Inference of natural selection from ancient DNA.

Evolutionary processes, including selection, can be indirectly inferred based on patterns of genomic variation among contemporary populations or species. However, this often requires unrealistic assumptions of ancestral demography and selective regimes. Sequencing ancient DNA from temporally spaced samples can inform about past selection processes, as time series data allow direct quantification of population parameters collected before, during, and after genetic changes driven by selection. In this Comment and Opinion, we advocate for the inclusion of temporal sampling and the generation of paleogenomic datasets in evolutionary biology, and highlight some of the recent advances that have yet to be broadly applied by evolutionary biologists. In doing so, we consider the expected signatures of balancing, purifying, and positive selection in time series data, and detail how this can advance our understanding of the chronology and tempo of genomic change driven by selection. However, we also recognize the limitations of such data, which can suffer from postmortem damage, fragmentation, low coverage, and typically low sample size. We therefore highlight the many assumptions and considerations associated with analyzing paleogenomic data and the assumptions associated with analytical methods

Mutual exclusivity of hyaluronan and hyaluronidase in invasive group A Streptococcus

A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen

Short-Term Memory Trace in Rapidly Adapting Synapses of Inferior Temporal Cortex

Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory

Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction

The overall effect of brain zinc (Zn2+) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn2+ can exacerbate the pathological features of AD, a deficit of Zn2+ intake has also been shown to increase the volume of amyloid plaques in AD transgenic mice. In this study, we investigated the effect of dietary Zn2+ supplementation (30 p.p.m.) in a transgenic mouse model of AD, the 3xTg-AD, that expresses both β amyloid (Aβ)- and tau-dependent pathology. We found that Zn2+ supplementation greatly delays hippocampal-dependent memory deficits and strongly reduces both Aβ and tau pathology in the hippocampus. We also evaluated signs of mitochondrial dysfunction and found that Zn2+ supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn2+ supplementation greatly increases the levels of brain-derived neurotrophic factor (BDNF) of treated 3xTg-AD mice. In summary, our data support the idea that controlling the brain Zn2+ homeostasis may be beneficial in the treatment of AD

The effects of problem-oriented policing on crime and disorder

Problem-oriented Policing (POP) was first introduced by Herman Goldstein in 1979. The approach was one of a series of responses to a crisis in effectiveness and legitimacy in policing that emerged in the 1970s and 1980s. Goldstein argued that police were not being effective in preventing and controlling crime because they had become too focused on the “means” of policing and had neglected the “goals” of preventing and controlling crime and other community problems. Goldstein argued that the unit of analysis in policing must become the “problem” rather than calls or crime incidents as was the case during that period. POP has had tremendous impact on American policing, and is now one of the most widely implemented policing strategies in the US. To synthesize the extant problem-oriented policing evaluation literature and assess the effects of problem-oriented policing on crime and disorder Eligible studies had to meet three criteria: (1) the SARA model was used for a problemoriented policing intervention; (2) a comparison group was included; (3) at least one crime or disorder outcome was reported with sufficient data to generate an effect size. The unit of analysis could be people or places. Several strategies were used to perform an exhaustive search for literature fitting the eligibility criteria. First, a keyword search was performed on an array of online abstract databases. Second, we reviewed the bibliographies of past reviews of problem-oriented policing. Third, we performed forward searches for works that have cited seminal problem-oriented policing studies. Fourth, we performed hand searches of leading journals in the field. Fifth, we searched the publications of several research and professional agencies. Sixth, after finishing the above searches we e-mailed the list of studies meeting our eligibility criteria to leading policing scholars knowledgeable in the area of problem-oriented policing to ensure we had not missed any relevant studies. For our ten eligible studies, we provide both a narrative review of effectiveness and a meta-analysis. For the meta-analysis, we coded all primary outcomes of the eligible studies and we report the mean effect size (for studies with more than one primary outcome, we averaged effects to create a mean), the largest effect, and the smallest effect. Because of the heterogeneity of our studies, we used a random effects model. Based on our meta-analysis, overall problem-oriented policing has a modest but statistically significant impact on reducing crime and disorder. Our results are consistent when examining both experimental and quasi-experimental studies. Conclusions: We conclude that problem-oriented policing is effective in reducing crime and disorder, although the effect is fairly modest. We urge caution in interpreting these results because of the small number of methodologically rigorous studies on POP and the diversity of problems and responses used in our eligible studies

Police-initiated diversion for youth to prevent future delinquent behavior: a systematic review

BackgroundOverly punitive responses to youth misconduct may have the unintended consequence ofincreasing the likelihood of future delinquency; yet, overly lenient responses may fail to serveas a corrective for the misbehavior. Police diversion schemes are a collection of strategiespolice can apply as an alternative to court processing of youth. Police-initiated diversionschemes aim to reduce reoffending by steering youth away from deeper penetration into thecriminal justice system and by providing an alternative intervention that can help youthaddress psychosocial development or other needs that contribute to their problem behavior.ObjectivesThe objective of this review was to synthesize the evidence on the effectiveness of pre-courtinterventions involving police warning or counseling and release, and cautioning schemes inreducing delinquent behavior.Search methodsA combination of 26 databases and websites were searched. References of relevant reviewswere also scanned to identify studies. We also consulted with experts in the field. Searcheswere executed by two reviewers and conducted between August 2016 and January 2017.Selection criteriaOnly experimental and quasi-experimental designs were eligible for this review. All quasiexperimentaldesigns must have had a comparison group similar to the police diversionintervention group with respect to demographic characteristics and prior involvement indelinquent behavior (i.e., at similar risk for future delinquent behavior). Additionally, studiesmust have included youth participants between 12 and 17 years of age who either underwenttraditional system processing or were diverted from court processing through a police-leddiversion program. Studies were also eligible if delinquency-related outcomes, includingofficial and non-official (self-report or third-party reporting) measures of delinquency werereported.Data collection and analysisThis study used meta-analysis to synthesize results across studies. This method involvedsystematic coding of study features and conversion of study findings into effect sizesreflecting the direction and magnitude of any police-led diversion effect. There were 19independent evaluations across the 14 primary documents coded for this review. From this,we coded 67 effect sizes of delinquent behavior post diversion across 31 diversion-traditionalprocessing comparisons. We analyzed these comparisons using two approaches. The firstapproach selected a single effect size per comparison based on a decision rule and the secondused all 67 effect sizes, nesting these within comparison condition and evaluation design.ResultsThe general pattern of evidence is positive, suggesting that police-led diversion modestlyreduces future delinquent behavior of low-risk youth relative to traditional processing.Authors’ conclusionsThe findings from this systematic review support the use of police-led diversion for low-riskyouth with limited or no prior involvement with the juvenile justice system. Thus, policedepartments and policy-makers should consider diversionary programs as part of the mix ofsolutions for addressing youth crime

Streptococcal M1 protein constructs a pathological host fibrinogen network

M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic-shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen that, unlike M1 or fibrinogen alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the complex formed between streptococcal M1 and human fibrinogen. A conformationally dynamic coiled-coil dimer of M1 was found to organize four fibrinogen molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock

Mutual exclusivity of hyaluronan and hyaluronidase in invasive group a streptococcus

Contains fulltext : 138923.pdf (publisher's version ) (Open Access)A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen