The rockefeller university

Mycobacterium tilburgii rarely causes disseminated disease. We describe a case of M. tilburgii infection in an otherwise healthy 33-year-old woman, who was found to carry bi-allelic mutations of the gene encoding the beta 1 chain of the IL-12 receptor.

Severe mental illnesses like schizophrenia and bipolar disorder are disabling, chronic conditions that are often accompanied by medical comorbidities. In this theoretical article, we review the allostatic load model representing the "wear and tear" that chronic stress exacts on the brain and body. We propose an innovative way of monitoring physical and psychiatric comorbidities by integrating the allostatic load model into clinical practice. By interpreting peripheral biomarkers differently, medical professionals can calculate a simple, count-based, allostatic load index known to predict diverse stress-related pathologies. In addition to screening for comorbidities, allostatic load indices can be used to monitor the effects of pharmacological and psychosocial interventions. This framework can also be used to generate a dialogue between patient and practitioner to promote preventive and proactive approaches to health care.

Climate warming has been linked to an apparent general decrease in body sizes of ectotherms, both across and within taxa, especially in aquatic systems. Smaller body size in warmer geographical regions has also been widely observed. Since body size is a fundamental determinant of many biological attributes, climate-warming-related changes in size could ripple across multiple levels of ecological organization. Some recent studies have questioned the ubiquity of temperature-size rules, however, and certain widespread and abundant taxa, such as diatoms, may be important exceptions. We tested the hypothesis that diatoms are smaller at warmer temperatures using a system of geothermally heated streams. There was no consistent relationship between size and temperature at either the population or community level. These field data provide important counterexamples to both James' and Bergmann's temperature-size rules, respectively, undermining the widely held assumption that warming favours the small. This study provides compelling new evidence that diatoms are an important exception to temperature-size rules for three reasons: (i) we use many more species than prior work; (ii) we examine both community and species levels of organization simultaneously; (iii) we work in a natural system with a wide temperature gradient but minimal variation in other factors, to achieve robust tests of hypotheses without relying on laboratory setups, which have limited realism. In addition, we show that interspecific effects were a bigger contributor to whole-community size differences, and are probably more ecologically important than more commonly studied intraspecific effects. These findings highlight the need for multispecies approaches in future studies of climate warming and body size.

A single high dose of interferon-beta (IFN beta) activates powerful cellular responses, in which many anti-viral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells down-regulate this initial response rapidly. However, the expression of many anti-viral proteins that do no harm is sustained, prolonging a substantial part of the initial anti-viral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFN beta-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced anti-viral genes that show prolonged expression are driven by distinct IFN stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFN beta, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFN beta-induced proteins, and to constitutive resistance to DNA damage.

Heterozygosity for dominant-negative STAT1 mutations underlies autosomal dominant Mendelian susceptibility to mycobacterial diseases. Mutations conferring Mendelian susceptibility to mycobacterial diseases have been identified in the regions of the STAT1 gene encoding the tail segment, DNA-binding domain and SH2 domain. We describe here a new heterozygous mutation, Y701C, in a Japanese two-generation multiplex kindred with autosomal dominant Mendelian susceptibility to mycobacterial diseases. This mutation affects precisely the canonical STAT1 tyrosine phosphorylation site. The Y701C STAT1 protein is produced normally, but its phosphorylation is abolished, resulting in a loss-of-function for STAT1-dependent cellular responses to interferon-gamma or interferon-alpha. In the patients' cells, the allele is dominant-negative for gamma-activated factor-mediated responses to interferon-gamma, but not for interferon-stimulated gene factor-3-mediated responses to interferon-alpha/beta, accounting for the clinical phenotype of Mendelian susceptibility to mycobacterial diseases without severe viral diseases. Interestingly, both patients displayed multifocal osteomyelitis, which is often seen in patients with Mendelian susceptibility to mycobacterial diseases with autosomal dominant partial IFN-gamma R1 deficiency. Multifocal osteomyelitis should thus prompt investigations of both STAT1 and IFN-gamma R1. This experiment of nature also confirms the essential role of tyrosine 701 in human STAT1 activity in natura.

