros sadios foram repetidos hemograma e citologia do lavado traqueobrônquico, no último dia (D21) do experimento. Não houve diferença significativa quanto às variáveis gamaglutamiltrasfrase (p=0,09), proteínas séricas (p=0,27) e globulinas (p=0,10) e a idade dos bezerros (p=0,15) entre os grupos. Os bezerros do grupo GSV e GCV levaram em média 11 e 12 dias para adoecerem, respectivamente. Contudo, não houve diferença estatística significativa entre os grupos (p=0,68). Em 34 bezerros (56,66%) foi diagnosticado broncopneumonia, sendo que 17 destes bezerros (50%) pertenciam ao grupo GCV e 17 (50%) ao grupo GSV. Com relação aos sinais clínicos, não houve diferença significativa entre os grupos em nenhum dos momentos estudados. Dos 34 bezerros que adoeceram 73,52% morreram pela doença, sendo 64,7% do GCV e 82,35% do GSV. A citologia do lavado traqueobrônquico não apresentou diferença significativa entre os grupos em nenhum dos momentos estudados (D0, DX, DY e D21). A suplementação com vitamina E não teve influência na profilaxia e no tratamento de broncopneumonia de bezerros.

O presente trabalho teve como objetivos avaliar os sinais clínicos, as concentrações do sulfeto de hidrogênio ruminal e as alterações anatomopatológicas associadas à intoxicação experimental por enxofre em bovinos. Foram utilizados dez bezerros mestiços leiteiros, sendo que quatro bovinos ingeriram ração sem sulfato de sódio (G1) e seis consumiram ração com sulfato de sódio (G2). Exames clínicos (temperatura retal, frequência cardíaca e respiratória e motricidade ruminal) e laboratoriais (hemograma, fibrinogênio, proteína plasmática, pH do fluido ruminal, concentração do sulfeto de hidrogênio ruminal, líquido cerebrospinal e histopatológico) foram realizados. A temperatura retal, frequência cardíaca, hemograma, fibrinogênio, proteína plasmática, pH do fluido ruminal e os valores do líquido cerebrospinal estavam dentro dos valores de referência para a espécie. Taquipnéia, hipomotricidade ruminal e elevados valores de sulfeto de hidrogênio ruminal foram observados nos bezerros do grupo G2. Um bezerro do grupo G2 apresentou sinais neurológicos e lesões histopatológicas de PEM. Dois animais de cada grupo foram eutanasiados. Lesões microscópicas foram observadas nos bezerros do G2. Histologicamente as alterações observadas foram necrose neuronal cortical e lesões hemorrágicas nos núcleos basais, tálamo, mesencéfalo, ponte e bulbo. O protocolo experimental constituído por uma dieta rica em carboidrato de alta fermentação, baixa quantidade de fibra efetiva e altos níveis de enxofre (0,52%) ocasionou alterações clinicas e histológicas e elevadas concentrações de sulfeto de hidrogênio ruminal compatíveis com quadro de intoxicação por enxofre.

Com o objetivo de desenvolver um modelo de hemodiálise (HD) em cães, foram estudados 18 animais, sem raça definida, machos, clinicamente sadios, com peso corporal variando entre sete e 14 kg. O acesso vascular foi obtido através de implantação do cateter de duplo lúmen em veia jugular externa. As sessões de HD, em número de cinco por animal, com até três horas de duração, foram realizadas em hemodialisadora de sistema proporcional com ultrafiltração (UF) controlada, com solução dialisante padrão e tampão bicarbonato. A UF foi ajustada para HD isovolêmica, utilizou-se perfil de sódio, e para anticoagulação heparina sódica. Os animais foram mantidos anestesiados com cloridrato de levomepromazina e propofol. Foram avaliados dados hematológicos, bioquímicos, hemogasometria, pressão arterial sistêmica e tempo de coagulação ativado. Foi observada diminuição do número global de hemácias, volume globular, hemoglobina e leucócitos. Em relação aos exames bioquímicos, houve manutenção nos níveis de sódio sérico, e quanto à hemogasometria, a manutenção da SO2. A pressão arterial sistêmica manteve-se constante. Os resultados obtidos no presente trabalho permitiram concluir que foi possível o desenvolvimento do modelo proposto e mostrou que a HD em cães é um método viável e seguro, que poderá contribuir para o tratamento clínico da insuficiência renal nesta espécie.To develop a model of hemodialysis (HD), 18 healthy dogs, without a defined breed, males, weighing 7-14 kg, were studied. A double lumen catheter was inserted into the jugular vein for vascular access. HD sessions, totalizing 5 for each dog, were performed with a proportional HD machine, controlled isovolemic ultrafiltration, standard dialysis solution and bicarbonate buffer. Sodium profile and sodium heparin were used. During HD sessions the dogs were kept anesthetized (levomepromazine and propofol). Hematological and biochemistry data, blood gas analysis, systemic arterial blood pressure, and activated clotting time were evaluated. Serum biochemistry e blood gas analysis showed, respectively, sodium and SO2 maintenance. Systemic blood pressure kept sustained during HD sessions. It could be concluded that it was possible to develop a HD dog model that is a safe and viable technique to be used in chronic renal failure patients.

