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The COVID-19 pandemic disrupted the delivery of preventative care and management of acute diseases. This study assesses the effect of the COVID-19 pandemic on coronary calcium score and coronary CT angiography imaging volume.A single institution retrospective review of consecutive patients presenting for coronary calcium score or coronary CT angiography examinations between January 1, 2020 to January 4, 2022 was performed. The weekly volume of calcium score and coronary CT angiogram exams were compared.In total, 1,817 coronary calcium score CT and 5,895 coronary CT angiogram examinations were performed. The average weekly volume of coronary CTA and coronary calcium score CT exams decreased by up to 83% and 100%, respectively, during the COVID-19 peak period compared to baseline (P0.0001). The post-COVID recovery through 2020 saw weekly coronary CTA volumes rebound to 86% of baseline (P = 0.024), while coronary calcium score CT volumes remained muted at only a 53% recovery (P0.001). In 2021, coronary CTA imaging eclipsed pre-COVID rates (P = 0.012), however coronary calcium score CT volume only reached 67% of baseline (P0.001).A significant decrease in both coronary CTA and coronary calcium score CT volume occurred during the peak-COVID-19 period. In 2020 and 2021, coronary CTA imaging eventually superseded baseline rates, while coronary calcium score CT volumes only reached two thirds of baseline. These findings highlight the importance of resumption of screening exams and should prompt clinicians to be aware of potential undertreatment of patients with coronary artery disease.

This review summarizes which body parts have taste function in which insect taxa. Evidence of taste by mouthparts, antennae, and tarsi is widespread. Mouthparts that commonly have taste function are the labium, including the labella and labial palps, the maxillae, including the galeae and maxillary palps, the inner surface of the labrum or clypeolabrum of chewers, and inside the precibarium/cibarium of hemipterans, which have piercing-sucking mouthparts. Tasting with mandibles has not been found, and tasting with the hypopharynx is seldom reported. Use of the antennae appears uncommon among fly species, but common among species of lepidopterans, hymenopterans, beetles, and bugs. Although tasting with legs, especially tarsi, is reported mostly for fly and lepidopteran species, there is also evidence of it for multiple species of beetles, grasshoppers, and hemipterans, and one species of a roach, an ant, and a bee. Ovipositor taste function has been supported for some species of flies, lepidopterans, hymenopterans, orthopterans, and odonates. Taste by wings has been much less studied, but has been documented in a few fly species. Taste remains unstudied for any species or any body parts of Archaeognatha, Dermaptera, Mantodea, Mecoptera, Phasmatodea, Megaloptera, Neuroptera, Phthiraptera, Psocoptera, Siphonaptera, as well as Raphidioptera, Strepsiptera, Embioptera, Notoptera, and Zoraptera. Across holometabolous insects, larvae have not often been examined, the exception being some species of lepidopterans, flies, and beetles. Taste studies of antenna and legs are uncommon for even lepidopteran and beetle larvae.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively attacks motor neurons, and leads to progressive muscle weakness and death. A common pathological feature is the misfolding, aggregation, and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43) proteins in more than 95% of ALS patients, suggesting a universal role TDP-43 proteinopathy in ALS. Mutations in SQSTM1/p62 have been identified in familial and sporadic cases of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate their target genes. Emerging evidence indicates that miRNA dysregulation is associated with neuronal toxicity and mitochondrial dysfunction, and also plays a pivotal role in ALS pathogenesis. Here, we report the first evidence that miR-183-5p is aberrantly upregulated in spinal cords of patients with ALS. Using luciferase reporter assays and miR-183-5p agomirs, we demonstrate that miR-183-5p regulates the SQSTM1/p62 3´-untranslated region to suppress expression. A miR-183-5p agomir attenuated SOSTM1/p62 expression and led to an increase in TDP-43 protein levels in neuronal and non-neuronal cells. In contrast, a miR-183-5p antagomir decreased TDP-43 but increased SQSTM1/p62 protein levels. The antagomir repressed formation of stress granules and aggregated TDP43 protein in neuronal cells under stress-induced conditions and protected against cytotoxicity. Knockdown of SQSTM1/p62 decreased total ubiquitination and increased TDP-43 protein aggregation, indicating that SQSTM1/p62 may play a protective role in cells. In summary, our study reveals a novel mechanism of TDP-43 proteinopathy mediated by the miR-183-5p and provides a molecular link between aberrant RNA processing and protein degradation, two major pillars in ALS pathogenesis.

