Neuropsychological training methods of visual rehabilitation for homonymous vision loss caused by postchiasmatic damage fall into two fundamental paradigms: “compensation” and “restoration”. Existing methods can be classified into three groups: Visual Scanning Training (VST), Audio-Visual Scanning Training (AViST) and Vision Restoration Training (VRT). VST and AViST aim at compensating vision loss by training eye scanning movements, whereas VRT aims at improving lost vision by activating residual visual functions by training light detection and discrimination of visual stimuli. This review discusses the rationale underlying these paradigms and summarizes the available evidence with respect to treatment efficacy. The issues raised in our review should help guide clinical care and stimulate new ideas for future research uncovering the underlying neural correlates of the different treatment paradigms. We propose that both local “within-system” interactions  and changes in more global “between-system” networks  contribute to both vision restoration and compensatory rehabilitation, which ultimately have implications for the rehabilitation of cognitive functions. Homonymous visual field defects (HVFD) are among the most serious deficits after cerebral artery stroke and traumatic brain injury (TBI) in adults  means. Among others, substitution methodologies include prosthesis , Audio-Visual Scanning Training (AViST), and Vision Restoration Training (VRT). We will present the rationale which has shaped these paradigms and detail their respective methodologies. We will then report the outcomes of each treatment, drawing upon the body of available literature and criticisms offered by alternative viewpoints. Finally, we will discuss emergent neuroimaging and electroencephalographic data which are beginning to uncover the neural mechanisms underlying these treatment approaches.The main difference between compensation and restoration is that the former primarily aims to recruit alternative unaffected brain regions that can play a compensatory role in the visual process, whereas the latter relies on the notion that stimulation of areas of partial injury  might induce synaptic plasticity and thus improvement to lost visual functions. Restoration techniques aim at modifying the visual system itself by lowering the threshold of perception. There has been a vigorous and controversial debate about whether vision restoration is possible at all  eye movement training. The term “unisensory” refers to tasks which draw upon a single sensory modality, i.e., vision, in order to enhance visual functions; there is no ancillary recruitment of other senses (such as auditory or somatosensory cues as discussed below).Compensatory approaches are oculomotor strategies which aim to train saccadic eye movements; thus, they do not specifically target the size of the scotoma but rather the field of view . Typically, this is accomplished by training patients to voluntarily (and consciously) explore arrays of visual stimuli—usually on computer screens Zihl, , 1999—buTotal training duration for VST is typically around 1 month, consisting of daily 1 h sessions. After about 5–6 weeks of VST, patients generally report improvements in scanning accuracy, exploration times and daily life activities  showed an increase of visual detections (without fixation requirement), improvements of visual search and reading abilities and a reduction in self-perceived disability in daily activities . The improvements were stable at a 1 month follow-up  suggests that the improvement in visual perception induced by the training is not due to an enlargement of the visual field, but rather to an activation of the visual responsiveness of the oculomotor system, reinforcing orientation towards the blind hemifield.Crucially, the amelioration cannot be attributed to a mere habituation effect whereby the training simply encourages saccades towards the hemianopic field; indeed, a similar training protocol, using unisensory visual stimuli instead of multisensory audio-visual stimuli, yielded no improvements in a control patient group , separated by a sharp and clearly definable visual field border. Rather, visual field defects actually comprise: (i) areas of total blindness; (ii) areas of consistent  visual detection; and (iii) areas where visual detection performance is present but inconsistent.Typically, visual field charts are based on applying standard static near-threshold perimetry using a low resolution stimulus presentation, presented in a monocular fashion. However, due to the rather low resolution, these perimetric tasks are not sensitive enough to decipher smaller regions of inconsistent  visual detection. Standard near-threshold testing methods predominantly delineate areas of vision loss vs. intact vision while the topography of the ARV which is typically located at the border zone along the defect remains unclear. By increasing the number of test positions it is theoretically possible to gain the missing information by means of near-threshold perimetry. However, this procedure is not used in clinical settings since it results in a tremendous increase in test duration. Supra-threshold high resolution perimetry (HRP) has therefore been used to test detection of light stimuli binocularly within a dense grid of stimulus presentations. This greater sensitivity has assisted with both the characterization of distinct regions of ARV, and the evaluation of treatment effects . Concerning the influence of age on VRT outcomes, Kasten et al.  could noIf and to what extent vision restoration can be achieved is a function of the amount of residual tissue and its activation state, and of the status of global neuronal networks , the training procedure is individually adapted to the patient’s specific deficit pattern. VRT is developed to specifically target ARV with the goal of strengthening these structures by repetitive activation. This is achieved by presentation of localized “static” stimuli along the visual field border or “dynamic” stimuli which appear first in either the blind or intact field and move to the nearest point in the ARV . Further, post-training visual field border shifts for patients with concentric visual field loss, as in glaucoma, typically move in a ring-like fashion in all directions towards the periphery  vs. compensation (VST), or a compensation/restoration hybrid (AViST).In general terms, restorative therapies aim at improving the magnitude of visual function, while VST and AViST compensate for the visual field loss. However, in terms of the neural mechanisms underlying the two approaches, each of these two ostensibly disparate treatment methodologies may well draw on both, local and distal, cortical reorganization mechanisms. This suggests that in case of visual rehabilitation, concepts of restoration and compensation can be both fluid and reciprocal. Broadly speaking, neuroplastic changes can be indexed into two categories, delineated by the associated lesion proximity and overall diffusivity of cortical reorganization. The first model, within systems plasticity, targets reconnection of damaged neural circuits proximal to, or within islands of spared tissue surrounded by the lesion  and duration. Indeed, VST training procedures usually last 5–6 weeks with daily 1 h sessions, the AViST training has a duration of 2 weeks with daily 4 h sessions, while the VRT approach consists of a 3–6 months training with daily 30 min sessions. Despite these duration differences, they each operate within an adaptive framework. Recent evidence supports adaptive treatments in order to ensure that patients are consistently challenged without being overly frustrated or fatigued by task demands, which is optimal for both maximising clinical outcome and avoiding patient drop outs (Klingberg, Broadly speaking, visual rehabilitation targeting restoration of a portion of the visual field, seems to represent an optimal approach to address visual field function and size. However, VRT consists of a long-lasting training protocol, which may not suit the life circumstances of all patients. Although there were no reports of drop outs or an extremely low rate in those VRT studies that were conducted in a laboratory setting (e.g., Kasten et al., Only by considering evidence from all fields of study, and employing an open, critical debate, can we make the fastest possible progress to help patients with partial blindness. Further, we should not simply consider local events at the lesion site or immediately around it, but also study the visual system in a holistic manner, including global brain network function, saccade-induced facilitations, cross- and/or multimodal influences and attentional mechanisms. Thus, by considering the topic in a holistic way we can serve both research needs and clinical necessities in a manner that is not microscopic but macro-scopic with the ultimate goal to optimize clinical care in vision rehabilitation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


AKT1 gene and cannabis use in the development of psychosis and an interaction between the length polymorphism of the serotonin transporter gene and childhood maltreatment in the development of persistent depressive disorder. Bipolar disorder has been underinvestigated, with only a single study showing an interaction between a functional polymorphism in the BDNF gene and stressful life events triggering bipolar depressive episodes. The first systematic search for gene–environment interactions has found that a polymorphism in CTNNA3 may sensitize the developing brain to the pathogenic effect of cytomegalovirus in utero, leading to schizophrenia in adulthood. Strategies for genome-wide investigations will likely include coordination between epidemiological and genetic research efforts, systematic assessment of multiple environmental factors in large samples, and prioritization of genetic variants.Severe mental illness (SMI) is a broad category that includes schizophrenia, bipolar disorder, and severe depression. Both genetic disposition and environmental exposures play important roles in the development of SMI. Multiple lines of evidence suggest that the roles of genetic and environmental factors depend on each other. Gene–environment interactions may underlie the paradox of strong environmental factors for highly heritable disorders, the low estimates of shared environmental influences in twin studies of SMI, and the heritability gap between twin and molecular heritability estimates. Sons and daughters of parents with SMI are more vulnerable to the effects of prenatal and postnatal environmental exposures, suggesting that the expression of genetic liability depends on environment. In the last decade, gene–environment interactions involving specific molecular variants in candidate genes have been identified. Replicated findings include an interaction between a polymorphism in the  Severe mental illness (SMI) includes the most disabling psychiatric disorders that typically require inpatient treatment, such as schizophrenia, bipolar disorder, and severe depression. Family and molecular genetic studies suggest that schizophrenia, bipolar disorder, and major depressive disorder share common etiology and there may be advantages in studying these disorders jointly –4. This Both genetic disposition and environmental exposures play important roles in the development of SMI. The risk of SMI runs in families and is shared in