A acidose láctica ruminal é causada pela ingestão excessiva de carboidratos de fermentação rápida sem uma prévia adaptação dos mocroorganismos, podendo com isso gerar distúrbios metabólicos graves aos ruminantes. Este trabalho tem por objetivo estudar o metabolismo oxidativo dos neutrófilos em ovinos tratados com a monensina sódica na acidose láctica ruminal induzida experimentalmente. Foram empregados 18 ovinos, machos, mestiços (Ideal x Merino), fistulados no rúmen; dos quais nove receberam 33 mg/kg da dieta do ionóforo ao dia, durante 30 dias, os demais ovinos pertenceram ao grupo controle. A acidose foi induzida fornecendo 15g de sacarose/kg de peso corporal. A avaliação clínica e as amostras de rúmen e sangüíneas foram obtidas antes (momento controle) 0h e às 6h, 12h, 24h e 48h pós-indução. Em ambos os grupos os animais apresentaram manifestações clínicas de acidose láctica ruminal 6 horas pós-indução. A partir deste período se observou uma diminuição significativa (p

Image data management in the semiconductor manufacturing environment is becoming more problematic as the size of silicon wafers continues to increase, while the dimension of critical features continues to shrink. Fabricators rely on a growing host of image-generating inspection tools to monitor complex device manufacturing processes. These inspection tools include optical and laser scattering microscopy, confocal microscopy, scanning electron microscopy, and atomic force microscopy. The number of images that are being generated are on the order of 20,000 to 30,000 each week in some fabrication facilities today. Manufacturers currently maintain on the order of 500,000 images in their data management systems for extended periods of time. Gleaning the historical value from these large image repositories for yield improvement is difficult to accomplish using the standard database methods currently associated with these data sets (e.g., performing queries based on time and date, lot numbers, wafer identification numbers, etc.). Researchers at the Oak Ridge National Laboratory have developed and tested a content-based image retrieval technology that is specific to manufacturing environments. In this paper, we describe the feature representation of semiconductor defect images along with methods of indexing and retrieval, and results from initial field-testing in the semiconductor manufacturing environment.

O presente estudo reporta o primeiro caso de infecção por Strongyloides sp. em Leopardus tigrinus no município de Botucatu, Estado de São Paulo, Brasil. Fezes do exemplar parasitado de L. tigrinus foram cultivadas em fezes eqüinas esterilizadas e foi realizada infecção experimental em gato (Felis catus domesticus) com três mil larvas L3 infectantes por via subcutânea, para a identificação da espécie de Strongyloides envolvida no parasitismo. As fêmeas partenogenéticas obtidas do animal experimental foram analisadas porém a comparação dos dados biométricos encontrados com os dados da literatura não permitiu a identificação da espécie. Este é o primeiro relato sobre a ocorrência de Strongyloides sp. Em L. tigrinusThe present study reports the first case of infection by Strongyloides sp. in Leopardus tigrinus in the municipality of Botucatu, State of São Paulo, Brazil. Feces of the infected L. tigrinus specimen were cultivated in sterilized equine feces and a cat (Felis catus domesticus) was experimentally infected with three thousand infective L3 subcutaneous route, in order to identify the Strongyloides species involved in the parasitism. Parthenogenetic females recovered from the experimental animals were analyzed but comparison between the biometric data found and the data in the literature did not enable identification of the species. This is the first report on the occurrence of Strongyloides sp. in L. tigrinus.

The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.

Guanidine alkaloids from sponges Monanchora spp. represent diverse bioactive compounds, however, the mechanisms underlying bioactivity are very poorly understood. Here, we report results of studies on cytotoxic action, the ability to inhibit EGF-induced neoplastic transformation, and the effects on MAPK/AP-1 signaling of eight rare guanidine alkaloids, recently isolated from the marine sponge Monanchora pulchra, namely: monanchocidin A (1), monanchocidin B (2), monanchomycalin C (3), ptilomycalin A (4), monanchomycalin B (5), normonanchocidin D (6), urupocidin A (7), and pulchranin A (8). All of the compounds induced cell cycle arrest (apart from 8) and programmed death of cancer cells. Ptilomycalin A-like compounds 1–6 activated JNK1/2 and ERK1/2, following AP-1 activation and caused p53-independent programmed cell death. Compound 7 induced p53-independent cell death without activation of AP-1 or caspase-3/7, and the observed JNK1/2 activation did not contribute to the cytotoxic effect of the compound. Alkaloid 8 induced JNK1/2 (but not ERK1/2) activation leading to p53-independent cell death and strong suppression of AP-1 activity. Alkaloids 1–4, 7, and 8 were able to inhibit the EGF-induced neoplastic transformation of JB6 P+ Cl41 cells. Our results suggest that investigated guanidine marine alkaloids hold potential to eliminate human cancer cells and prevent cancer cell formation and spreading.

