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BACKGROUND: Prospective genetic evaluation of patients at our referral research hospital presents clinical research challenges. OBJECTIVE: This study sought not only a single-gene explanation for participants’ immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune-phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: We developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% ≥18 years, and had diverse immune presentations. Overall, 327/1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9/22, 40.9%). One-quarter of the molecular diagnoses (92/361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251/361 (69.5%) of these molecular diagnoses could translate into ≥1 management option. CONCLUSION: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Background Post-infectious inflammatory response syndrome(PIIRS) is a previously reported complication of non-HIV cryptococcal meningitis (CM) involving a pathological T cell-mediated neuroinflammatory response once the fungus has been cleared. Although corticosteroids have been successfully used as therapy, side effects preclude prolonged use. Additionally, alternative targeted agents may be required as adjunctive therapy in steroid-refractory PIIRS. We report the clinical course in 3 patients in whom Janus kinase (JAK) inhibitor use led to favorable outcomes when used along with corticosteroids. Methods Medical records of three previously healthy CM-PIIRS patients admitted to the NIH between January 2021 to December 2021 were used to prepare this report. All were transferred from another facility due to worsening neurological status. Neurological exam and radiological findings were compared at baseline and one month after ruxolitinib initiation. CSF parameters including cellular markers of T-cell inflammation (HLA-DR+ CD4+ and HLA-DR+ CD8 cells and monocytes) and soluble CSF cytokines, including IL-6 and sCD25, were also included in the comparison. Results One patient was on 1mg/kg oral prednisone for 8 months with no improvement in symptoms despite VP shunt placement. The other two had also been on moderate-dose oral steroids for approximately 6 weeks for a recent diagnosis of PIIRS. All three were started on ruxolitinib (5-10 mg PO BID) as an adjunct to prednisone with a significant improvement in their neurological status, CSF inflammatory markers, and radiological findings. CSF fungal cultures remained negative with no occurrence of adverse events 3 months after ruxolitinib initiation. Therapy with ruxolitinib allowed continued corticosteroid taper without clinical flairs of disease in each patient. Conclusion The selective JAK1/2 inhibitor, ruxolitinib, was safe in a small group of HIV-negative patients with CM. This agent may offer promise in conjunction with corticosteroids in the treatment of non-HIV CM patients with refractory PIIRS who are at risk for adverse side effects related to prolonged steroid use. Further study will be required to determine efficacy, tolerability and ability to reduce corticosteroid use. Disclosures All Authors: No reported disclosures.

During breed development, domestic dogs have undergone genetic bottlenecks and sustained selective pressures, as a result distinctive genomic diversity occurs to varying degrees within and between breed groups. This diversity can be identified using standard methods or combinations of these methods. This study explored the application of a combined selection index, composite selection signals (CSS), derived from multiple methods to an existing genotype dataset from three breed groups developed in distinct regions of Asia: Qinghai-Tibet plateau dogs (adapted to living at altitude), Xi dogs (with superior running ability) and Mountain hounds (used for hunting ability). The CSS analysis confirmed top ranked genomic regions on CFA10 and CFA21 in Qinghai-Tibet plateau dogs, CFA1 in Xi dogs and CFA5 in Mountain hounds. CSS analysis identified additional significant genomic regions in each group, defined by a total of 1,397, 1,475 and 1,675 significant SNPs in the Qinghai-Tibetan Plateau dogs, Xi dogs and Mountain hounds, respectively. Chitinase 3 Like 1 (CHI3L1) and Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6) genes were located in the top ranked region on CFA7 (0.02–1 Mb) in the Qinghai-Tibetan Plateau dogs. Both genes have been associated with hypoxia responses or altitude adaptation in humans. For the Xi dogs, the top ranked region on CFA25 contained the Transient Receptor Potential Cation Channel Subfamily C Member 4 (TRPC4) gene. This calcium channel is important for optimal muscle performance during exercise. The outstanding signals in the Mountain dogs were on CFA5 with 213 significant SNPs that spanned genes involved in cardiac development, sight and generation of biochemical energy. These findings support the use of the combined index approach for identifying novel regions of genome diversity in dogs. As with other methods, the results do not prove causal links between these regions and phenotypes, but they may assist in focusing future studies that seek to identify functional pathways that contribute to breed diversity.