Docking protein 7 (DOK7) congenital myasthenic syndrome (CMS) is characterized by limb-girdle weakness and lack of fluctuating fatigability simulating many familial myopathies. Albuterol is the first line of therapy in view of consistent improvement. Two brothers with progressive predominant biceps weakness for 1-3 years responded to prednisone treatment for 40-50 years. Various studies including muscle biopsy and many laboratory studies were unsuccessful for the definite diagnosis. Gene study, 40 years after the initial evaluation, confirmed the diagnosis of DOK7 CMS. These are the first reported cases of DOK7 CMS associated with a sustained benefit from corticosteroids.

A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1β, TNF-α, iNOS, and IL-6. Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease. Posttranscriptional pathways of mRNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine- and uridine-rich element (ARE) which is present in the 3' untranslated region (UTR) of the mRNAs encoding these inflammatory mediators. (ARE)-binding proteins (AUBPs) such as Human antigen R (HuR), Tristetraprolin (TTP) and KH- type splicing regulatory protein (KSRP) are key nodes for directing these posttranscriptional pathways and either promote (HuR) or suppress (TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.

BackgroundIdiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complementC4in IIM pathology was unknown.MethodsWe elucidated the gene copy number (GCN) variations of totalC4,C4AandC4B, longandshort genesin 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.ResultsThe large study populations helped establish the distribution patterns of variousC4GCN groups. Low GCNs ofC4T(C4T=2+3) andC4Adeficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28–2.91), p=5.0×10−53forC4T, and 2.82 (2.48–3.21), p=7.0×10−57forC4Adeficiency. Contingency and regression analyses showed that among patients withC4Adeficiency, the presence ofHLA-DR3became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% hadHLA-DR3with an OR of 11.02 (1.44–84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies.ConclusionsC4Adeficiency is relevant in dermatomyositis,HLA-DRB1*03is important in IBM and bothC4Adeficiency andHLA-DRB1*03contribute interactively to risk of polymyositis.

WHO's 2021-30 road map for neglected tropical diseases (NTDs) outlines disease-specific and cross-cutting targets for the control, elimination, and eradication of NTDs in affected countries. For schistosomiasis, the criterion for elimination as a public health problem (EPHP) is defined as less than 1% prevalence of heavy-intensity infections (ie, ≥50 Schistosoma haematobium eggs per 10 mL of urine or ≥400 Schistosoma mansoni eggs per g of stool). However, we believe the evidence supporting this definition of EPHP is inadequate and the shifting distribution of schistosomiasis morbidity towards more subtle, rather than severe, morbidity in the face of large-scale control programmes requires guidelines to be adapted. In this Viewpoint, we outline the need for more accurate measures to develop a robust evidence-based monitoring and evaluation framework for schistosomiasis. Such a framework is crucial for achieving the goal of widespread EPHP of schistosomiasis and to meet the WHO road map targets. We encourage use of overall prevalence of schistosome infection (instead of the prevalence of heavy-intensity infections), development of species-dependent and age-dependent morbidity markers, and construction of a standardised monitoring and evaluation protocol.