proportion to the degree of biological relatedness , 6. The In utero exposure to infection, lack of nutrients, maternal stress, perinatal complications, social disadvantage, urban upbringing, ethnic minority status, childhood maltreatment, bullying, traumatic events, and cannabis use have all been found to contribute to one or more types of SMI. Some of these exposures appear to be responsible for substantial proportion of cases of SMI. For example, the availability of vitamin D during the prenatal development may be responsible for 44% cases of schizophrenia  gene. COMT codes an enzyme that metabolizes dopamine, the principal neuromediator involved in the positive symptoms of psychosis. A single nucleotide polymorphism (SNP)  substitutes valine by methionine (Met) at position 158, leading to the production of an enzyme that is much less efficient than the native Val variant. Caspi and colleagues found that use of cannabis in adolescence led to psychotic symptoms and disorders specifically in individuals carrying the more efficient Val alleles at the functional Val158Met COMT polymorphism , but it appears remarkably robust: the gene–environment interaction between AKT1 rs2494732 and cannabis replicated across three analyses in the primary report , has been shown to moderate the effects of childhood maltreatment on depression: individuals carrying the short alleles of 5-HTTLPR are prone to develop persistent depressive disorder if they experience maltreatment in childhood (66Met) in the brain-derived neurotrophic factor (BDNF) gene has been reported to interact with stressful life events and childhood maltreatment in the development of depression, with Met allele carriers being more likely to develop depression after exposure to adversity (BDNF Met allele carriers with a history of childhood abuse were also more likely to develop psychotic-like experiences (Additional single candidate gene studies investigated genetic variants with known gene–environment interactions in common mental disorders. The reatment . Collip g adults . Perhapshildhood , 80, 106hildhood . This efdversity , 108. Freriences ; this geeriences .BDNF Val66Met polymorphism were more likely to develop depressive episodes following stressful life events than Val allele homozygotes (Compared to both major depressive disorder and schizophrenia, gene–environment interactions in bipolar disorder have been understudied. Only a single published study has reported that people with bipolar disorder who carried Met alleles at the ozygotes .All the studies reviewed above were restricted to the exploration of one or more polymorphisms in one or more genes that were selected based on their presumed functionality in relation to the disorder or the exposure of interest, i.e., they were candidate gene studies. The study of genetic associations across phenotypes has demonstrated that researchers had not been able to select the right candidate genes: most strong genetic associations turned out to be in genes that no one suspected to be involved . In addiin utero (CTNNA3 gene was found to significantly interact with maternal cytomegalovirus infection in causing schizophrenia after correcting for the number of tests performed. It did not reach the accepted genome-wide level of significance. CTNNA3 encodes a cadherin-associated protein that had been liked to cardiomyopathy, but not suspected to be involved in SMI. It remains to be established whether this gene–environment interaction will prove to be robust in replication.To date, only one systematic search for gene–environment interactions in SMI has been carried out. A group of Danish researchers have searched the genome for genetic variants that may sensitize individuals to developing schizophrenia after being exposed to cytomegalovirus in utero . In 488 in utero  (this reAdequately powered genome-wide searches for gene–environment interactions should be a priority for the next decade of research. Since the statistical power for detecting gene–environment interactions is lower than statistical power for detecting direct gene-disorder associations , 113, laThe move to systematic genome-wide gene–environment studies will have to overcome major challenges in addition to sample size . SeveralAnother challenge lies in the selection of environmental variables to be assessed. A potentially large number of environmental exposures might be contributing to SMI Table . Yet, wiSeveral initiatives have been launched with the aim to collect a systematic selection of environmental variables in addition to genetic material from moderately large samples –120. ObtThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Guest Associate Editor Helen Fisher declares that, despite having collaborated with the author Rudolf Uher, the review process was handled objectively.


Marker-assisted selection (MAS) refers to the use of molecular markers to assist phenotypic selections in crop improvement. Several types of molecular markers, such as single nucleotide polymorphism (SNP), have been identified and effectively used in plant breeding. The application of next-generation sequencing (NGS) technologies has led to remarkable advances in whole genome sequencing, which provides ultra-throughput sequences to revolutionize plant genotyping and breeding. To further broaden NGS usages to large crop genomes such as maize and wheat, genotyping-by-sequencing (GBS) has been developed and applied in sequencing multiplexed samples that combine molecular marker discovery and genotyping. GBS is a novel application of NGS protocols for discovering and genotyping SNPs in crop genomes and populations. The GBS approach includes the digestion of genomic DNA with restriction enzymes followed by the ligation of barcode adapter, PCR amplification and sequencing of the amplified DNA pool on a single lane of flow cells. Bioinformatic pipelines are needed to analyze and interpret GBS datasets. As an ultimate MAS tool and a cost-effective technique, GBS has been successfully used in implementing genome-wide association study (GWAS), genomic diversity study, genetic linkage analysis, molecular marker discovery and genomic selection under a large scale of plant breeding programs. Plant breeding can be accomplished through two major strategies, classical breeding and molecular breeding. Classical plant breeding uses the deliberate interbreeding of closely related individuals to produce new cultivars with desirable traits. As it needs a long period and several generations to select and evaluate useful genotypes, classical breeding could be limited to address global food security and meet the increasing requirements of food demands . MoleculPlant molecular breeding has advanced so rapidly that several types of molecular markers have been developed and used for decades. The restriction fragment length polymorphism (RFLP) was firstly applied as DNA markers in plant genotyping . RFLP teIn combination with the genome and expressed sequence tags (ESTs) in model plant species , Sanger Molecular markers are extremely useful in plant genetics and breeding. Markers are prerequisite for gene mapping and tagging, segregation analysis, genetic diagnosis, forensic examination, phylogenetic analysis and numerous biological applications . AlthougThe high demand for low cost sequence data has driven the development of high-throughput sequencing (or next-generation sequencing) technologies that can produce 1000 or millions of sequences concurrently. Next-generation sequencing (NGS) relies on massively parallel sequencing and imaging techniques to yield several 100s of millions to several 100s of billions of DNA bases per run . SeveralAll NGS strategies follow a similar protocol for DNA template preparation, where universal adapters are ligated at both ends of randomly sheared DNA fragments. They also rely on the cyclic interrogation of millions of clonally amplified DNA molecules immobilized on a synthetic surface to generate up to several billions of sequences in a massively parallel fashion. Sequencing is performed in an iterative manner, where the incorporation of one or more nucleotides is followed by the emission of a signal and its detection by the sequencer . Most NGFor Illumina NGS sequencers, DNA molecules and primers are first attached on a slide and amplified with polymerase so that local clonal DNA colonies are formed. To determine the sequence, four types of reversible terminator bases (RT-bases) are added and non-incorporated nucleotides are washed away. A camera takes images of the fluorescently labeled nucleotides, then the dye, along with the terminal 3′ blocker, is chemically removed from the DNA, allowing for the next cycle to begin. Unlike pyrosequencing, the DNA chains are extended one nucleotide at a time and image acquisition can be performed at a delayed moment, allowing for very large arrays of DNA colonies to be captured by sequential images taken from a single camera . NGS canNGS technologies commercialized by Illumina generate shorter reads, ranging from 50 to 300 bp, with sequencing throughputs ranging from 1.5 to 600 Gbp depending on the platform being used. Several instruments are commercialized by Illumina, ranging from the bench top MiSeq sequencer to the high-throughput HiSeq2500 sequencer. The Illumina sequencing technology combines clonal amplification of a single DNA molecule with a cyclical sequencing-by-synthesis approach. The PCR amplification is performed using a solid phase amplification protocol to generate up to 1,000 copies of an original molecule of DNA, grouped together into a cluster. Sequencing is performed with proprietary reversible fluorescent terminator deoxyribonucleotides, in a series of cycles consisting of single base extension, fluorescence detection  and cleavage of both the fluorescent label and of the chemical moieties at the 3′ hydroxyl position to allow for the next cycle to occur .The application of NGS technologies highlights the striking impact of these massively parallel platforms on genotyping, which have expanded from previously focused readouts from a variety of DNA preparation protocols to a genome-wide scale and have fine-tuned their resolution to single base precision . NGS hasFigure 1 simplifies the GBS technology by summarizing the steps needed for any plant species and some potential application of the results.Advances in NGS have driven the costs of DNA sequencing down to the point that GBS is now feasible for high diversity and large genome species . GBS is PstI/MspI) GBS protocol, which provides a greater degree of complexity reduction and uniform library for sequencing than the original protocol using ApeKI, has now been developed and applied to both wheat and barley (GBS combined with genome-independent imputation provides a simple and efficient method for genetic map construction in any pseudo-testcross progeny . The GBSd barley . Sonah eTwo different GBS strategies have been developed with the Ion PGM system . (A) ResThe value of sequencing restriction site associated genomic DNA (RAD) for high density SNP discovery and genotyping was first demonstrated by GBS was originally developed for high resolution association studies in maize and, like RAD, has been extended to a range of species with complex genomes. Unlike other high density genotyping technologies which have mainly been applied to general interest “reference” genomes, the low cost of GBS makes it an powerful approach on discovering and genotyping SNPs in a