An autosomal recessive form of inherited cerebellar abiotrophy (CA) that is characterized by a degeneration of Purkinje and granule cells in the cerebellar cortex occurs in the Australian working kelpie dog breed. The clinical signs of CA include ataxia, head tremor, motor in-coordination, wide-based stance, and high-stepping gait. Investigation of clinical and pathological features indicated two closely related diseases with differences in age of onset. A genome-wide association study on 45 CA affected and 290 normal healthy Kelpies identified two significantly associated loci, one on CFA9 and a second on CFA20. Dogs homozygous for the risk haplotype on CFA20 (23 dogs) show clinical signs before ten weeks of age. Missense variants in the sixth exon of disruptor of telomeric silencing 1-like (DOT1Lp.R200Q) and in the only exon of Leucine Rich Repeat And Ig Domain Containing 3 (LINGO3p.R359C), both on CFA20, segregate with the associated risk marker which has incomplete penetrance (42%). Affected dogs homozygous for the risk haplotype on CFA9 have later onset ataxia. A missense variant in exon 5 of Vacuole Membrane Protein 1 (VMP1 p.P160Q) on CFA9 segregates as a fully penetrant Mendelian recessive with later-onset CA. Across mammals, the variety of causative loci so far identified as influencing cerebellar disorders reinforces the complexity of the pathways that contribute to cerebellar development and function, and to the pathophysiological mechanisms that may lead to cerebellar ataxia.

In 2018, a university-wide brand update prompted the University of Idaho Library to re-examine their website development practices and move towards a static web approach that leverages librarian skillsets and provides the library greater control over its systems and data. This case study describes the methodological reasons behind the decision to use the static site generator Jekyll over a Content Management System (CMS) and the practical steps taken to create a sustainable and agile development model. The article details the ways this static web approach (nicknamed “Lib-STATIC”) facilitates cross-departmental communication, collaboration, and innovative feature development for library staff members of varying technical abilities. (Post print version of published article)

The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa. IMPORTANCE The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.

Objectives The aims of this study were to (1) describe the results of a survey on the clinical features of lymphoma in Australian Border Collies and (2) investigate familial clustering of lymphoma-affected dogs by means of pedigree analyses. Methods Clinical and pedigree information was collected from surveys completed by owners or breeders of Australian Border Collies. Relationships between dogs were derived from pedigree data and kinship was analysed by network and cluster-based algorithms. Results A total of 246 respondents completed the survey and 57 lymphoma-affected Australian Border Collies were identified. The mean age of diagnosis was 9.16 (SD ± 3.43) years and the median was 9.7 years (range 2-15 years). The odds of female dogs affected with lymphoma were twice those of males in the reported data (OR = 2.06; 95% CI = 1.13-3.73; P = 0.02). Multicentric, high-grade B-cell lymphoma was the most common form in these dogs. Pedigree analyses identified 21 affected dogs that descended from two sires and 28 cases with a common female ancestor. Average inbreeding between both affected and unaffected dogs was similar (0.16, SD ± 0.06 and 0.15, SD ± 0.06, respectively). Conclusion The survey confirmed the presence of a relatively large number of cases of lymphoma in Australian Border Collies, consistent with our previous report of increased risk in this breed. Some dogs were diagnosed at a very young age, but the age ranged over the normal lifespan. Pedigree analyses identified multiple cases within family groups, suggesting a heritable component of the disease in this breed.

Background Lymphoma is common in the dog. Studies of population risk factors primarily have been derived from referral institution or insurance data. Objective To identify and quantify the host risk factors for lymphoma in a broad population of Australian dogs. Animals Data on 6201 client owned dogs were retrieved from a commercial veterinary laboratory, a general practice group and 2 referral hospitals. Methods Data collected included breed, sex, and neuter status. A reference population of 640 105 dogs was generated from the referral hospitals and from council registration data. The risk of lymphoma by sex and neuter status was calculated as odds ratios (OR). Results The study identified 30 breeds at increased risk of lymphoma, 15 that have not been reported previously, and 26 breeds at decreased risk, 18 that have not been reported previously. Males were over represented compared to females with an OR of 1.1 (95% CI, 1.1–1.2; P < .001). Neutered animals were at higher risk compared to intact animals with an OR of 3.2 (95% CI, 2.9–3.5) which was found in both males (OR, 2.8; 95% CI; 2.5–3.2) and females (OR, 4.4; 95% CI, 3.5–5.1). Conclusions and Clinical Importance Breed, sex, and neuter status alter the risk of lymphoma in dogs. These 3 factors must be considered when evaluating lymphoma risk as potential markers of underlying differences in disease etiology. Comparison of breeds at increased and decreased risk could be advantageous when evaluating specific etiological factors.

This paper focuses on the relationship between two important business indices: the degree to which a country's business is centrally regulated, and the level of business corruption perceived in that country. The main purpose and methodology is to analyze the data from 47 globally dispersed countries based on the Organization for Economic Cooperation and Development (OECD) Product and Market Regulation Index and Transparency International's Corruption Perceptions Index from 2013. The statistical methodology using regression analysis demonstrates that there is a significant negative relationship between levels of perceived corruption and levels of regulation. This paper empirically confirms that corruption tends to increase with low levels of regulations. The results of this study can be useful for policy makers, managers, and research; as such, the authors provide appropriate recommendations for policy-makers and business leaders. While there are examples from several countries in this paper, the authors provide many sources and literature from the United States as most readers can easily relate to them. The limitations of the study and suggestions for future research are also stated. Overall, the findings of this study show that more product market regulation is a significant factor in demonstrating less perceived corruption for the 47 countries selected for this research. Our results demonstrate that countries with high levels of regulation have low perceived levels of corruption. In this focused empirical study, the authors found that more regulation is associated with less perceived corruption. So, what explanations might be advanced? Perhaps the answer lies in the ability of business regulation to actually make a difference in the level of corruption, even presuming there is a desire to do so. If we assume it is desirable to reduce the level of corporate corruption, and that one of the mechanisms to achieve this objective is through sensible business regulation