Following recovery from meticillin-resistant Staphylococcus pseudintermedius (MRSP) infection of any type, dogs may continue to carry MRSP asymptomatically on skin and mucosae, contributing to the spread of this multidrug-resistant, veterinary hospital-associated pathogen with zoonotic potential to others and into the environment.This study determined which canine anatomic and household environmental sites are most sensitive for sampling to identify carriage and contamination.Fifty-one dogs and 22 households, MRSP-positive on at least one tested site, were sampled on 132 and 40 occasions over time, respectively. Dogs were swabbed at six sites (mouth, nose, conjunctiva, skin, prepuce/vulva, perianal area); household environments were sampled using contact plates (mannitol salt agar [MSA] and MSA + 6 mg/L oxacillin [MS+]) on five sites. MRSP was isolated after enrichment, grown on MSA/MS+ and was confirmed by PCR. Generalized estimating equations were used for calculation of sensitivity (95% confidence interval) for each site/combination.Each anatomical and environmental site yielded MRSP at least once. MRSP was isolated from only a single site in 27.3% of dogs, with the buccal mucosa showing the highest sensitivity (63.8%). Multi-site sampling of a minimum of four canine anatomical or four environmental sites, respectively, was needed to achieve95% sensitivity.The canine buccal mucosa should be included in MRSP sampling protocols, ideally in addition to at least three other anatomical sites. Likewise, environment sampling should be of multiple household sites in cases where it is used as a part of clinical case management.Après la guérison d'une infection à Staphylococcus pseudintermedius (MRSP) résistante à la méticilline, les chiens peuvent continuer à être porteurs asymptomatiques de MRSP sur la peau et les muqueuses, contribuant ainsi à la propagation de cet agent pathogène multirésistant, associé aux hôpitaux vétérinaires et présentant un potentiel zoonotique et dans l'environnement.Cette étude a déterminé quels sites anatomiques canins et environnementaux domestiques sont les plus sensibles pour l'échantillonnage afin d'identifier le portage et la contamination. MÉTHODES ET MATÉRIEL: Cinquante et un chiens et 22 habitations, positifs au MRSP sur au moins un site testé, ont été échantillonnés respectivement à 132 et 40 reprises au fil du temps. Les chiens ont été écouvillonnés à six endroits (bouche, nez, conjonctive, peau, prépuce/vulve, région périanale); les environnements domestiques ont été échantillonnés à l'aide de boîtes de contact (gélose au sel de mannitol [MSA] et MSA + 6 mg/L d'oxacilline [MS+]) sur cinq sites. Le MRSP a été isolé après enrichissement, cultivé sur MSA/MS+ et confirmé par PCR. Des équations d'estimation généralisées ont été utilisées pour le calcul de la sensibilité (intervalle de confiance à 95 %) pour chaque site/combinaison. RÉSULTATS: Chaque site anatomique et environnemental a donné au moins une fois un MRSP. Le MRSP a été isolé à partir d'un seul site chez 27,3 % des chiens, la muqueuse buccale présentant la sensibilité la plus élevée (63,8 %). Un échantillonnage multisite d'au moins quatre sites anatomiques canins ou quatre sites environnementaux, respectivement, était nécessaire pour atteindre une sensibilité 95 %.La muqueuse buccale canine devrait être incluse dans les protocoles d'échantillonnage du MRSP, idéalement en plus d'au moins trois autres sites anatomiques. De même, l'échantillonnage de l'environnement doit porter sur plusieurs sites domestiques dans les cas où il est utilisé dans le cadre de la gestion des cas cliniques.INTRODUCCIÓN: Después de recuperarse de cualquier tipo de infección por Staphylococcus pseudintermedius resistente a la meticilina (MRSP), los perros pueden continuar siendo portadores de MRSP de forma asintomática en la piel y las mucosas, lo que contribuye a la propagación de este patógeno, que está asociado a hospitales veterinarios y que es resistente a múltiples fármacos con potencial zoonótico a otros perros y en el medio ambiente. OBJETIVOS: Este estudio determinó qué sitios ambientales domésticos y anatómicos caninos son más sensibles en la toma de muestras para identificar el transporte y la contaminación. MÉTODOS Y MATERIALES: Cincuenta y un perros y 22 hogares, MRSP positivo en al menos un sitio analizado, fueron muestreados en 132 y 40 ocasiones a lo largo del tiempo, respectivamente. Se tomaron muestras de los perros en seis sitios (boca, nariz, conjuntiva, piel, prepucio/vulva, área perianal); Se tomaron muestras de ambientes domésticos usando placas de contacto (agar manitol salino [MSA] y MSA + 6 mg/L de oxacilina [MS+]) en cinco sitios. MRSP se aisló después del enriquecimiento, se cultivó en MSA/MS+ y se confirmó mediante PCR. Se usaron ecuaciones de estimación generalizadas para el cálculo de la sensibilidad (intervalo de confianza del 95 %) para cada sitio/combinación. RESULTADOS: Cada sitio anatómico y ambiental arrojó MRSP al menos una vez. MRSP se aisló de un solo sitio en el 27,3 % de los perros, y la mucosa bucal mostró la mayor sensibilidad (63,8 %). Se necesitó un muestreo multilocalización de un mínimo de cuatro sitios anatómicos caninos o cuatro ambientales, respectivamente, para lograr una sensibilidad95 %. CONCLUSIONES Y RELEVANCIA CLÍNICA: la mucosa bucal canina debe incluirse en los protocolos de muestreo de MRSP, idealmente además de al menos otros tres sitios anatómicos. Del mismo modo, el muestreo ambiental debe ser de múltiples localizaciones domésticas en los casos en que se utilice como parte del manejo de casos clínicos.Nach der Erholung von einer Infektion mit einem Methicillin-resistenten Staphylococcus pseudintermedius (MRSP) eines jeden Typs können Hunde weiterhin asymptomatische Träger von MRSP auf der Haut und auf den Schleimhäuten sein, was zu einer Weiterverbreitung dieses multi-resistenten Keims, welcher mit Tierarztpraxen in Zusammenhang steht, zoonotisches Potential für andere und für die Umgebung aufweist, beiträgt.Diese Studie identifizierte die anatomischen Körperstellen der Hunde sowie die Umweltlokalisationen des Haushalts, die am sensibelsten sind, um Träger und Kontamination zu identifizieren.Von einundfünfzig Hunden und 22 Haushalten, die an mindestens einer Stelle MRSP-positiv getestet waren, wurde 132 bzw 40-mal im Verlauf der Zeit Proben genommen. Den Hunden wurde mittels Tupfer an sechs Stellen Proben entnommen (Mund, Nase, Bindehaut, Haut, Präputium/Vulva, Perianalgegend); in der Haushaltsumgebung wurden mittels Kontaktplatten (Mannitolsalzagar [MSA] und MSA + 6 mg/L Oxacillin [MS+]) an fünf Stellen Proben entnommen. Ein MRSP konnte nach einer Anreicherung isoliert werden, wuchs auf MSA/MS+ und wurde mittels PCR bestätigt. Generalisierte Schätzgleichungen wurden zur Kalkulierung der Sensibilität (95% Konfidenzintervall) für jede Stelle/Kombination angewendet.Jede anatomische und Umweltstelle lieferte mindestens einmal einen MRSP. MRSP wurde nur von einer einzigen Stelle bei 27,3% der Hunde isoliert, wobei die Backenschleimhaut die höchste Sensibilität (63,8%) aufwies. Eine multiple Probenahme von mindestens vier anatomischen bzw vier Umweltstellen war nötig, um eine95%ige Sensibilität zu erreichen.Die Backenschleimhaut des Hundes sollte bei MRSP Probenahme Protokollen inkludiert werden, idealerweise zusätzlich zu mindestens drei anderen anatomischen Körperstellen. Ebenso sollte die Probenahme aus der Umwelt an multiplen Stellen im Haushalt erfolgen, wenn es sich um Fälle handelt, wo es als Teil des klinischen Managements eingesetzt wird.背景: メチシリン耐性ブドウ球菌 (MRSP) 感染から回復後も、犬は皮膚や粘膜に無症候性にMRSP を保持し続け、この多剤耐性動物病院関連病原体を他人や環境へ拡散させる可能性がある。 目的: 本研究の目的は、保菌や汚染を特定するためのサンプリングに最も感度が高い犬の解剖学的部位および家庭環境を特定することであった。 材料と方法: 少なくとも 1 つの検査部位で MRSP 陽性を示した 51 頭の犬および22 世帯を、それぞれ 132 回および40 回にわたりサンプリングした。犬は 6 部位 (口、鼻、結膜、皮膚、包皮/外陰部、肛門周囲) を綿棒で拭き取り、家庭環境は、5 箇所でコンタクトプレート (マンニトール塩寒天 [MSA] および MSA + 6 mg/L オキサシリン [MS+]) を使用してサンプリングされた。MRSPは濃縮後に分離し、MSA/MS+で増殖させ、PCRで確認した。一般化推定方程式を用いて、各部位/組み合わせごとに感度 (95% 信頼区間)を算出した。 結果: 各解剖学的部位および環境箇所から少なくとも 1 回 MRSP が検出された。 MRSP は 27.3% の犬で単一部位から分離され、頬粘膜が最も高い感度 (63.8%) を示した。 95% 以上の感度を達成するには、それぞれ犬から最低 4 解剖学的部位または 4環境箇所のマルチサイト サンプリングが必要であった。 結論と臨床的関連性: 犬頬粘膜はMRSPサンプリングプロトコルに含めるべきであり、理想的には少なくとも他の3つの解剖学的部位に加えて含めるべきである。同様に、環境サンプリングは、臨床的な症例管理の一部として使用する場合には、複数の家庭用部位を対象とすべきである。.背景: 从任何类型的耐甲氧西林假中间葡萄球菌 (MRSP) 感染中恢复后，犬的皮肤和粘膜可能继续无症状地携带MRSP，导致这种具有人畜共患病潜力的多重耐药、兽医医院相关病原体传播给其他人和进入环境。 目的: 本研究确定了哪些犬解剖和家庭环境部位的携带和污染，采样识别最敏感。 方法和材料: 51只犬和22户家庭，至少一个检测点 MRSP 阳性，随时间推移分别采样132次和40次。在6个部位(口、鼻、结膜、皮肤、包皮/外阴、肛周)擦拭犬；在5个部位使用接触平板(甘露醇盐琼脂 [MSA] 和MSA + 6 mg/L苯唑西林 [MS +])对家庭环境进行采样。富集后分离MRSP，在MSA/MS + 上生长并经 PCR 证实。使用广义估计方程计算每个研究中心/组合的敏感性(95%置信区间)。 结果: 每个解剖和环境部位至少产生一次MRSP。27.3%的犬仅从单个部位分离出MRSP，其中颊黏膜表现出最高的敏感性 (63.8%)。分别需要对至少4个犬解剖部位或4个环境部位进行多部位采样，敏感性达到 95%。 结论和临床相关性: 除至少3个其他解剖部位外，理想情况下，MRSP采样方案中应包括犬颊粘膜。同样，应在多个家庭位点进行环境采样，选择临床病例管理环境。.Após a recuperação de qualquer tipo de infecção por Staphylococcus pseudintermedius resistente à meticilina (MRSP), os cães podem continuar a ser portadores MRSP de forma assintomática na pele e mucosas, contribuindo para a disseminação deste patógeno multirresistente, associado ao hospital veterinário com potencial zoonótico para outros e no ambiente.Este estudo determinou quais locais anatômicos caninos e domiciliares são mais sensíveis para amostragem para identificação de portadores e contaminação. MÉTODOS E MATERIAIS: Cinquenta e um cães e 22 domicílios, MRSP-positivos em pelo menos um local testado, foram amostrados em 132 e 40 ocasiões ao longo do tempo, respectivamente. Coletou-se as amostras utilizando-se swabs em seis locais (boca, nariz, conjuntiva, pele, prepúcio/vulva, região perianal); os ambientes domiciliares foram amostrados utilizando placas de contato (ágar sal manitol [MSA] e MSA + 6 mg/L de oxacilina [MS+]) em cinco locais. MRSP foi isolado após enriquecimento, cultivado em MSA/MS+ e confirmado por PCR. Equações de estimativa generalizada foram usadas para cálculo de sensibilidade (intervalo de confiança de 95%) para cada local/combinação.Cada sítio anatômico e ambiental apresentou MRSP pelo menos uma vez. MRSP foi isolado de um único sítio em 27,3% dos cães, com a mucosa oral apresentando a maior sensibilidade (63,8%). A amostragem em vários locais de um mínimo de quatro locais anatômicos caninos ou quatro locais ambientais, respectivamente, foi necessária para atingir 95% de sensibilidade. CONCLUSÕES E RELEVÂNCIA CLÍNICA: A mucosa oral canina deve ser incluída nos protocolos de amostragem de MRSP, idealmente além de pelo menos três outros sítios anatômicos. Da mesma forma, a amostragem do ambiente deve ser de vários locais domiciliares nos casos em que é usada como parte do gerenciamento de casos clínicos.