variety of crop species and populations. As a technically simple, highly multiplexed technology, GBS is suitable for population studies, germplasm characterization, plant genetics, and breeding in diverse crops and it has widely been applied in many large crop genomes to saturate the mapping and breeding populations with 10–100s of 1000s of SNP markers .Construction of GBS libraries is based on reducing genome complexity with restriction enzymes REs; . This apGenotyping-by-sequencing is an ideal platform for studies ranging from single gene markers to whole genome profiling . One of As GWAS require 100s of 1000s to millions of markers to generate sufficient information and coverage, the emergence of NGS technologies has greatly improved such marker resolution . RecentlGBS has been shown to be a valid tool for genomic diversity studies . For exaArabidopsis, er (Landsberg erecta) line. indica ×japonica mapping population consisting of 176 rice recombinant inbred lines and mapped the recombined hot and cold spots and quantitative trait loci (QTLs) for leaf width and aluminum tolerance. After the efficiency of multiplexed SNP genotyping for diversity, mapping and breeding applications were evaluated, ari-e) is located on barley chromosome 5H , and a frequent cutter, MspI (CCGG)] were employed to improve the reduction of genome complexity in barley and wheat (MspI is inhibited when the DNA is methylated at the external “C.” In epigenetic studies, however, the activity of the isoschizomer HpaII is inhibited by methylation at any of two “C.” Because of the wide utilization of HpaII, the methylation of the internal “C” in epigenetic regulation studies seems to be much more important than the methylation of the external “C.” Therefore, the possibility that developmental responses in plants may affect the SNP identification when using the enzyme MspI cannot be ignored, but is likely reduced.Epigenetic studies have revealed the importance of differential DNA methylation in numerous biological systems. Two restriction enzymes [a rare cutter, nd wheat . It may Orphan plant species without a known genomic sequence represent the vast majority of crops over the world. The GBS protocol for wheat and barley and subsequent genetic analyses  were carGenotyping-by-sequencing is a novel application of NGS protocols for discovering and genotyping SNPs for crop improvement. The low cost of GBS makes it an attractive approach to saturate the mapping and breeding populations with a high density of SNP markers. Successive improvements of the sequencing chemistries and base-calling software will allow NGS technologies to deliver higher sequencing throughputs per run, which in turn enables deeper multiplexing for a fixed average sequencing depth per sample. As the amount and quality of sequence information generated per run keeps increasing, which allows even higher plexing and lower costs per samples, GBS has become a cost-competitive alternative to other whole genome genotyping platforms. It can be anticipated that high density of SNP markers from NGS will be extensively applied to GWAS, MAS, and GS. Plant breeders will be able to sequence even large crop genomes and establish high density of genetic linkage maps from breeding populations. Future applications of GBS to crop improvement may allow plant breeders to conduct MAS or GS on a novel germplasm or species without first having to develop any prior molecular tools. As the sequence-based genotyping is available for whole range of genomic studies, GBS will stand to be one of major components in plant genetics and breeding.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The model made clear and testable predictions about how different brain variables, both structural and functional, were related to cognitive function, focusing on the core construct of compensatory scaffolding. The present paper provides a revised model that integrates new evidence about the aging brain that has emerged since STAC was published 5 years ago. Unlike the original STAC model, STAC-r incorporates life-course factors that serve to enhance or deplete neural resources, thereby influencing the developmental course of brain structure and function, as well as cognition, over time. Life-course factors also influence compensatory processes that are engaged to meet cognitive challenge, and to ameliorate the adverse effects of structural and functional decline. The revised model is discussed in relation to recent lifespan and longitudinal data as well as emerging evidence about the effects of training interventions. STAC-r goes beyond the previous model by combining a life-span approach with a life-course approach to understand and predict cognitive status and rate of cognitive change over time. Decades of behavioral research in the latter part of the 20th century characterized a variety of age-related cognitive deficits including memory problems, executive processing dysfunction and declines in speed of processing that typify normal older adults  with computations mediated by the primary network, they are less efficient than primary networks in their youthful state. New evidence consistent with this proposition  may not prevent age-related decline of brain structure and function, but rather enable enhanced scaffolding, so that despite neural degradation, cognitive function continues to be high. It follows from this example that high ability or highly educated older adults with normal cognitive function could harbor greater neural degradation than their less educated counterparts Stern , 2002. IAspects of STAC-r have parallels to the concepts of brain reserve and cognitive reserve advanced by Stern Stern . Brain rIn sum, neural resource enrichment is an ongoing process that confers beneficial neural resources across brain structure, function and compensatory potential, depending upon the nature of the enrichment variable and the overall condition of a given brain. It is worth noting that, most likely, there is a broad range of additional potential influences that could enhance brain structure, function and/or scaffolding, including familial, social and emotional relations, among other variables  and AD, and even a few labs  where the focus is on mechanisms of cognitive health and well-being. The initial amyloid imaging data are congruent with autopsy data and show that at least 20 % of seemingly healthy adults aged 60 and over carry elevated levels of brain amyloid  and overall cognitive function . With respect to the STAC-r model, the most relevant studies are those that have included neuroimaging data. Neural data, particularly fMRI approaches, are needed to understand how the aging brain has changed after a substantive intervention, and what form the changes take. While the mechanisms of training are largely unknown, training could cause fundamental changes in neural structure through volumetric increases and network connectivity, or it could affect compensatory mechanisms.The most ambitious training intervention conducted to date on older adults was a large, multi-site trial enrolling over 2800 participants (Ball et al. An increasing number of studies are examining the impact of cognitive training on neural structure and function in older adults (Lustig et al. Another approach taken to interventions is to immerse or engage participants in an environment designed to promote scaffolding through cognitive challenge, and determine whether sustained exposure to the enriched environment creates new scaffolding and maintains or even improves cognition (e.g., Stine-Morrow et al. What mechanisms underlie these observed improvements in cognition? As Nyberg et al.  recentlyAn important challenge for the field is to understand how strongly different extrinsic factors modify trajectories of aging, the developmental time course of such influences and, relatedly how much plasticity exists in the aging brain at different stages of the life course. For example, some enriching influences may be greatest in youth, whereas others may be most effective at middle age. Might there be others that yield their greatest advantages in older age?Brain imaging continues to give rise to new measures of brain structure and function, such as resting state connectivity, multivoxel pattern analysis, and measures of network variability. It is not yet known which measures are most informative about the mechanisms underlying cognitive function, nor do we know which measures are most sensitive predictors of cognitive change over time. While STAC-r treats these brain indices as roughly equivalent, future research can help to clarify their relative sensitivity to different life- course influences and their relation to compensatory processes that can maintain optimal cognitive function. One suggestion is that increased focus on resting state networks may be especially informative as they are more likely to reflect actual changes in brain mechanisms, rather than task-based strategy differences due to age or induced by an intervention. The application of new measures to assess network efficiency will also advance our understanding of the functional properties of declining and reorganized networks.Along these lines, future research may be able to identify brain patterns characteristic of neural health and neural decline. STAC-r predicts that the ability to maintain youthful levels of brain structure and function over time, relying minimally on compensatory scaffolding, will be associated with greatest efficiency and minimal cognitive decline. Longitudinal brain and performance data obtained over a period a decade or more, would likely permit neuroscientists to test these predictions and ultimately predict future cognitive status effectively based on brain measurements obtained at an earlier age. It is noteworthy that major pathologic indicators of brain health account for considerably less than 50 % of variation in the rate and onset of cognitive decline (Boyle et al. Apart from life course influences on the trajectories of aging, it is critical to understand whether and how interventions applied later in life can forestall or reverse cognitive decline. STAC-r posits a two-fold influence: on compensatory scaffolding and on brain status; however little is currently known about the mechanistic bases for training effects, or the factors that limit training success, especially in older adults. Training could improve the efficiency of the primary network, leading to less reliance on compensatory processes (Lustig et al. Like STAC, STAC-r is a conceptual model that combines adverse and favorable influences on brain structure and function to determine cognitive status. Whereas STAC focused on adverse effects of aging together with beneficial effects of compensation, STAC-r incorporates life-course influences that enhance, preserve, or compromise brain status, compensatory potential, and ultimately cognitive function over time. The model is compatible with concepts of reserve and posits that like compensatory scaffolding these can be affected in positive or negative ways by factors that enrich or deplete neural resources. Given the vast complexity of the human brain and the huge quantities of neurobiological now being accrued, the interpretative challenge confronting neuroscientists is immense. We hope that the STAC and STAC-r models can provide fertile roadmaps for hypothesis development and testing. Here we suggest some questions and directions for future research.


Streptococcus pyogenes  is an exclusive human bacterial pathogen. The virulence potential of this species is tremendous. Interactions with humans range from asymptomatic carriage over mild and superficial infections of skin and mucosal membranes up to systemic purulent toxic-invasive disease manifestations. Particularly the latter are a severe threat for predisposed patients and lead to significant death tolls worldwide. This places GAS among the most important Gram-positive bacterial pathogens. Many recent reviews have highlighted the GAS repertoire of virulence factors, regulators and regulatory circuits/networks that enable GAS to colonize the host and to deal with all levels of the host immune defense. This covers in vitro and in vivo studies, including animal infection studies based on mice and more relevant, macaque monkeys. It is now appreciated that GAS, like many other bacterial species, do not necessarily exclusively live in a planktonic lifestyle. GAS is capable of microcolony and biofilm formation on host cells and tissues. We are now beginning to understand that this feature significantly contributes to GAS pathogenesis. In this review we will discuss the current knowledge on GAS biofilm formation, the biofilm-phenotype associated virulence factors, regulatory aspects of biofilm formation, the clinical relevance, and finally contemporary treatment regimens and future treatment options. Streptococcus pyogenes belongs to the serological group A among the streptococci  and is an exclusively human pathogen. GAS causes significant disease worldwide and adds a large burden to national health care systems  immunoglobulin and complement factor degradation  and (ii) general complement inhibition , (iii) extracellular matrix and serum protein binding via multiple MSCRAMMS  , (iv) dysregulation of coagulation , and (v) cytotoxic and cytolytic activity toward various host cell types . Depending on the presence of phage-related chromosomal islands as variable parts of the accessory genome in the different GAS serotypes, a variable number of superantigens  is expressed and secreted  initial adherence and microcolony formation, (ii) biofilm maturation with production of a matrix of extracellular polymeric substances (EPS), and (iii) detachment of sessile cells—it is not unexpected that virulence factor expression patterns differ in these respective stages , hyaluronic acid capsule biosynthesis (hasA), M-protein (emm3) and the cysteine protease SpeB (speB), was observed while competence-associated com genes were upregulated in comparison to planktonic cells exposed to epithelial cells -types, have been shown to lose their ability to form biofilms when treated with trypsin, thereby removing trypsin-sensitive surface proteins  of surface associated adhesive structures is necessary to mediate initial adherence and autoaggregation of the bacteria. As mentioned above, structures potentially involved are pili, M- or M-like proteins, PrtF2, Scl1, or AspA. The importance of the respective structures in different GAS strains/M-serotypes/FCT-types obviously differs. Also regulatory mechanisms are not ubiquitous among GAS strains. While in some strains environmental signals such as a low pH are needed to induce biofilm formation, other strains produce biofilms in a pH-independent manner. It is likely that some of the adhesive structures are more important to mediate the initial adherence to abiotic surfaces while others will be crucial for adherence to biotic structures. For sure the latter will be of more significance in the patient. A concerted investigation of all surface structures mentioned above in terms of the involvement in biofilm formation on biotic surfaces is still missing.speB in these strains reconstitutes the biofilm phenotype of the wild type strain. Also chemical inhibition of SpeB activity increases biofilm masses of MGAS5005Δsrv  and other secreted enzymes are associated with the biofilm lifestyle of GAS. SpeB as a secreted cysteine protease is suspected to degrade peptides that stabilize the biofilm matrix  is a structural component of biofilm matrix, there is no direct prove for eDNA in GAS biofilms yet  transcripts in GAS strain HSC5 during biofilm maturation. Furthermore, they found a mutant defective of capsule biosynthesis to be unable to form a solid biofilm under flow conditions, while under static conditions the biofilm masses were unaffected by this mutation  on keratinocytes in comparison to keratinocyte-exposed planktonic bacteria  pheromones SHP2 and SHP3. These peptide pheromones are encoded downstream of two genes encoding for the Rgg-like transcriptional regulators Rgg2 and Rgg3, respectively  response regulator of the CovRS two component system probably binds directly to the speB expression via indirect mechanisms  are most commonly treated utilizing penecillin in combination with clindamycin. The combination with clindamycin proved to be beneficial to prevent GAS toxin production during therapy , potentially resulting in recurrent infections and persistent carriage  is of special interest. It was shown that this multimeric N-acetylmuramoyl-L-alanine amidase hydrolyzes GAS cell walls and eliminates bacterial cells  Krause, . Shen an Krause, . These asof and sfb1 genes encoding for fibronectin binding streptococcal surface proteins, resulting in reduced human tissue binding and biofilm formation capacity  for topic wound treatment. Maddocks and others described medihoney to inhibit the expression of Pseudomonas aeruginosa can induce dispersion of biofilms of GAS and other bacteria. If such substances could be administered in patients in combination with conventional antibiotics, this would probably lead to eradication of GAS biofilm associated infections (Davies and Marques, It has furthermore been shown that the fatty acid messenger cis-2-decenoic acid produced by Streptococcus oralis and Streptococcus salivarius, protect epithelial cells from GAS adherence. This observation indicates a role of these bacteria in host health. It was reported that S. oralis could induce protection of eukaryotic cells even without largely binding to the cells or producing bacteriocins affecting GAS (Fiedler et al., S. salivarius was shown to provide host cell protection against GAS by forming an impermeable biofilm so the host epithelial cells are inaccessible for initial GAS tissue colonization (Fiedler et al., S. salivarius K12 to antagonize GAS growth by expressing the lantibiotics salivarin A2 and B subsequently influencing GAS biofilm formation (Di et al., Beside the chemical treatment of mature GAS biofilms, also probiotic effects of physiological bacteria on GAS biofilm formation have been reported (Guglielmetti et al., The standard antibiotic medication for patients with GAS infections is not sufficient to eradicate GAS biofilms. Alternative or additional therapeutics are currently investigated. Phage lysin C represents the most promising candidate for clinical application. However, more efforts are needed in developing treatment strategies to prevent extensive and repeated antibiotic treatment in patients with biofilm associated recurrent GAS infections.Due to the high tolerance of GAS biofilms toward antibiotics, GAS biofilms are likely to be associated with antibiotic treatment failure in patients. Therefore, the major future challenge will be the development of new therapeutic strategies to prevent the extensive use of antibiotics on patients with recurrent GAS biofilm associated infections. As can be seen from this review, we are just at the beginning of understanding the GAS biofilm phenotype and its relevance for GAS pathogenesis. Therefore, extensive further studies on the biological processes involved in GAS biofilm formation are necessary.in vivo. Furthermore, more efforts are needed to decipher the role of individual virulence factors and gene regulation circuits in GAS biofilm development in vivo, since most of the current knowledge is based on in vitro data.A major question in this context is which environmental factors trigger GAS biofilm formation. It is highly likely that apart from carbon source, external pH, and peptide pheromone levels, host innate immune responses trigger GAS biofilm development emm- or FCT-type, antibiotic resistance or presence/absence of certain virulence factors, needs to be elucidated. Ideally, such studies will lead to phenotypic profiles that will allow deducing the potential of GAS isolates for biofilm formation.Since the GAS biofilm formation capacity is very strain specific, it will be important to include the determination of the biofilm phenotype of GAS strains into epidemiological investigations. Particularly the relation of the biofilm phenotype to other parameters frequently studied in GAS epidemiology, e.g., Such tools would facilitate the specific treatment of patients with recurrent infection potentially associated with GAS biofilms. The most promising candidates for clinical application in GAS biofilm eradication in patients are specific phage lysins such as PlyC, since they have excellent MBEC values. Research in this area should be intensified toward application in clinical practice.