Canine (Canis lupus familiaris) atopic dermatitis (AD) shares similar clinical signs to human AD. The abnormal immune response of AD is orchestrated by T lymphocytes, and may include variable involvement of cytokines, regulatory T (Treg) cells, eosinophils, mast cells and other immune components. Helper T (Th)2 cytokines often predominate initially, followed by Th1 cytokines in more chronic phases.Pro-inflammatory and Treg cytokines have been shown to play a role in human AD, yet their importance is not clear in canine AD. Hence, this study aimed to measure the concentrations of cytokines/chemokines not traditionally associated with Th1/Th2 response.Canine AD patients (n = 27), compared to control dogs (n = 11).A total of 19 plasma cytokines were assayed using canine specific multiplex immuno-assays.The plasma concentrations of CXC Motif Chemokine Ligand 8 (CXCL8), interleukin (IL)-7 and IL-15 cytokines were elevated in canine AD patients, compared to control dogs. In addition, stem-cell factor (SCF) concentrations were reduced in the plasma of canine AD patients compared to control dogs. Distinct cytokine profiles were found in dogs belonging to the Staffordshire breeds, a group with increased risk of AD. In particular, granulocyte-macrophage colony-stimulating factor (GM-CSF) had significantly elevated concentrations.Some of the plasma cytokine alterations in canine AD described here, particularly of IL-7, have not been reported previously. Monitoring these distinctive cytokine alterations could be useful for diagnosis and monitoring of canine AD in dogs.La dermatite atopique (DA) canine (Canis lupus familiaris) partage des signes cliniques similaires à la DA humaine. La réponse immunitaire anormale de la DA est orchestrée par les lymphocytes T et peut inclure une implication variable des cytokines, des cellules T régulatrices (Treg), des éosinophiles, des mastocytes et d'autres composants immunitaires. Les cytokines Helper Th2 prédominent souvent au début, suivies par les cytokines Th1 dans les phases plus chroniques. HYPOTHÈSE/OBJECTIFS: Il a été démontré que les cytokines pro-inflammatoires et Treg jouent un rôle dans la DA humaine, mais leur importance n'est pas claire dans la DA canine. Par conséquent, cette étude visait à mesurer les concentrations de cytokines/chimiokines non traditionnellement associées à la réponse Th1/Th2.Chiens AD (n = 27), comparés aux chiens témoins (n = 11). MATÉRIELS ET MÉTHODES: Au total, 19 cytokines plasmatiques ont été dosées à l'aide d'immunotests multiplex spécifiques canins. RÉSULTATS: Les concentrations plasmatiques de CXC Motif Chemokine Ligand 8 (CXCL8), d'interleukine (IL)-7 et de cytokines IL-15 étaient élevées chez les chiens atteints de DA par rapport aux chiens témoins. De plus, les concentrations de facteur de cellules souches (SCF) ont été réduites dans le plasma des patients atteints de DA par rapport aux chiens témoins. Des profils de cytokines distincts ont été trouvés chez les chiens appartenant aux races Staffordshire, un groupe présentant un risque accru de DA. En particulier, le facteur de stimulation des colonies de granulocytes-macrophages (GM-CSF) avait des concentrations significativement élevées.Certaines des altérations des cytokines plasmatiques dans la DA canine décrites ici, en particulier de l'IL-7, n'ont pas été rapportées auparavant. Le suivi de ces altérations cytokiniques distinctives pourrait être utile pour le diagnostic et le suivi de la DA canine.INTRODUCCIÓN: la dermatitis atópica (AD) canina (Canis lupus familiaris) comparte signos clínicos similares a la AD humana. La respuesta inmune anormal de la AD está orquestada por linfocitos T y puede incluir una participación variable de citoquinas, células T reguladoras (Treg), eosinófilos, mastocitos y otros componentes inmunitarios. Las citoquinas auxiliares T (Th)2 a menudo predominan inicialmente, seguidas de las citoquinas Th1 en fases más crónicas. HIPÓTESIS/OBJETIVOS: Se ha demostrado que las citoquinas proinflamatorias y Treg desempeñan un papel en la AD humana, pero su importancia no está clara en la AD canina. Por lo tanto, este estudio tuvo como objetivo medir las concentraciones de citoquinas/quimioquinas no asociadas tradicionalmente con la respuesta Th1/Th2. ANIMALES: pacientes caninos con AD (n = 27), en comparación con perros control (n = 11). MÉTODOS Y MATERIALES: se analizaron un total de 19 citoquinas del plasma utilizando inmunoensayos multiplex específicos caninos. RESULTADOS: las concentraciones en el plasma de la quimioquina ligando 8 del motivo de quimioquina CXC (CXCL8), interleuquinas (IL)-7 e IL-15 estaban elevadas en los pacientes caninos con AD, en comparación con los perros control. Además, las concentraciones de factor de células madre (SCF) se redujeron en el plasma de los pacientes caninos con AD en comparación con los perros control. Se encontraron perfiles de citoquinas distintos en perros pertenecientes a las razas Staffordshire, un grupo con mayor riesgo de AD. En particular, el factor estimulante de colonias de granulocitos y macrófagos (GM-CSF) tenía concentraciones significativamente elevadas. CONCLUSIONES Y RELEVANCIA CLÍNICA: algunas de las alteraciones de las citoquinas del plasma en la AD canina descritas aquí, en