OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.

Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections

Results of soy-based meal replacement formula on weight, anthropometry, serum lipids & blood pressure during a 40-week clinical weight loss trial

BACKGROUND: To evaluate the intermediate-term health outcomes associated with a soy-based meal replacement, and to compare the weight loss efficacy of two distinct patterns of caloric restriction. METHODS: Ninety overweight/obese (28 < BMI ≤ 41 kg/m(2)) adults received a single session of dietary counseling and were randomized to either 12 weeks at 1200 kcal/day, 16 weeks at 1500 kcal/d and 12 weeks at 1800 kcal/d (i.e., the 12/15/18 diet group), or 28 weeks at 1500 kcal/d and 12 weeks at 1800 kcal/d (i.e., the 15/18 diet group). Weight, body fat, waist circumference, blood pressure and serum lipid concentrations were measured at 4-week intervals throughout the 40-week trial. RESULTS: Subjects in both treatments showed statistically significant improvements in outcomes. A regression model for weight change suggests that subjects with larger baseline weights tended to lose more weight and subjects in the 12/15/18 group tended to experience, on average, an additional 0.9 kg of weight loss compared with subjects in the 15/18 group. CONCLUSION: Both treatments using the soy-based meal replacement program were associated with significant and comparable weight loss and improvements on selected health variables

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

Oral rehydration versus intravenous therapy for treating dehydration due to gastroenteritis in children: a meta-analysis of randomised controlled trials

BACKGROUND: Despite treatment recommendations from various organizations, oral rehydration therapy (ORT) continues to be underused, particularly by physicians in high-income countries. We conducted a systematic review of randomised controlled trials (RCTs) to compare ORT and intravenous therapy (IVT) for the treatment of dehydration secondary to acute gastroenteritis in children. METHODS: RCTs were identified through MEDLINE, EMBASE, CENTRAL, authors and references of included trials, pharmaceutical companies, and relevant organizations. Screening and inclusion were performed independently by two reviewers in order to identify randomised or quasi-randomised controlled trials comparing ORT and IVT in children with acute diarrhea and dehydration. Two reviewers independently assessed study quality using the Jadad scale and allocation concealment. Data were extracted by one reviewer and checked by a second. The primary outcome measure was failure of rehydration. We analyzed data using standard meta-analytic techniques. RESULTS: The quality of the 14 included trials ranged from 0 to 3 (Jadad score); allocation concealment was unclear in all but one study. Using a random effects model, there was no significant difference in treatment failures (risk difference [RD] 3%; 95% confidence intervals [CI]: 0, 6). The Mantel-Haenzsel fixed effects model gave a significant difference between treatment groups (RD 4%; 95% CI: 2, 5) favoring IVT. Based on the four studies that reported deaths, there were six in the IVT groups and two in ORT. There were no significant differences in total fluid intake at six and 24 hours, weight gain, duration of diarrhea, or hypo/hypernatremia. Length of stay was significantly shorter for the ORT group (weighted mean difference [WMD] -1.2 days; 95% CI: -2.4,-0.02). Phlebitis occurred significantly more often with IVT (number needed to treat [NNT] 33; 95% CI: 25,100); paralytic ileus occurred more often with ORT (NNT 33; 95% CI: 20,100). These results may not be generalizable to children with persistent vomiting. CONCLUSION: There were no clinically important differences between ORT and IVT in terms of efficacy and safety. For every 25 children (95% CI: 20, 50) treated with ORT, one would fail and require IVT. The results support existing practice guidelines recommending ORT as the first course of treatment in appropriate children with dehydration secondary to gastroenteritis

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

An experimental test of host’s life history traits modulation in response to cuckoo parasitism risk

Hosts can counteract parasites through defences based on resistance and/or tolerance. The mechanistic basis of tolerance, which involve defensive mechanisms minimizing parasite damage after a successful parasitic attack, remains poorly explored in the study of cuckoo-host interactions. Here, we experimentally explore the possibility that the risk of great spotted cuckoo Clamator glandarius parasitism may induce tolerance defences in magpie Pica pica hosts through plasticity in life-history traits. We predict that magpies exposed to auditory cues indicating high parasitism risk will more likely exhibit resistance and/or modify their life-history traits to minimize parasitism costs (i.e. tolerance) compared to magpies under low parasitism risk. We found that manipulating the perceived parasitism risk did not affect host resistance (i.e. rejection of parasitic eggs) nor host life-history traits. Unexpectedly, host's egg volume increased over the season in nests exposed to auditory cues of control non-harmful hoopoes Upupa epops. Our results do not provide support for inducible defences (either based on resistance or tolerance) in response to risk of parasitism in magpie hosts. Even so, we encourage studying plastic expression of breeding strategies in response to risk of cuckoo parasitism to achieve a better understanding of the mechanistic basis of tolerance defences.This work was supported by the Spanish Ministry of Education and Science/FEDER (Projects CGL2011-27561/BOS and CGL2014-56769-P to D. P. and J.M.A.). D.P. was supported by the Government of Extremadura while writing (contract number TA13002). M.E.G. was supported by the Spanish Ministry of Economy and Competitiveness (grant number BES-2012-051898).

Testing Multiple Coordination Constraints with a Novel Bimanual Visuomotor Task

The acquisition of a new bimanual skill depends on several motor coordination constraints. To date, coordination constraints have often been tested relatively independently of one another, particularly with respect to isofrequency and multifrequency rhythms. Here, we used a new paradigm to test the interaction of multiple coordination constraints. Coordination constraints that were tested included temporal complexity, directionality, muscle grouping, and hand dominance. Twenty-two healthy young adults performed a bimanual dial rotation task that required left and right hand coordination to track a moving target on a computer monitor. Two groups were compared, either with or without four days of practice with augmented visual feedback. Four directional patterns were tested such that both hands moved either rightward (clockwise), leftward (counterclockwise), inward or outward relative to each other. Seven frequency ratios (3∶1, 2∶1, 3∶2, 1∶1, 2∶3. 1∶2, 1∶3) between the left and right hand were introduced. As expected, isofrequency patterns (1∶1) were performed more successfully than multifrequency patterns (non 1∶1). In addition, performance was more accurate when participants were required to move faster with the dominant right hand (1∶3, 1∶2 and 2∶3) than with the non-dominant left hand (3∶1, 2∶1, 3∶2). Interestingly, performance deteriorated as the relative angular velocity between the two hands increased, regardless of whether the required frequency ratio was an integer or non-integer. This contrasted with previous finger tapping research where the integer ratios generally led to less error than the non-integer ratios. We suggest that this is due to the different movement topologies that are required of each paradigm. Overall, we found that this visuomotor task was useful for testing the interaction of multiple coordination constraints as well as the release from these constraints with practice in the presence of augmented visual feedback