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Heart failure (HF) is a costly, challenging and highly prevalent medical condition. Hospitalization for acute decompensation is associated with high morbidity and mortality. Despite application of evidence-based medical therapies and technologies, HF remains a formidable challenge for virtually all healthcare systems. Repeat hospitalizations for acute decompensated HF (ADHF) can have major financial impact on institutions and resources. Early and accurate identification of impending ADHF is of paramount importance yet there is limited high quality evidence or infrastructure to guide management in the outpatient setting. Historically, ADHF was identified by physical exam findings or invasive hemodynamic monitoring during a hospital admission; however, advances in medical microelectronics and the advent of device-based diagnostics have enabled long-term ambulatory monitoring of HF patients in the outpatient setting. These monitors have evolved from piggybacking on cardiac implantable electrophysiologic devices to standalone implantable hemodynamic monitors that transduce left atrial or pulmonary artery pressures as surrogate measures of left ventricular filling pressure. As technology evolves, devices will likely continue to miniaturize while their capabilities grow. An important, persistent challenge that remains is developing systems to translate the large volumes of real-time data, particularly data trends, into actionable information that leads to appropriate, safe and timely interventions without overwhelming outpatient cardiology and general medical practices. Future directions for implantable hemodynamic monitors beyond their utility in heart failure may include management of other major chronic diseases such as pulmonary hypertension, end stage renal disease and portal hypertension. Cardiovascular disease remains the leading cause of death in the United States and worldwide To contain costs and standardize management of patients hospitalized for ADHF, the Centers for Medicare and Medicaid Services have recently introduced regulations to withhold or reduce payments for unnecessary hospitalizations for HF  technology which had already established the safety of right ventricular pacing leads and was being used in the target population. Early devices used innovative transvenous lead technology to provide mixed venous oxygen saturation and pressures in the right ventricle (RV)  , and pulmonary artery pressure (PAP) ambulatory heart failure monitoring implantable devices were developed as purely diagnostic devices Figures . LAP monN = 1200) to verify the robustness, safety and usefulness of CardioMEMS in the complex real-world setting, particularly in reducing the rate of HF hospital readmissions and in improving patients' quality of life .Monitoring of PAP has been used for decades by cardiologists to detect early signs of HF in the intensive care setting  consisting of a coil and capacitor encased in silicone, with a nitinol wire loop at each end of the sensor Figure . The CarPatients enrolled in the CHAMPION trial were asked to make daily measurements of their PAPs using their portable electronic unit and a special pillow containing an antenna to take daily sensor readings which are transmitted through a modem or cellphone to a secure patient database  is accessible to healthcare professionals to view the interrogated data. The HeartPOD, CardioMEMS and other non-EP  implantable monitoring systems have built-in, untapped features including cardiac output, heart rate variability, and electrocardiographic monitoring. If officially approved by the FDA, these additional monitoring parameters will likely improve characterization of hemodynamic derangements, and potentially reduce false-positive results, and associated resource utilization.Both the HeartPOD and CardioMEMS systems use a physician-guided self-management model that is intuitive and conceptually sound. However, experts in the field have universally acknowledged the challenges in conducting implantable monitoring trials to demonstrate impacts on clinical outcomes, particularly with how the interrogated physiologic data are handled  between PCWP and LAP in all settings with the PCWP being consistently 35% higher than the LAP. A more contemporary study of lightly sedated dogs reported that the mean PCWP accurately reflected LAP . However, a study of 43 dogs and 30 patients in severe hemorrhagic, traumatic or septic shock noted that a dangerous rise in PAP was not reflected by PCWP or even central venous pressure . The PCWP is often considered to reflect left ventricular preload and pulmonary capillary hydrostatic pressure, however, there is ongoing debate about the validity of this assumption in the setting of various conditions including chronic pulmonary disease, mechanical ventilation and pulmonary venous scarring. In principal, the LAP would be a more accurate measurement as it is physically and physiologically closer to the gold standard, LVEDP, however it is more invasive to measure. A brief literature review did not reveal any studies comparing the three measurements simultaneously, however there are a few studies comparing LAP and PCWP. In 1962, the PAP, PCWP, and LAP measurements of 11 patients with either clinically normal hearts or suspected mitral valve disease were studied with right heart catheterization in a control state, during a norepinephrine infusion, and during positive and negative intraalveolar pressures  Furthermore, in advanced HF patients with known arrhythmias, there can be a role to assess the clinical impact of supraventricular arrhythmias such as atrial fibrillation and ventricular arrhythmias, as well as addressing the question of whether these rhythm disturbances are causal or secondary to ADHF. Additionally, with the pressure to avoid indwelling lines, invasive procedures and overburdening intensive care units, pre-existing internal devices that monitor filling pressures could facilitate the management of these particularly high risk patients when admitted for both cardiac and non-cardiac issues, including perioperative hemodynamic and fluid management.In advanced HF patients with left ventricular assist devices (LVAD) who are recurrently admitted with symptoms of congestion and fluid overload, LAP and PAP monitors may potentially help to discern elevated left sided filling pressures from other causes of dyspnea, and volume overload . However, further clinical review and evaluation still may be necessary to exclude a failing right ventricle in response to LVAD placement and manage other non-cardiac etiologies for recurrent hospitalizations. These devices may also be able to detect low filling pressures in patients with LVADs who urgently need increased intravascular volume in order for optimal device function and cardiac output. It remains to be seen whether regulatory agencies and transplantation societies will endorse the use of implantable LAP or PAP monitors as an alternative to indwelling PA catheters in the pre-heart transplant setting, with the intent to obviate the need for hospitalization in the intensive care unit and periodic replacement of PA catheters that are associated with procedural and other risks including line infection, sepsis, and thromboembolism.N = 16) met criteria based on continuously observed PAP over the first week post-implantation. This implies that an implantable heart monitor may assist with improved diagnosis of pulmonary hypertension and perhaps better guide future trials targeting pulmonary hypertension (Frantz et al., There are also innumerable non-cardiac scenarios in which continuous assessment of cardiac hemodynamics and filling pressures would be invaluable. A recently published substudy of the CHAMPION trial found that of the 217 patients who did not meet criteria for pulmonary hypertension during the implantation right heart catheterization, 48.8% (The review was initially conceived of and manuscript outlined by all authors. DM prepared the first draft in collaboration with EF. RD and DS provided substantial revisions and contributions. DS contributed Figure Rahul N. Doshi has served as a consultant for St. Jude Medical, Inc. David M. Shavelle is a consultant and received research support from St Jude Medical, Inc. Deirdre M. Mooney and Erik Fung declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A prominent hypothesis of hemispheric specialization for human speech and music states that the left and right auditory cortices (ACs) are respectively specialized for precise calculation of two canonically-conjugate variables: time and frequency. This spectral-temporal asymmetry does not account for sex, brain-volume, or handedness, and is in opposition to closed-system hypotheses that restrict this asymmetry to humans. Mustached bats have smaller brains, but greater ethological pressures to develop such a spectral-temporal asymmetry, than humans. Using the Heisenberg-Gabor Limit  to frame mustached bat literature, we show that recent findings in bat AC (1) support the notion that hemispheric specialization for speech and music is based on hemispheric differences in temporal and spectral resolution, (2) discredit closed-system, handedness, and brain-volume theories, (3) underscore the importance of sex differences, and (4) provide new avenues for phonological research. The finding that damage to the left cerebral hemisphere in humans impairs receptive language  is seminal to the field of neuroscience  and cetaceans . These two hypotheses are generally respected as plausible explanations for language lateralization in humans and are not mutually exclusive.Neuroscientists have proposed numerous hypotheses to explain this asymmetry. An early hypothesis erroneously credited to Paul Broca relates both left lateralization of language function and, via decussation, right handedness to a general left hemispheric dominance common to most humans Harris, . This “BTwo other hypotheses are mutually exclusive and have thus generated much debate in the last half century. The first of these is the “closed system” hypothesis, which argues that neural mechanisms underlying receptive auditory communication in humans  are unique to humans, specific for speech and language, and are contained within a “speech organ” in the left hemisphere  as an umbrella-term for hypotheses that explain auditory hemispheric specialization via a trade-off between acoustic spectral and temporal resolution  auditory cortex due to (1) the fact that individuals in this species primarily orient themselves and communicate with each other using complex auditory signals and (2) the vast and well-established literature describing the auditory cortical maps in this species.Our aim here is to further validate either the closed-system or domain-general hypothesis of receptive auditory communication by exploring this last implication of ASTIR. We base our exploration of ASTIR around the functional organization of the mustached bat   Joos, . The AcoThe Heisenberg-Gabor Limit demonstrates that simultaneous, precise measurements of a function in both the temporal (time) and