particular de IL-7, no se han publicado previamente. El seguimiento de estas alteraciones distintivas de las citoquinas podría ser útil para el diagnóstico y seguimiento de la AD canina en perros.Die atopische Dermatitis (AD) des Hundes (Canis lupus familiaris) zeigt ähnliche klinische Zeichen wie die AD des Menschen. Die abnormale Immunantwort der AD wird durch die T Lymphozyten verursacht und kann eine unterschiedliche Beteiligung von Zytokinen, regulatorischen T (Treg) Zellen, Eosinophilen, Mastzellen und andere Immunkomponenten zeigen. Helfer T (Th)2 Zytokine sind anfangs oft dominant, gefolgt von Th1 Zytokinen in den mehr chronischen Phasen.Es konnte gezeigt werden, dass pro-entzündliche und Treg Zytokine eine wichtige Rolle bei der AD des Menschen spielen, ihre Bedeutung bei der AD des Hundes ist jedoch unklar. Daher war das Ziel dieser Studie die Messung der Konzentrationen von Zytokinen/Chemokinen, die traditionellerweise nicht mit einer Th1/Th2 Antwort im Zusammenhang stehen.Canine AD Patienten (n = 27) im Vergleich zu Kontrollhunden (n = 11).Insgesamt wurden 19 Zytokine mittels spezifischen caninen Multiplex Immuno-Assays im Plasma bestimmt.Die Plasmakonzentrationen von CXC Motif Chemokin Ligand 8 (CXCL8) sowie den Zytokinen Interleukin (IL)-7 und IL-15 waren bei den Hunden mit AD im Vergleich zu den Kontrollhunden erhöht. Zusätzlich waren die Konzentrationen des Stammzellfaktors (SCF) im Plasma von Hunden mit AD im Vergleich zu den Kontrollhunden reduziert. Deutliche Zytokinprofile wurden bei Hunden, die zu den Staffordshire Rassen gehören, bei denen es sich um eine Gruppe mit einem erhöhten AD Risiko handelt, gefunden. Im Speziellen war der Granulozyten-Makrophagenkolonie-stimulierende Faktor (GM-CSF) signifikant erhöht.Einige der Veränderungen der Plasmazytokine, die hier bei den Hunden mit AD beschrieben wurden, im Speziellen IL-7, wurden bisher noch nicht publiziert. Eine Überwachung dieser klaren Zytokin Veränderungen könnte bei der Diagnose und beim Monitoring von Hunden mit AD nützlich sein.背景: 犬 (Canis lupus familiaris)アトピー性皮膚炎(AD)は、ヒトのADと臨床症状が類似している。アトピー性皮膚炎の異常な免疫反応は、Tリンパ球を中心に、サイトカイン、レギュラトリーT(Treg) 細胞、好酸球、マスト細胞、その他の免疫成分が関与している可能性がある。初期にはヘルパーT(Th)2サイトカインが優勢で、より慢性的な段階ではTh1サイトカインが続くことが多い。 仮説/目的: 炎症性サイトカインおよびTregサイトカインは、ヒトのADにおいて役割を果たしていることが示されているが、犬ADにおいてはその重要性は明らかではない。そこで本研究では、従来はTh1/Th2反応に関連していなかったサイトカイン/ケモカインの濃度を測定することを目的とした。 被検動物: 犬AD症例(n=27)および対照犬 (n=11) を比較した。 材料と方法: 計19種類の血漿サイトカインを、犬特異的マルチプレックス免疫測定法を用いて測定した。 結果: 犬AD症例では、CXC Motif Chemokine Ligand 8(CXCL8) 、インターロイキン (IL)-7、IL-15サイトカインの血漿濃度が対照犬と比較して上昇していた。また、犬AD症例の血漿中の幹細胞因子 (SCF) 濃度は、対照犬に比べて低下していた。ADのリスクが高いとされるスタッフォードシャー種に属する犬では、独特のサイトカインプロファイルが見られた。特に、顆粒球-マクロファージコロニー刺激因子 (GM-CSF) の濃度が有意に上昇していた。 結論と臨床的妥当性: 今回報告された犬ADにおける血漿中のサイトカインの変化のうち、特にIL-7の変化はこれまでに報告されていないものである。これらの特徴的なサイトカインの変化をモニタリングすることは、犬AD診断やモニタリングに有用であると考えられる。.背景: 犬 (家犬) 特应性皮炎 (AD) 的临床症状与人类AD相似。AD的异常免疫反应由T淋巴细胞协调, 可能包括细胞因子、调节性T(Treg) 细胞、嗜酸性粒细胞、肥大细胞和其他免疫组分的不同参与。辅助性T(Th)2细胞因子最初通常占主导地位, 在更慢性阶段紧随其后的是Th1细胞因子。 假设/目标: 促炎细胞因子和Treg细胞因子已被证明在人类AD中发挥作用, 但它们在犬AD中的重要性尚不清楚。因此, 本研究旨在测量传统上与Th1/Th2反应无关的细胞因子/趋化因子的浓度。 动物: AD患犬(n=27)与对照犬 (n=11) 相比。 方法和材料: 共有19种血浆细胞因子采用犬特异性多重免疫分析法进行检测。 结果: 与对照犬相比, 犬AD患者的CXC基序趋化因子配体8(CXCL8) 、白细胞介素 (IL)-7和IL-15细胞因子的血浆浓度升高。此外, 与对照犬相比, AD患犬血浆中的干细胞因子 (SCF) 浓度降低。在斯坦福德犬身上发现了不同的细胞因子谱, 斯坦福德犬罹患AD的风险增加。尤其是粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 的浓度显著升高。 结论和临床相关性: 本文描述的犬AD中的一些血浆细胞因子改变, 特别是IL-7的改变, 以前没有报道过。监测这些独特的细胞因子变化可能有助于诊断和监测AD患犬。.A dermatite atópica (DA) canina (Canis lupus familiaris) apresenta sinais clínicos similares à DA humana. A resposta imune anormal da DA é orquestrada por linfócitos T, e pode incluir o envolvimento variável de citocinas, células T regulatórias (Treg), eosinófilos, mastócitos e outros componentes imunes. As citocinas derivadas de linfócitos T helper (Th)2 geralmente predominam na fase inicial, seguidas pelas citocinas Th1 na fase mais crônica. HIPÓTESE/OBJETIVOS: Citocinas pró-inflamatórias e citocinas Treg tem demonstrado funções na DA humana, mas a sua importância ainda não é clara na DA canina. Desta forma, este estudo teve o objetivo de mensurar as concentrações de citocinas/quimiocinas não tradicionalmente associadas às respostas Th1/Th2. ANIMAIS: pacientes com DA canina (n = 27), comparados a cães controles (n = 11). MATERIAIS E MÉTODOS: Um total de 19 citocinas plasmáticas foram avaliadas utilizando imunoensaios multiplex específicos para cães.As concentrações plasmáticas de CXC Motif Chemokine Ligand 8 (CXCL8), interleucina (IL)-7 e IL-5 estavam aumentaas nos cães com DA, comparado aos cães controle. Além disto, as concentrações do fator de célula tronco (SCF) estavam reduzidas no plasma dos pacientes com DA canina comparada aos cães controle. Foram encontrados perfis de citocinas distintos nos cães pertencentes às raças Staffordshire, um grupo com maior risco de DA. Em particular, o fator estimulador de colônias de macrófagos-granulócitos (GM-CSF) apresentou concentrações significativamente elevadas. CONCLUSÕES E IMPORTÂNCIA CLÍNICA: Algumas das alterações nas citocinas plasmáticas na DA canina descritas aqui, particularmente IL-7, não haviam sido descritas anteriormente. O monitoramento dessas alterações distintas de citocinas pode ser útil para o diagnóstico e monitoramento da DA em cães.