The stress-response corticotropin-releasing factor (CRF) and dynorphin systems are critically involved in alcohol drinking and "anxiety"-related behaviors. Selectively bred Sardinian alcohol-preferring (sP) rats display high inherent "anxiety"-related behaviors, in comparison with their alcohol-nonpreferring counterpart (sNP rats). The present study was undertaken to investigate: (1) if there were genetically determined differences in basal gene expression levels of CRF, CRF-R1, preprodynorphin (ppDyn) and kappa opioid receptor (KOP-r) between sP and sNP rats; specifically, mRNA levels of the above genes were measured in the central amygdala (CeA), hypothalamus and other stress responsive and mesolimbic regions of alcohol-naive sP and sNP rats; and (2) if the above mRNA levels were altered by voluntary alcohol drinking in sP rats exposed to the standard, homecage 2-bottle "alcohol vs. water" choice regimen 24 h/day for 17 days. Higher basal CRF mRNA levels were found only in CeA of alcohol-naive sP rats, compared with sNP rats; these levels were decreased after alcohol consumption. In contrast, ppDyn mRNA levels in CeA of sP rats were increased by alcohol consumption, but with no basal difference from sNP rats. Although higher basal ppDyn mRNA levels were found in hypothalamus of sP rats, compared with sNP rats, there was no alteration after alcohol drinking in sP rats. No difference for the above mRNA levels was observed in other regions, including nucleus accumbens shell or core, caudate-putamen, ventral tegmental area and medial/basolateral amygdala, between the two rat lines before or after alcohol consumption. Our results demonstrate the existence of genetically determined high basal CRF mRNA levels in CeA of sP rats. Alcohol consumption decreased CeA CRF mRNA levels with parallel increases in CeA ppDyn mRNA levels. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Using data from proton-antiproton collisions at root s = 1.96 TeV recorded by the CDF II detector at the Fermilab Tevatron, evidence for the excited resonance state Lambda(b)*(0) pi(-) pi(+) is presented in its Lambda(0)(b) pi(-) pi(+) decay followed by the Lambda(0)(b) -> Lambda(+)(c) pi(-) and Lambda(+)(c) -> pK(-) pi(-) decays. The analysis is based on a data sample corresponding to an integrated luminosity of 9.6 fb(-1) collected by an online event selection based on charged-particle tracks displaced from the proton-antiproton interaction point. The significance of the observed signal is 3.5 sigma. The mass of the observed state is found to be 5919.22 +/- 0.76 MeV/c(2) in agreement with similar findings in proton-proton collision experiments.

BackgroundDeep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. MethodsWe studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. ResultsFour patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. ConclusionsAll the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.) Dermatophyte infections are unusual but can cause serious invasive disease. In this report, autosomal recessive CARD9 deficiency indicated a potential genetic susceptibility to deep dermatophytosis, a severe invasive fungal infection. Deep dermatophytosis is a rare, invasive, sometimes life-threatening, fungal infection caused by dermatophytes.(1) These filamentous fungi are ubiquitous and usually cause benign infections that are limited to keratinized tissues and lead to onychomycosis, tinea corporis, tinea cruris, tinea pedis, or tinea capitis.(2) In deep dermatophytosis, dermatophytes invade the dermis and hypodermis and disseminate to the skin, hair, nails, lymph nodes, and brain.(3) Deep dermatophytosis has been reported in patients with the human immunodeficiency virus and patients who are receiving immunosuppressive therapy.(3) It was first described in 1959 in otherwise apparently healthy persons as dermatophytic disease.(1) Forty-five cases have been reported ...

Holliday junctions (HJs), the DNA intermediates of homologous recombination, need to be faithfully processed in order to preserve genome integrity. In human cells, the BLM helicase complex promotes nonnucleolytic dissolution of double HJs. In vitro, HJs may be nucleolytically processed by MUS81-EME1, GEN1, and SLX4-SLX1. Here, we exploit human SLX4-null cells to examine the requirements for HJ resolution in vivo. Lack of BLM and SLX4 or GEN1 and SLX4 is synthetically lethal in the absence of exogenous DNA damage, and lethality is a consequence of dysfunctional mitosis proceeding in the presence of unprocessed HJs. Thus, GEN1 activity cannot be substituted for the SLX4-associated nucleases, and one of the HJ resolvase activities, either of those associated with SLX4 or with GEN1, is required for cell viability, even in the presence of BLM. In vivo HJ resolution depends on both SLX4-associated MUS81-EME1 and SLX1, suggesting that they are acting in concert in the context of SLX4.