This study on Dalí in the United States examines the links between this Spanish Surrealist and American culture—a symbiotic relationship that would prove instrumental to the artist’s success and subsequent recognition as a global cultural figure. In this sense, this monograph offers an innovative and broader-than-usual perspective on the painter from Empordà, who is most often considered within the context of his European cultural ties: Catalan, Spanish, or even French. Dalí himself recognized: “Only America was wealthy enough, had enough fresh intelligence and available energy to fulfill my hypertrophic self and put up with my whims.” He was not mistaken; the United States would bring Dalí the stardom he desired—a land of dreams the artist succeeded in conquering and captivating forever. The chapters of this study analyze his stay in the country, from the moment he arrived to his periods in Virginia, New York, and the West Coast. They reveal some of the circumstances, methods and keys to Dalí's success, as well as the stages of an evolving body of work that would find perpetual renewal, enrichment and universal appreciation on North American soil.

The process of the development of a citizen science platform on Ocean Literacy designed and implemented during the lock down period of 2020 is described. As restrictions due to the COVID-19 health emergency did not allow researchers to organise public events and field data collection activities related to Ocean Literacy, it was decided to take advantage of this situation by building an online platform to bring Ocean Literacy issues directly into citizens' homes. The massive use of digital tools by all civic communities during this time has enabled both the implementation of this idea and rendering it effective. The pandemic control measures then provided a unique opportunity to focus citizen attention on the collection of household data and information and to highlight the more or less direct connections between citizens' lifestyles and the eco-marine system. Short questionnaires were used to ascertain and highlight citizens' household behaviours and daily attitudes during the lockdown towards water use, seafood consumption and plastic material use and disposal. Data and information were also proposed, collected and analyzed in terms of: general environmental awareness of the respondents, perception regarding their purchasing choices during this particular period, as well as any changes in lifestyles and habits during the lockdown with respect to previous periods. The collected data enabled the improvement of our knowledge on some aspects of people's domestic habits as well as their perception vs. real knowledge about the proposed environmental issues. We also realized that it is increasingly crucial for scientists to directly and extensively involve people and schools in educational and outreach activities and events as a good practice of science-society interaction. But to achieve good results there is a need to develop appropriate communication tools and effective involvement strategies to promote their widespread participation in citizen science projects.