Anderson, T., Gaines, A., Leachman, C., & Williamson, EP. (2017). Faculty and instructor perceptions of open educational resources in engineering. Post-print. The Reference Librarian. http://dx.doi.org/10.1080/02763877.2017.1355768.

Elephant-mediated transmission of tuberculosis is assumed to be similar to human models, which state close and prolonged contact with an infected individual is required for transmission. Although considered a risk factor for infection, several case studies have reported that close contact with an elephant is not always necessary for transmission, and the role of aerosolized bacteria remains unclear. To investigate aerosol-mediated transmission of pathogenic bacteria from elephants, a method for the detection of aerosols using an adapted sampling system was developed. A commensal bacterium was isolated from the upper respiratory tract of elephants (Elephas maximus) and was used as a proxy organism to detect aerosolized droplets in the sampling system. It was found that elephants are capable of producing aerosolized bacterial particles of a size small enough to remain airborne for prolonged periods and penetrate the lower regions of the human respiratory tract.

Recent advances in technology for both describing and interrogating the sequence and structure of animal genomes and their functional variation have presented opportunities for scientists to more clearly understand the complexity of bovine milk protein structure and utility and the control of milk protein gene expression. Using these technologies in conjunction with protein sequence data, we can begin to understand the significance of naturally occurring genetic variation influencing milk protein production and composition and how the proteins in colostrum and milk are processed/digested into biologically active peptides. The challenge is to translate this information into useful nutritional and nutraceutical products that help to underpin the commercial viability of the dairy industry. Recent advances in genetic technologies provide the potential for accurate selection of desirable traits in dairy cow populations through genomic methods. Milk composition may also be modified through gene editing, although consumer acceptance of genetically modified foods is still an issue. We present a review of the current status of bovine milk genomics, including functional genomics and gene editing approaches, and discuss the roles, characteristics, and key bioactivities of the major bovine milk proteins and their encrypted peptides.

German shepherd dogs (GSDs) are a popular breed affected by numerous disorders. Few studies have explored genetic variations that influence canine blood metabolite levels. To investigate genetic variants affecting the natural metabolite variation in GSDs. A total of 82 healthy GSDs were genotyped on the Illumina CanineHD Beadchip, assaying 173,650 markers. For each dog, 74 metabolites were measured through liquid and gas chromatography mass spectrometry (LC–MS and GC–MS) and were used as phenotypes for genome-wide association analyses (GWAS). Sliding window and homozygosity analyses were conducted to fine-map regions of interest, and to identify haplotypes and gene dosage effects. Summary statistics for 74 metabolites in this population of GSDs are reported. Forty-one metabolites had significant associations at a false discovery rate of 0.05. Two associations were located around genes which encode for enzymes for the relevant metabolites: 4-hydroxyproline was significantly associated to D-amino acid oxidase (DAO), and threonine to l-threonine 3-dehydrogenase (LOC477365). Three of the top ten haplotypes associated to 4-hydroxyproline included at least one SNP on DAO. These haplotypes occurred only in dogs with the highest 15 measurements of 4-hydroxyproline, ranging in frequency from 16.67 to 20%. None of the dogs were homozygous for these haplotypes. The top two haplotypes associated to threonine included SNPs on LOC477365 and were also overrepresented in dogs with the highest 15 measurements of threonine. These haplotypes occurred at a frequency of 90%, with 80% of these dogs homozygous for the haplotypes. In dogs with the lowest 15 measurements of threonine, the haplotypes occurred at a frequency of 26.67% and 0% homozygosity. DAO and LOC477365 were identified as candidate genes affecting the natural plasma concentration of 4-hydroxyproline and threonine, respectively. Further investigations are needed to validate the effects of the variants on these genes.