Coorte constituída por 4.876 crianças nascidas vivas, em hospitais do Município de Maringá-PR (Brasil), em 1989, foi acompanhada com a finalidade de estimar a probabilidade de morrer no primeiro ano de vida. As variáveis de estudo foram sexo, peso ao nascer, idade da mãe, subgrupos etários e causa básica de morte. A probabilidade de morte no primeiro ano de vida foi estimada em 19,9 por mil, sendo que 77,3% dos óbitos ocorreram no período neonatal. As causas perinatais, juntamente com as anomalias congênitas, responderam por mais de 80% dos óbitos, e as doenças infecciosas e parasitárias, por apenas 1,1%. A probabilidade de morrer no primeiro ano de vida devido às afecções originadas no período perinatal foi superior nas crianças nascidas de parto normal (20,3 por mil) em relação à das nascidas por cesárea (9 por mil). O risco de morrer foi maior nos filhos de mulheres adolescentes, nas crianças nascidas com peso inferior a 2.500g. Os resultados chamam a atenção para a necessidade de melhorar a qualidade da assistência pré-natal, ao parto e ao recém-nascido e sugerem possível associação entre maior mortalidade e pior nível socioeconômico.A birth-cohort of 4,876 children born alive in hospital were selected and followed through up to the age of one year with a view to estimating the risk of dying in the first year of life. All of them were born in 1989, in one of the the seven hospitals of an urban area of Southern Brazil and the only requirement for belonging to the cohort was that of residence on the area. The selected variables were: sex, birthweight, age at moment of death, urderlying cause of death, and maternal age. The estimated probability of dying in the first year was of 19.9 per 1,000 (77.3% of the deaths occurred during the neonatal period). Perinatal causes and congenital malformations contributed to 80% of the deaths, and infectious diseases were the underlying cause of death in only 1.1% of the losses. The risk of dying in the first year of life due to afections arising during the perinatal period was higher among vaginally delivered babies (20.3 per 1,000) than it was for those born by caesarian section (9 per 1,000). A higher probability of death was present among infants born to adolescent mothers, and those with low birthweight (less than 2,500g). The results brought out the need for improving the quality of prenatal and infant care. They also suggested the hypothesis of a possible association between higher infant mortality and lower socio-economic level.

Com o objetivo de avaliar a real situação do Registro Civil, no Município de Maringá, PR, Brasil, foram estudados 4.876 nascimentos vivos ocorridos nos seus hospitais, em 1989, filhos de mulheres nele residentes. São apresentadas as etapas que permitiram identificar, dentre a população de estudo, os nascimentos registrados (mesclagem de dois arquivos). A estimativa máxima da taxa de sub-registro, no primeiro ano de vida, foi igual a 9,1%, variando segundo idade da mãe (quanto mais jovem, maior a taxa), situação previdenciária (indigentes com a maior estimativa) e paridade (primíparas, menor valor), permitindo aventar a hipótese de associação entre sub-registro e piores níveis socioeconômicos.With a view to evaluating the real situation of the vital statistics as regards their completeness in the city of Maringá, Paraná State, Brazil, 4,876 hospital live births which occurred during 1989 were studied. The rate of under-registration was estimated as 9.1%, varying according to maternal age, parity and financial condition. The results lead to the hypothesis of an association between under registration and lower socioeconomical levels. The study also describes all the necessary steps to establish the link between the two sets of events, live birth and legal registration.

Chlamydiae are obligate intracellular pathogens that must coordinate the acquisition of host cell-derived biosynthetic constituents essential for bacterial survival. Purified chlamydiae contain several lipids that are typically found in eukaryotes, implying the translocation of host cell lipids to the chlamydial vacuole. Acquisition and incorporation of sphingomyelin occurs subsequent to transport from Golgi-derived exocytic vesicles, with possible intermediate transport through endosomal multivesicular bodies. Eukaryotic host cell-derived sphingomyelin is essential for intracellular growth of Chlamydia trachomatis, but the precise role of this lipid in development has not been delineated. The present study identifies specific phenotypic effects on inclusion membrane biogenesis and stability consequent to conditions of sphingomyelin deficiency. Culturing infected cells in the presence of inhibitors of serine palmitoyltransferase, the first enzyme in the biosynthetic pathway of host cell sphingomyelin, resulted in loss of inclusion membrane integrity with subsequent disruption in normal chlamydial inclusion development. Surprisingly, this was accompanied by premature redifferentiation to and release of infectious elementary bodies. Homotypic fusion of inclusions was also disrupted under conditions of sphingolipid deficiency. In addition, host cell sphingomyelin synthesis was essential for inclusion membrane stability and expansion that is vital to reactivation of persistent chlamydial infection. The present study implicates both the Golgi apparatus and multivesicular bodies as key sources of host-derived lipids, with multivesicular bodies being essential for normal inclusion development and reactivation of persistent C. trachomatis infection.