Background Complications of urogenital schistosomiasis include acute inflammatory and chronic fibrotic changes within the urogenital tract. Disease burden of this neglected tropical disease is often underestimated, as only active, urine egg-patent Schistosoma infection is formally considered. Previous studies have focussed on short-term effects of praziquantel treatment on urinary tract pathology, demonstrating that acute inflammation is reversible. However, the reversibility of chronic changes is less well studied. Methods Our study compared, at two time points 14 y apart, urine egg-patent infection and urinary tract pathology in a cohort of women living in a highly endemic area having intermittent praziquantel treatment(s). In 2014 we matched 93 women to their findings in a previous study in 2000. Results Between 2000 and 2014 the rate of egg-patent infection decreased from 34% (95% confidence interval [CI] 25 to 44) to 9% (95% CI 3 to 14). However, urinary tract pathology increased from 15% (95% CI 8 to 22) to 19% (95% CI 11 to 27), with the greatest increase seen in bladder thickening and shape abnormality. Conclusions Despite praziquantel treatment, fibrosis from chronic schistosomiasis outlasts the presence of active infection, continuing to cause lasting morbidity. We suggest that future efforts to eliminate persistent morbidity attributable to schistosomiasis should include intensified disease management.

Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA-binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by short hairpin RNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Because bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV cross-linking and RNA immunoprecipitation, we show that HuR bound to the 3′-untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target. Mol Cancer Res; 9(5); 648–59. ©2011 AACR.

Supplementary Information

Supplementary Data

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies.Significance:Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas.This article is highlighted in the In This Issue feature, p. 1611

Supplementary Figures S1-S2 from The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance

Purpose: Enzalutamide, a second-generation androgen antagonist, was approved by the U.S. Food and Drug Administration (FDA) for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study was performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment.Experimental Design: Male C57BL/6 or TRAMP (transgenic adenocarcinoma of the mouse prostate) prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiologic and immunologic effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was assessed. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated.Results: Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4+ T-cell proliferation and regulatory T cell (Treg) functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the ability of Twist-vaccine to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared with other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors.Conclusions: These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC. Clin Cancer Res; 19(22); 6205–18. ©2013 AACR.

File (tmp-LBN-Report_PH-DMPK-UAB-19-001_SRI-42127 _Mouse IP Plasma Brain PK) provides pharmacokinetic data for Fig. S14.

Supplementary materials including tables, figures, and detailed methods.

PDF file - 2461K, Supplemental Table 1: Cellular immune responses to multiple tumor antigens after combination therapy with MDV3100 and Twist-vaccine.

Numerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT) process is involved in solid tumor progression, metastasis, and drug resistance. Several transcription factors have been implicated as drivers of EMT and metastatic progression, including Twist. Overexpression of Twist has been shown to be associated with poor prognosis and drug resistance for many carcinomas and other tumor types. The role of Twist in experimental cancer metastases has been principally studied in the 4T1 mammary tumor model, where silencing of Twist in vitro has been shown to greatly reduce in vivo metastatic spread. Transcription factors such as Twist are generally believed to be “undruggable” because of their nuclear location and lack of a specific groove for tight binding of a small molecule inhibitor. An alternative approach to drug therapy targeting transcription factors driving the metastatic process is T-cell–mediated immunotherapy. A therapeutic vaccine platform that has been previously characterized consists of heat-killed recombinant Saccharomyces cerevisiae (yeast) capable of expressing tumor-associated antigen protein. We report here the construction and characterization of a recombinant yeast expressing the entire Twist protein, which is capable of inducing both CD8+ and CD4+ Twist-specific T-cell responses in vivo. Vaccination of mice reduced the size of primary transplanted 4T1 tumors and had an even greater antitumor effect on lung metastases of the same mice, which was dependent on Twist-specific CD8+ T cells. These studies provide the rationale for vaccine-induced T-cell–mediated therapy of transcription factors involved in driving the metastatic process. Cancer Res; 74(7); 1945–57. ©2014 AACR.

PDF file - 358KB, Expression of EMT marker expression in primary tumor and lung metastases.

PDF file - 138KB, Expression of murine Twist protein in S. cerevisiae Yeast.

PDF file - 208KB, Recombinant Yeast-Twist vaccination does not induce toxicity.

The insect equivalent of taste buds are gustatory sensilla, which have been found on mouthparts, pharynxes, antennae, legs, wings, and ovipositors. Most gustatory sensilla are uniporous, but not all apparently uniporous sensilla are gustatory. Among sensilla containing more than one neuron, a tubular body on one dendrite is also indicative of a taste sensillum, with the tubular body adding tactile function. But not all taste sensilla are also tactile. Additional morphological criteria are often used to recognize if a sensillum is gustatory. Further confirmation of such criteria by electrophysiological or behavioral evidence is needed. The five canonical taste qualities to which insects respond are sweet, bitter, sour, salty, and umami. But not all tastants that insects respond to easily fit in these taste qualities. Categories of insect tastants can be based not only on human taste perception, but also on whether the response is deterrent or appetitive and on chemical structure. Other compounds that at least some insects taste include, but are not limited to: water, fatty acids, metals, carbonation, RNA, ATP, pungent tastes as in horseradish, bacterial lipopolysaccharides, and contact pheromones. We propose that, for insects, taste be defined not only as a response to nonvolatiles but also be restricted to responses that are, or are thought to be, mediated by a sensillum. This restriction is useful because some of the receptor proteins in gustatory sensilla are also found elsewhere.

Autophagy receptors are essential for the recognition and clearance of specific cargos by selective autophagy, which is essential for maintaining MAPT proteostasis. Previous studies have implicated different autophagy receptors in directing distinct species of MAPT to autophagy, but the underlying mechanisms have not been fully investigated. Here we examine how the autophagy receptors NBR1 and SQSTM1 differentially engage specific forms of MAPT and facilitate their clearance. In primary neurons depletion of NBR1, unlike depletion of SQSTM1, significantly increased phosphorylated MAPT levels. The specificity of the interactions were confirmed using in vitro binding assays with purified proteins. We provide direct evidence that NBR1 preferentially binds to monomeric MAPT, while SQSTM1 interacts predominantly with oligomeric MAPT, and that the co-chaperone BAG3 regulates the specificity of these interactions. Using an in vitro pulldown assay, we show that SQSTM1 only binds to monomeric MAPT when BAG3 is absent and fails to bind when BAG3 is present. The opposite is true of NBR1; its binding to monomeric MAPT was dependent on the presence of BAG3. Interestingly, in Alzheimer’s disease brain the association of NBR1 with BAG3 was significantly decreased. In a mouse model, ablation of BAG3 in neural cells disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT. Overall, our results uncover a novel role for BAG3 in regulating the specificity of selective autophagy receptors in targeting different species of MAPT and provide compelling evidence that BAG3 plays a key role in maintaining MAPT proteostasis.HighlightsFirst direct evidence of the district role of NBR1 and SQSTM1 in binding with monomeric and oligomeric MAPT, respectively.Demonstration of a novel mechanism by which BAG3 regulates the specificity of the recognition of monomeric MAPT by NBR1 and oligomeric MAPT by SQSTM1.Conditional knockout of BAG3 in the brain disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT.