Despite the rapid expansion of and investment in urban residency programs, a key tenet of the residency model—that they prepare teachers for targeted urban settings—remains largely unexamined. Although some might argue that a “good teacher” can transcend contexts—we ask in this issue whether there may be particular features of the setting or context that are important for new teachers to learn about. In the papers in our special issue, the authors examine more closely what kind of preparation may be necessary for specific contexts. This themed issue features scholarship that examines efforts to prepare teachers for clinical practice in particular contexts. The articles share evidence from three residency programs (each engaged in systematic data collection) on opposite sides of the US to point to features of the context that may matter for teaching; the design of opportunities to learn in these programs; and data that sheds light upon these questions. Given recent findings about the strong retention of graduates of ‘context-specific programs’ these examinations not only provide insight into the promise of urban residency programs but also serve as a call for programs to be epecially clear about the specific features of the setting that may matter for teaching.

Urban teacher residencies have emerged as an innovation for recruiting, preparing, and retaining teachers for high-need urban schools. Though residencies aim to prepare teachers for specific urban contexts, we know little about how context is conceptualized in the teacher education curriculum or what teachers learn about it. This study finds that participants in one residency in San Francisco came to see context as complex and layered, interrupting stigmas often associated with urban schools. Participants felt well prepared to teach in particular high-need settings, but their knowledge and skills did not necessarily transfer to other urban settings in the same city.

Cells of the immune system undergo activation and subsequent proliferation in the normal course of an immune response. Infrequently, the molecular and cellular events that underlie the mechanisms of proliferation are dysregulated and may lead to oncogenesis, leading to tumor formation. The most common forms of immunological cancers are lymphomas, which in dogs account for 8%-20% of all cancers, affecting up to 1.2% of the dog population. Key genes involved in negatively regulating proliferation of lymphocytes include a group classified as tumor suppressor genes (TSGs). These genes are also known to be associated with progression of lymphoma in humans, mice, and dogs and are potential candidates for pathological grading and diagnosis. The aim of the present study was to analyze TSG profiles in stimulated leukocytes from dogs to identify genes that discriminate an activated phenotype. A total of 554 TSGs and three gene set collections were analyzed from microarray data. Cluster analysis of three subsets of genes discriminated between stimulated and unstimulated cells. These included 20 most upregulated and downregulated TSGs, TSG in hallmark gene sets significantly enriched in active cells, and a selection of candidate TSGs, p15 ( CDKN2B), p18 ( CDKN2C), p19 ( CDKN1A), p21 ( CDKN2A), p27 ( CDKN1B), and p53 ( TP53) in the third set. Analysis of two subsets suggested that these genes or a subset of these genes may be used as a specialized PCR set for additional analysis.

Identification of genomic variants within dogs is important for understanding genetic factors contributing to breed diversity and phenotypic traits. This study aimed to identify sources of variation in the Bullmastiff using high-density signal intensity and whole-genome sequence data. Close to 3000 copy number variants (CNVs) were identified in Bullmastiff dogs using Canine HD BeadChip data. When CNVs were collated, 82 CNV regions (CNVRs) were detected, 50% in transcribed regions encompassing 432 genes. Fifty of the CNVRs detected have not been reported in other breeds and represent potential breed-specific variants. A proportion of the CNVR variants with predicted modifying effects on gene pathways may contribute to breed traits. Approximately 5 million putative variants per dog, inclusive of single nucleotide polymorphisms (SNPs), multi-nucleotide polymorphisms (MNPs) and insertion and deletions (INDELs), were identified from DNA sequence data on a small number of animals. Identification of genetic variants in the Bullmastiff highlights sources of variation in the breed and molecular markers that will assist in future trait and disease investigations in dogs.

The breast-feeding neonate depends on mother’s milk for both macronutrients and micronutrients including minerals. The goals of the present study were to document the effects of genetic background in mice on milk concentrations of select minerals and to use genome-wide association study (GWAS) to identify quantitative trait loci (QTL) regulating milk mineral concentrations. Milk samples from lactating mice in each of 31 different inbred strains of the mouse diversity panel (MDP) were analyzed by inductively coupled plasma—optical emission spectroscopy to determine the concentrations of calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg), sodium (Na), phosphorus (P), sulfur (S), and zinc (Zn). GWAS identified a single pleiotropic milk mineral concentration QTL (Mmcq) on chromosome 3 for Ca, Mg, and P. For the remaining minerals, six QTL were detected for Fe, four for K, three for Zn, and one for S. Intersecting the Mmcq with published chromatin immunoprecipitation sequence data identified 15 out of 4633 high-linkage disequilibrium single-nucleotide polymorphisms that resided in signal transducer and activation of transcription 5 (STAT5) binding regions. A milk Fe-associated locus (Mmcq9) on chromosome 1 contained an SNP that localized to a STAT5 binding region and intersected with a HOMER motif predicted to bind the transcriptional regulator E74-Like ETS transcription factor 5. This locus also contained the genes for solute carrier family (Slc) members Slc9a2, Slc9a4, Slc39a10, and Slc40a1. Expression analysis of these transporters supports the conclusion that Slc9a2 and Slc40a1 within the mammary gland could mediate the effect of Mmcq9 on milk Fe concentration.

Clinical instructional rounds have recently gained national and international attention as a pedagogical innovation that can help school administrators, leaders, and sometimes teachers move past the impenetrability of siloed classrooms to study teaching and learning across school sites and even districts. While rounds are an increasingly widespread form of professional development for administrators and teachers, they are less commonly used in preservice programs with teacher candidates. This article describes how an urban teacher residency program strives to strengthen the connections between the fieldwork and the coursework of novice teachers through clinical instructional rounds within and across the educational settings in an urban school district. It also describes the findings from research into what candidates seem to learn by participating in instructional rounds and how this might impact their future practice. The findings suggest that rounds can be useful for helping teacher candidates develop deeper understandings of the educational systems where they will work, facilitate their learning of diverse teaching practices, and develop an appreciation of diverse student's strengths across contexts. They also suggest that rounds are not a silver bullet, and candidates can develop reductionist views of student ability and disjointed understandings about how school systems work. The implications of this research are discussed in terms of considerations for how teacher educators can employ rounds as a tool for deepening candidates’ understandings of students, classrooms, schools, and the systems that support urban youth.

Cryptococcal meningoencephalitis (CM) is a major cause of central nervous system (CNS)-linked mortality worldwide. High mortality frequently occurs despite antifungal drug treatment and pathogen elimination, and increasing evidence suggests over-exuberant host immune responses promote CM pathogenesis. Our goal was to dissect the role of two major groups of cells recruited to CNS (myeloid cell and T cell) and determine whether and how their crosstalk drives CM immunopathology. To study this, we developed a murine model that reproduces major features of human CM. Using this model, we found mice mortality did not directly correlate with CNS fungal burden, but instead was synchronized with the accumulation of ultra-Th1 polarized CD4 T cells and CCR2+ monocytes (Mo). Recruitment of Mo into the CNS was impaired in CCR2−/− mice, and these mice survived significantly longer and displayed fewer neurological symptoms despite higher brain fungal burden compared to WT mice. Mechanistically, we found that 1) CCR2+ Mo contributed to CXCR3+IFNγhi CD4 T cell accumulation and their ultra-Th1 polarization through modulating CXCL9/CXCL10 production. 2) CXCR3 deletion resulted in diminished CD4 T cell recruitment, Th1 polarization and conferred markedly protection against CM mortality; 3) robust IFNγ production by CD4 T cells corresponded to massive iNOS expression in Mo, which propose excessive NO production potentially contributes to neuronal injury. Collectively, we showed CCR2+ Mo and CXCR3+ CD4 T cells interact to promote mutual recruitment and activation, causing profound CNS damage during CM. Regulation of Mo and T cell function may become therapeutic strategy to aid current anti-fungal drug treatment that is frequently ineffective.

Teacher education in the United States has been widely criticized for its uneven and often poorly supported approach to preparing novices for clinical practice. In 2010, the Blue Ribbon Panel on Clinical Preparation and Partnerships for Improved Student Learning (commissioned by the National Council for Accreditation of Teacher Education) released a report titled “Transforming Teacher Education Through Clinical Practice: A National Strategy to Prepare Effective Teachers.” The report called for teacher education to “be turned upside down,” a dramatic shift from traditional approaches to preparing teachers to “programs that are fully grounded in clinical practice and interwoven with academic content and professional courses” (p. ii). Many preparation programs in the United States are engaged in efforts to become more clinically rich in their approach to teacher preparation. This chapter will examine the call for more clinically rich approaches to English language arts teacher education, and will highlight how such a shift is integral to more socially just teacher preparation programs. Particular features of two clinically rich English language arts teacher preparation programs, one in California the other in New York, will be described and research focusing on the programs will be highlighted in an effort to share lessons learned.