spectral (frequency) domains is impossible, because refined temporal resolution only comes at the expense of spectral resolution and vice-versa, as shown in Figure Independent groups of researchers postulated that the specialization for speech and music characteristic of the left and right hemispheres of humans, respectively, stems from the use of narrow temporal windows by left auditory cortex and wide temporal windows by right auditory cortex  generate sonar signals to orient themselves and hunt insects  and FM (FM1−4) components  than the sum of the responses elicited when the individual CF and FM components are presented alone. For instance, neurons in the FM-FM processing subregion are facilitated by pulse-echo pairs of FMs  and tuned to their delays   processing subregion   this refined frequency discrimination is performed by neurons in the DSCF area .For mustached bats, both refined spectral and temporal resolution are essential to tracking the velocity and range of targets. Like momentum and position or frequency and time, precise sonar measurements of velocity and range are impossible to achieve on the same time scale Parker, . This DoDoppler Ambiguity exposes a potential flaw in ASTIR. Velocity and range are processed within the bilateral, cortically adjacent subregions of DSCF, CF/CF, and FM-FM, despite being canonically-conjugate variables. Thus, echolocation demonstrates that the ethological need to precisely calculate canonically-conjugate variables is not necessarily sufficient biological pressure to impose hemispheric specialization. Indeed, anterior auditory field (AAF) in rodents  is facilitated such that its magnitude is greater than the sum of response magnitudes elicited by each call-component alone. Such band-pass filtered call-components may elicit responses of greater magnitude than the entire natural social call due to the absence of spectral energy traversing inhibitory response areas. Further, similar to FM-FM neurons, DSCF neuron responses to social calls are greatly diminished by reversing the call, but this phenomenon in DSCF neurons may be attributed to asymmetrical inhibitory areas flanking the narrow, excitatory echo-CF2 range.Likewise, the magnitudes of DSCF neuron responses to certain social calls are known to be comparable to and may even surpass the magnitudes of their responses to pulse-echo CF components Kanwal, , 2006. C2 range , and some curvilinear or sinusoidal FM calls have instantaneous rates higher than 5 kHz/ms . Many neurons in the DSCF area are responsive to rapidly-modulated call components that traverse the echo-CF Kanwal, . FM sele Kanwal, . FurtherEven the most elaborate neural circuits are subject to physical laws. Thus, the mustached bat auditory system is no exception to the Heisenberg-Gabor Limit. The ability of DSCF neurons to detect and respond to such rapid modulations of frequency necessitates that they make use of some form of narrow temporal window. However, neurons in the DSCF area are defined by their refined spectral resolution, which requires the use of a wide temporal window. The constraint that neurons in the DSCF area must process auditory signals using both wide and narrow temporal windows creates a fundamental conflict between integration and resolution.In theory, DSCF neurons may have evolved in such a way as to contend with this conflict. Potential strategies include (1) having one group of DSCF neurons process signals using wide temporal windows and another group using narrow windows, (2) having each neuron contain a group of synaptic or dendritic microcircuits which process signals using wide temporal windows and another set that does so using narrow windows, and (3) metabolically adjusting excitatory and inhibitory response areas such that temporal windows are wide while hunting and narrow while socializing. However, all but the first of these strategies would be energy-intensive, computationally problematic, or behaviorally untenable. The second strategy is computationally problematic on two counts. First, temporal domain computations would be performed either faster and/or at a more consistent pace than spectral domain computations, creating a bottleneck at the axon hillock by which the slow and/or intermittent flow of spectral computations interferes with the rapid and/or steady flow of temporal computations. Second, a method would be needed to differentiate between any firing patterns elicited by the spectral and temporal components of signals since they would be generated within the same neuron and thus propagating down the same axon(s). The third strategy is energy-intensive for an organism with an already high metabolism and behaviorally untenable since the bats constantly echolocate, even in social situations  can be processed within bilateral adjacent cortical regions. However, there are key differences in the acoustic structure of biosonar signals and social calls as well as the neural circuitry used to process them. CF components always precede FM components during echolocation whereas the same cannot be said of composites  and other sequences of social calls  and refined temporal information (in the form of rapid FM-type syllables traversing the echo-CF2 range). Thus, the DSCF area would need to contend with two subpopulations that intermittently perform computations on different time scales while sharing many of the same inputs and projections. If their inputs largely originate from one cochlea (itself subject to the Heisenberg-Gabor Limit), how one population with refined spectral and another with refined temporal resolution managed to co-exist  within the cochleotopic axis of A1 would be difficult to understand.Neither possibility exists for the two hypothetical populations of DSCF neurons. During communication, both neural populations would intermittently receive refined spectral information  responsible for processing rapidly changing signals within a narrow temporal window is connected to an adjacent region responsible for fine frequency discrimination , the resulting circuit will only be as fast as its slowest node. That is to say that the region responsible for fine frequency discrimination will become an unnecessary rate-limiting step, slowing down the processes of other adjacent regions responsible for rapid auditory processing. Housing the spectral and temporal processing regions in different hemispheres would allow the auditory cortices in both hemispheres to process signals at rates ideal for maximizing spectral and temporal information while allowing them to communicate via the corpus callosum as needed. Second, A1 is an example of primary sensory cortex. In mustached bats and other animals, there is an advantage to processing auditory signals with refined spectral (velocity) and temporal (communication) information at this level of the cortical hierarchy. Appropriating a region adjacent to a primary sensory cortical area like A1, which has different cytoarchitecture from A1 and could otherwise perform higher-level analyses on information it receives from A1, would not necessarily be evolutionarily advantageous or neuro-plastically trivial. Such a waste of cortical resources would be egregious if the sole purpose for appropriating this adjacent region was to analyze Fourier-transformed  versions of the same auditory information processed by A1. This waste of cortical resources becomes even more nonsensical when there is another A1 on the other side of the brain that is ideally situated to perform an analysis of Fourier-transformed versions of the same information in parallel.Taken from another perspective, ASTIR asserts that the human brain developed this specialization due to environmental pressures necessitating precise acoustic calculation of time and frequency, especially as they relate to speech and music  in the left and right hemispheric FM-FM areas Suga,  in a sin2 range  of FMs, specifically by changing their durations (Δt) while keeping their bandwidths (Δf) constant. Spectral domain processing was tested by varying the bandwidths of FMs while maintaining their rates at the preferred rate for each neuron. FMs were always paired at onset with a CF at the best frequency in the pulse-FM1 range so as to optimize neural responses via facilitation.On the other hand, the spectral and temporal domain processing of neurons within the left and right hemispheric DSCF areas of six bats were directly tested using linear FMs centered on each neuron's best frequency in the echo-CFLH = 88, RH = 70) in the DSCF areas of six bats in showed profound hemispheric differences that conformed to ASTIR  and showed greater variance  amongst right DSCF neurons than those on the left. Likewise, latencies of responses elicited by FMs optimized for the spectral and temporal selectivities of each neuron  showed even greater hemispheric differences, such that latencies were nearly twice as long  and showed almost 20 times the variance in the right hemisphere relative to the left . Left DSCF neurons selected for FMs with faster rates (1 kHz/ms) than those on the right (0.2 kHz/ms) whereas right DSCF neurons selected for FMs with narrower bandwidths (3.5 kHz) than those on the left (4.4 kHz). Right DSCF neurons also selected for FMs with durations over twice as long (34 ms) as those on the left (14 ms) and had longer response durations (31 ms) than those on the left as well (20 ms). Further analyses ruled out the possibility of FM duration selectivity and hierarchical linear modeling ruled out the possibility that these results were biased to individual bats.Responses recorded from 158 neurons  in the DSCF areas of four female mustached bats  and variance  across hemispheres, comparable to those of the left hemisphere in males. Left and right DSCF neurons also selected for FMs with similar rates  and bandwidths . However, like males, right DSCF neurons from female bats also selected for FMs with significantly longer durations (65 ms) and had longer response durations relative to those on the left (37 ms). Likewise, response latencies to FMs in females were significantly longer on the right (30 ms) than on the left (17 ms), similar to males. Left DSCF neurons were again less selective for slow FM rates in females but to a far lesser extent than in males. There were no appreciable hemispheric differences in spectral domain processing in females. Yet, response characteristics of neurons in the right DSCF areas of female bats showed multiple signs of processing sounds using longer integration windows relative to those in the left hemisphere. Like in males, female bats displayed no selectivity for FM durations, and these results were not biased to individual bats.The same study described above reported recordings not only from neurons in the DSCF areas of six male mustached bats but also reported recordings from 168 neurons (Despite these sex differences in hemispheric specialization, what must be emphasized is that ASTIR appears to be a feature of both the male and female mustached bat auditory cortex. Further, data collected from multiple species suggests that these sex differences represent less a flaw in the hypothesis proposed here than a feature of hemispheric specialization for communication sounds. Hemispheric specialization for song production and perception is greater in male than in female songbirds (Nottebohm and Arnold, Placing mustached bat echolocation and communication into a computational context via the Heisenberg-Gabor Limit allows us to begin answering longstanding questions. First, the fact that ASTIR appears to be greater in male bats and that advantages for temporal and spectral domain processing are found in the left and right hemispheres respectively, and not vice-versa, strongly suggest that hemispheric specialization in mustached bats is analogous to such specialization in the human brain. Second, ASTIR's presence within the brains of mustached bats, when coupled with the fact that neither echolocation nor communication represents a closed system in this species, is evidence against closed-system hypotheses of speech processing. If ASTIR can occur in mustached bats and amongst the same neurons responsible for processing both biosonar signals and social calls, a language-only “speech organ” existing within the left superior temporal gyri of humans seems unnecessary. Third, ASTIR's presence in mustached bats is even stronger evidence against brain-volume and handedness hypotheses. The small brains of mustached bats and the large brains of humans are capable of having similar hemispheric differences. Mustached bats also do not have hands or even use tools.in-utero and during infancy are known to modulate hemispheric specialization for speech and language in humans (Geschwind and Galaburda, Nonetheless, this theoretical discussion of neural mechanisms of hemispheric specialization and the evidence supporting their existence in mustached bat auditory cortex raises many questions. Those questions stemming from sex differences are admittedly some of the most difficult: Why do these sex differences exist? What adaptive purpose do they serve? The hypothesis presented above asserts that powerful ethological pressures related to hunting and socialization in mustached bats underlies the development of ASTIR in mustached bat auditory cortex. However, some form of ethological pressure also drove hemispheric specialization for communication in humans and songbirds while leaving some startling exemptions for females in those species. It is likely that the sex differences for hemispheric specialization in mustached bats are present for the same reason similar sex differences are present in humans and songbirds. However, there is no consensus on why these sex differences exist in any of these species. Testosterone levels 2 are higher in frequency amongst female bats (Suga et al., To this end, current results in the mustached bat may be more useful for questioning answers than for answering questions. Specifically, anthropologists have associated sex differences in hemispheric specialization for speech and language with the respective hunter and gatherer roles of men and women Joseph, . This anNeurophysiological studies employing more sophisticated equipment and experimental designs will be needed to fully explore this sex dependent asymmetry. Mapping studies could determine if males and females have a different spatial distribution of neurons in the auditory cortex or a different morphology of auditory cortical fields. Neuropharmacological techniques previously used in the study of neural selectivity for social calls in bats (Klug et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Microbial activities are most often shaped by interactions between co-existing microbes within mixed-species communities. Dissection of the molecular mechanisms of species interactions within communities is a central issue in microbial ecology, and our ability to engineer and control microbial communities depends, to a large extent, on our knowledge of these interactions. This review highlights the recent advances regarding molecular characterization of microbe-microbe interactions that modulate community structure, activity, and stability, and aims to illustrate how these findings have helped us reach an engineering-level understanding of microbial communities in relation to both human health and industrial biotechnology. In addition, microbial interactions may be dynamic and dependent on environmental context, and microbial communities can have different spatial interactive distributions ranging from metabolic interactions between unassociated planktonic cells in the ocean4 and long-distance electrical signaling within microbial communities6 to local cell-cell interactions occurring within surface-attached biofilms7. Furthermore, a series of recent studies have shown that microbe-microbe and microbe-host interactions can also be mediated by small, air-transmittable molecules10.Most microbial species are embedded within ecological communities containing many species that interact with one another and their physical environment. Virtually all important microbial activities are shaped by interactions between co-existing microbes within mixed-species communities. These interactions -based phylogenies or full metagenomic sequencing has now resulted in a much deeper understanding of the interplay between the human microbiome and bacterial pathogens with respect to infectious disease development. For example, studies of the microbial communities in certain chronic infections such as cystic fibrosis (CF) have revealed clear correlations between loss of community diversity and disease progression18. CF patients are predisposed to airway infections from a number of bacterial opportunistic pathogens, among whichPseudomonas aeruginosa,Staphylococcus aureus,Haemophilus inﬂuenzae, andBurkholderia cepacia complex (BCC) have been directly associated with CF lung disease21. However, recent studies based on culture-independent methods have demonstrated the presence of many additional bacterial species previously undetected by culture and have revealed a greater microbial diversity in CF airways than previously recognized20. CF airways clearly represent a complex and diverse polymicrobial ecosystem, and, as the disease symptoms become more severe, the CF lung microbiota becomes dominated by the primary pathogen (which most often is the opportunistic pathogenP. aeruginosa)18. These results are suggestive of a wider role of the respiratory microbiota and highlight the importance of interactions between the primary pathogen and the microbiota in relation to disease progression.In relation to infectious diseases, it is becoming increasingly clear that interactions between bacterial pathogens and other microbial species present at the infection site  can influence disease phenotype or clinical outcome. One example of the importance of such pathogen-microbiota interactions is the well-established role of the intestinal commensal microbiota regarding the prevention of colonization of invading microorganisms including bacterial pathogens in a process known as colonization resistanceStaphylococcus aureus in the nasal cavity22 and enteropathogenicEscherichia coli23 andVibrio cholera24 in the gut. Despite these exciting observations, we are still far from being able to efficiently harness the protective capability of the commensal microbiota against pathogens. Nevertheless, these and related findings clearly point toward chemical and/or biological interference with microbial interaction networks within diseased hosts as alternative treatment strategies against pathogens.There are several recent and parallel examples of interactions between the commensal microbiota and possible pathogens which are responsible for limiting colonization and infections by bacterial pathogens such as25 or to potentiate pathogen expansion or virulence28. Although it is obviously challenging to identify and characterize microbial interspecies interactions in infected hosts, interdisciplinary approaches that combine classical microbiologicalin vitro cultivation techniques with advancing technologies such as three-dimensional (3D) printing29, imaging mass spectrometry30, and development of realistic and controllablein vitro model systems31 now make it possible to begin systematically teasing apart the interactions among cultivated key community members and to determine how these interactions modify pathogen behaviors.The findings mentioned above highlight the importance of research aimed at systematic mapping of interspecies interactions regarding different types of bacterial infections in combination with the identification and molecular characterization of these interactions. In other words, it is now critical to move beyond correlative research and studies focused on generating microbiome “parts” lists and to instead begin to focus on causality and function at the molecular level. Indeed, a few pioneering studies have recently illustrated these points very clearly, and there are now clear examples of identified microbe-microbe interactions mediated by bacterial metabolites and gene products that function either to limit pathogen colonization33, and this has logically led to the emerging concept of community-based cell factories in