In Plato’s Philebus, Socrates argues that human life must consist of knowledge and pleasure if it is to be good. Part of this demonstration is an account of the parts of knowledge whereby knowledge can be more or less pure, more or less blended with extraneous elements such as sensation and practice. When pure, it cleaves to truth, pure and simple. For, as we must admit, knowledge is true, whatever else it is. Knowledge may make humans good, i.e. enable them to do well, reliably and flexibly what they do, but has its good above and beyond human existence – it is not restricted to human existence. The suggestion is that Plato here in fact determines knowledge by using its end – its final cause is used to determine its formal cause: what knowledge is for tells us what it is. Instead of giving an analysis along the lines of the final, failed account of the Theaetetus (“justified true belief”), knowledge is thereby given a functional account. Part of this suggestion is that knowledge must be true, and this is what guarantees its stability: its end is internal to it. The good of knowledge is truth. This is what enables it to act as a guide to the soul. The further attributes of this clan, knowledge, flow from truth and their relation to it: exactness, clarity, and purity. For insofar as they are pure, and unmixed with extraneous elements such as practice or sensation, they are concerned simply with exact units, things that are just what they are, so their clarity is not troubled by anything. It is dialectic that investigates and establishes this.

Disseminated intravascular coagulation (DIC) is a rare complication of endovascular aortic repair, commonly associated with type I or type III endoleaks. DIC is also known as consumption coagulopathy because excessive thrombin formation and secondary fibrinolysis leads to consumption of coagulation factors with hyperfibrinolysis and activation of platelets, which can lead to excessive bleeding. We present the case of an 80-year-old woman who had undergone thoracic endovascular aortic repair for a type B aortic dissection that was complicated by a series of recurrent endoleak-induced DICs requiring multiple thoracic endovascular aortic repair extensions to cover the entire thoracoabdominal aorta. The DIC persisted despite the resolution of the endoleaks.

Extreme precipitation events are expected to become more intense and frequent with climate change. This climatic shift may impact the structure and dynamics of natural communities and the key ecosystem services they provide. Changes in species abundance under these extreme conditions are thought to be driven by functional traits, morpho-physiological characteristics of an organism that impact its fitness. Future environmental conditions may, therefore, favour different functional traits to those in present-day communities.Here, we measure functional traits on 586 vascular plants in a temperate grassland where precipitation has been experimentally manipulated for six years. We calculated community-weighted means of five functional traits (plant height, leaf dry matter content, leaf thickness, specific leaf area, and leaf phosphorus concentration) and compared community-weighted means between three levels of precipitation: drought (−50%), irrigated (+50%), and control. Additionally, we contrasted treatments at two different timings along the growing season: mid-season and late-season.We expected altered community-weighted means for traits associated with a conservative use of water that will result from increased summer stress-induced intraspecific variability in the mid-season and from community composition changes in the late-season, after the field is cut, a common management action across most European grasslands.In the drought treatment, we found significantly lower community-weighted mean plant height and leaf dry matter content. However, we only observed these differences after the mid-season cut. We also observed an increase in leaf phosphorus concentration in the drought treatment before the mid-season cut. A combination of changes in community composition and intraspecific variation contributed to these differences, with community composition being more important after the cut. Species with higher height, leaf dry matter content, and lower leaf thickness showed a more pronounced abundance decline at the drought plots. We observed no changes in functional traits community-weighted means in the irrigated treatment compared to those in control and drought treatments.Synthesis. Our results suggest how the functional trait composition of grassland communities may shift under climate change-induced drought, stressing the interacting effects with growing season stages.