which synthetic microbial communities are rationally designed and engineered to produce valuable chemicals. Recent studies have indeed demonstrated the potential value of such engineered mixed-species communities as production platforms. In one recent example, a synthetic mixed-species community ofE. coli andSaccharomyces cerevisiae was engineered to produce complex pharmaceutical molecules including precursors of the anti-cancer drug paclitaxel34. By engineering the two organisms to host specific portions of the biosynthetic pathways, it was possible to construct a co-culture system in which an intermediate metabolite was first produced byE. coli and then further functionalized byS. cerevisiae to give the final product. This study is the first demonstration of the segregation of long and complex biosynthetic pathways into separate organisms each carrying portions of the pathway, which not only enables parallel optimization of the independent pathway modules but also makes it possible to use the best match between particular pathway modules and specific hosts. In another recent study, a fungal-bacterial community was engineered to convert lignocellulosic biomass into biofuels35. Here, the community contained the fungusTrichoderma reesei, which can hydrolyze lignocellulosic biomass into soluble saccharides, and the bacteriumE. coli, which can metabolize these saccharides into isopropanol. In this example, one species provided the carbon source for the second species, which in turn was able to produce the final product on its own.In nature, microbes form interacting mixed-species communities to accomplish complex chemical conversions through division of labor among the individual organisms. We have successfully harnessed the power of such natural microbial communities in food and other industries for decadesIt is clear from these and other studies that successful engineering of community-based microbial cell factories relies greatly on our molecular understanding of microbe-microbe interactions and how these influence community assembly, stability, and activity.36. This general instability of synthetic communities limits their translation into real-world applications in industrial biotechnology, and achieving long-term maintenance of synthetic communities is a significant challenge that must be solved.Unlike their natural counterparts, synthetic communities are often unstable. For example, different growth rates among the constituent organisms and secretion of toxic metabolites during growth can influence the stability of the community and will often lead to single-species domination or extinction of the communityet al.34 used knowledge of the metabolic capacities of the constituent organisms to construct a specific environment that favored community stability:E. coli can use xylose as a carbon source, but when grown on this carbon source,E. coli excretes acetate, which is inhibitory to its own growth. On the other hand,S. cerevisiae can use acetate as a carbon source but not xylose. The use of a specific carbon source (in this case xylose) thus created a mutualistic interaction between the two organisms, which in turn stabilized the community.Although we still have an incomplete understanding of the multiple competitive and cooperative interactions that control microbial community assembly and activity, many different strategies have been successfully employed to increase the stability of synthetic communities. In the first example described above, ZhouT. reesei andE. coli) described in the previous section, Mintyet al.35 took advantage of the particular co-operator/cheater relationship that existed in their engineered fungal-bacterial community and used ecological theory to establish specific conditions (in terms of population sizes) that could stabilize this interaction.In the other mixed-species community  and their activities within the human host have been found to be more complex than previously realized48.A fundamental principle in biology is that structure (form) and function are inseparable elements. For example, spatial separation of cells that are then subsequently linked together through controlled proximity is an organizational theme frequently observed at all levels in biology36. Recent advances in fluidics-based bacterial cultivation chambers49, 3D printing methods29, and other micro-patterning techniques50 represent exciting areas in this direction that may advance our ability to efficiently design and control the spatial organization of cells within microbial communities.Regarding the construction of community-based cell factories, it is certainly a possibility that alternative community-stabilizing methods should build on knowledge of structure/function relationships. Indeed, it has been shown that spatial separation and artificial positioning of cells within synthetic microbial communities improve community function and stabilityAs either members of infection communities within colonized hosts or part of synthetic communities for sustainable bioproduction, both pathogenic and industrially relevant bacteria are placed in polymicrobial environments in which interactions and spatial position modulate their activity. In both areas, there is a clear need to move beyond the current sequenced-based technologies often used to characterize complex microbial communities and to begin to identify and characterize the function of microbial interactions and the role of spatial organization. The examples shown here illustrate that such knowledge can provide new strategies for better control of bacterial infection and optimized utilization of community-based microbial cell factories. Finally, we emphasize that although our discussion is focused on examples of multispecies bacterial systems in relation to disease and biosynthesis, we believe these are indeed representative examples of an awakening field within microbial ecology focused on understanding species interactions in many types of polymicrobial ecosystems.


FDG-PET/CT is widely used to diagnose cardiac inflammation such as cardiac sarcoidosis. Physiological myocardial FDG uptake often creates a problem when assessing the possible pathological glucose metabolism of the heart. Several factors, such as fasting, blood glucose, and hormone levels, influence normal myocardial glucose metabolism. The effect of outdoor temperature on myocardial FDG uptake has not been reported before. We retrospectively reviewed 29 cancer patients who underwent PET scans in warm summer months and again in cold winter months. We obtained myocardial, liver, and mediastinal standardized uptake values (SUVs) as well as quantitative cardiac heterogeneity and the myocardial FDG uptake pattern. We also compared age and body mass index to other variables. The mean myocardial FDG uptake showed no significant difference between summer and winter months. Average outdoor temperature did not correlate significantly with myocardial SUVmax in either summer or winter. The heterogeneity of myocardial FDG uptake did not differ significantly between seasons. Outdoor temperature seems to have no significant effect on myocardial FDG uptake or heterogeneity. Therefore, warming the patients prior to attending cardiac PET studies in order to reduce physiological myocardial FDG uptake seems to be unnecessary. The outside temperature between summer and winter varies greatly in Finland, exposing people to either very cold or very warm weather. The body adapts to these changes in ambient temperature in various ways; brown adipose tissue (BAT), for example, is known to be activated during the colder months , so commWe found no significant difference in myocardial FDG uptake between warm summer months and cold winter months. Our study population comprised nearly as many subjects with a higher myocardial SUV in summer than in winter as subjects with a higher myocardial SUV in winter. The change in myocardial SUVs between summer and winter throughout the study population was quite dispersed, so we observed no consistent change. Outside temperature or changes in it therefore do not seem to be a significant factor influencing the metabolism of the heart.Standard protocol requires that patients rest at least one hour before scanning, so in each case, they spend time indoors prior to their PET study. If the heart is able to adapt rapidly to warmer conditions, that is, within an hour, it could influence our findings.Because the patients in our study were all cancer patients, their fast lasted only 6 hours before the PET scan, contrary to the longer, 12-hour fast used when assessing cardiac inflammation such as CS. This is a minor limitation, as the purpose of our study was to investigate intraindividual physiological variation in myocardial FDG uptake.We did not control the time each subject spent outdoors before their scans. Our study aimed to compare scans taken in different seasons and the effect of a long time exposure to different ambient temperatures on myocardial FDG uptake. All of the subjects in this study were mobile outpatients and not in-house patients representative of a typical patient for a PET scan at our institution.We could not evaluate the possible effect of blood glucose levels on the seasonal variation in myocardial FDG uptake, since the blood glucose levels were not routinely noted at the time of the first scans. At the time of the second scan, however, we found no significant correlation between the blood glucose levels and the myocardial SUVs.In conclusion, our study shows that outside temperature changes between seasons seem to have no significant effect on myocardial FDG uptake. In addition, seasonal variance in outside temperature does not affect heterogeneity of myocardial FDG uptake. The glucose metabolism of the myocardium does not react to seasonal temperature changes in the same way as brown adipose tissue does, so such temperature changes should not be a confounding factor in myocardial FDG-PET studies, such as when a diagnosis of cardiac sarcoidosis is in question. Warming the patients prior to cardiac FDG-PET studies to lower the physiological myocardial FDG uptake seems to be unnecessary.