Exosomes are small nanovesicles of about 100 nm in diameter that act as intercellular messengers because they can shuttle RNA, proteins and lipids between different cells. Many studies have found that exosomes also play various roles in viral pathogenesis. Hepatitis A virus  and Hepatitis C virus  two single strand plus-sense RNA viruses, in particular, have been found to use exosomes for viral transmission thus evading antibody-mediated immune responses. Paradoxically, both viral exosomes can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate immune activation and type I interferon production. This article will review recent findings regarding these two viruses and outline how exosomes are involved in their transmission and immune sensing. HCV de novo infection of naïve cells [in vivo.Subsequent studies could also show evidence of virion-independent exosomal transmission of viral RNA and ve cells ,26,27,28Picornaviridae family  but recent studies have found that the virus particles can be engulfed by host membranes that resemble exosomes and as such are secreted from infected cells in a way that protects the virus from antibody-mediated immune responses [Like HCV, Hepatitis A virus (HAV) is a hepatotropic positive-strand RNA virus that employs similar strategies to inhibit innate immune responses using protease mediated cleavage of innate immune adaptors ,33,34. Uesponses . This maesponses . As withesponses   and E1/E2 glycoproteins this process does not require full virus assembly ,41,42. Tet al. .vs. virion targeting to MVBs. Interestingly, it has been shown that HCV relies on the ESCRT protein HRS for export of its nucleocapsids, which was dispensable for eHAV release suggesting that while many viruses hijack the ESCRT machinery for their export there are mechanistic differences [In contrast, for HAV it has been shown that exosomally packaged virions termed eHAV and not viral RNA exosomes are responsible for pDC activation and spread of infection. Similar to HCV RNA, HAV virion incorporation into exosomes requires certain components of the ESCRT machinery although they differ slightly between the two viruses. eHAV packaging and release was shown to be dependent on the ESCRT proteins Alix and VPS4B but not on other components like TSG101, HRS, CHMP4A, CHMP4B, and CHMP4C ,40. Thisferences ,45.Both concentrated HCV (which is enveloped) and HAV (which is not enveloped) particles fail to activate pDCs. In both cases, close contact of pDCs with infected hepatocytes or highly concentrated viral exosomes were necessary for induction of interferon-alpha production ,40. Thisin vivo or in vitro. It is not clear whether HCV or HAV (non-enveloped) virions are taken up by pDCs via viral or other receptors although it is clear that neither virus can replicate in pDCs nor do they activate interferon. The fact that HCV virus particles can impair pDC function in infected patients suggests that an interaction does occur but why this does not lead to viral RNA uptake and recognition by TLRs in the pDCs is a question that future studies should address.It is likely that both HCV and HAV exosomes are taken up by pDCs via an endocytic mechanism involving exosomal surface proteins although such mechanisms have been poorly defined for any kind of exosomes et al., have also found that HCV negative-sense RNA, a replication intermediate, can be found in exosomes of treatment non-responders although the significance of this remains to be elucidated.Despite the ability of HCV and HAV exosomes to activate innate immune signaling in pDCs both types of vesicles can also infect naïve hepatocytes. In the case of HCV this can be achieved via exosomes containing just the positive-sense viral RNA genome as it can occur in the absence of viral structural proteins ,27,53. AHAV exosomes, or eHAV, have also been shown to be highly infectious circulating particles. In fact, eHAVs and not non-enveloped HAVs seem to be the predominant form of circulating viral particles in infected humans and chimpanzees. Unlike HAV, eHAV particles are resistant to neutralizing antibodies, which may explain the late appearance of virus-specific antibodies in infected patients . Non-envin vivo since eHAV is the predominant form found in the blood of infected patients and chimpanzees and is fully infectious, whereas non-enveloped, classical HAV is found in the feces of infected animals or humans [The role of viral exosomes in HCV and HAV infection seems paradoxical since, on the one hand, these exosomes activate the innate immune response via pDCs, and on the other hand they mask infectious viral RNA or particles from antibody-mediated immune responses. It is possible that exosomes evolved as a defense mechanism to activate innate immunity despite viral strategies to block these pathways in infected cells. However, the viruses may have co-evolved to use exosomes to spread undetected by the adaptive immune response. In the case of HAV, the latter certainly seems to be the principal mechanism r humans . Furthervs. free virus infection in vivo is difficult to determine since, unlike HAV, the viral particles exhibit a similar size and density to viral exosomes and contamination of exosome preparations with free virus is difficult to exclude. However, using an immune-isolation protocol to try and largely separate virus from viral exosomes Bukong et al., show that HCV-exosomes can be found in the circulation of infected patients and that these vesicles are infectious and largely resistant to neutralization by anti-HCV-E2 antibodies [HCV infection on the other hand leads to sustained inflammation of the liver characterized by induction of type I and type-III interferons and an abundance of pDCs. Cell culture experiments using subgenomic replicon cells suggest that exosomal HCV infection is inefficient compared to free virus infection . The contibodies ,27. It iin vitro) may prevent infection of cell types other than hepatocytes, which represent the natural, and therefore likely the optimal host cell type of HCV. Lastly, it is also possible that HCV exosomes only exhibit auto- or paracrine transfer mechanisms although they can be found in the blood stream of infected individuals.It is not known how HCV (or eHAV) exosomes are internalized by pDCs but several well described HCV entry receptors have been found to be dispensable for exosomal HCV transmission to hepatocytes. Never the less, exosomal HCV spread  seems to retain exclusive tropism for hepatocytes. There are several possible explanations for these findings that should be addressed in future investigations. Strong post-entry restrictions may prevent viral replication and release in cells other than hepatocytes. Alternatively, the very low infectivity of HCV exosomes compared to HCV virus (at least de novo infection, respectively. In the case of HAV infection the latter seems to be more important since pDCs largely disappear from infected livers at the peak of infection, whereas in the case of HCV infection pDC activation characterized by type I interferon production may be a major contributor to liver inflammation and disease progression. Although type I interferons are generally considered to be a major first line of host defense after viral infection recent studies suggest that sustained interferon production may in some way contribute to viral persistence [It is becoming increasingly clear that exosomes play an important role in many viral infections . In the sistence ,63,64. Hsistence . For othsistence . TLR7 desistence . Taken t


Cognitive function defines performance in objective tasks that require conscious mental effort. Extreme environments, namely heat, hypoxia, and cold can all alter human cognitive function due to a variety of psychological and/or biological processes. The aims of this Focused Review were to discuss; (1) the current state of knowledge on the effects of heat, hypoxic and cold stress on cognitive function, (2) the potential mechanisms underpinning these alterations, and (3) plausible interventions that may maintain cognitive function upon exposure to each of these environmental stressors. The available evidence suggests that the effects of heat, hypoxia, and cold stress on cognitive function are both task and severity dependent. Complex tasks are particularly vulnerable to extreme heat stress, whereas both simple and complex task performance appear to be vulnerable at even at moderate altitudes. Cold stress also appears to negatively impact both simple and complex task performance, however, the research in this area is sparse in comparison to heat and hypoxia. In summary, this focused review provides updated knowledge regarding the effects of extreme environmental stressors on cognitive function and their biological underpinnings. Tyrosine supplementation may help individuals maintain cognitive function in very hot, hypoxic, and/or cold conditions. However, more research is needed to clarify these and other postulated interventions. Cognitive function defines performance in objective tasks that require conscious mental effort  experienced occupational heat stress, which was strongly and significantly associated with workplace accident rates  at ~37°C , and the design employed to attain an increase in Tc (passive or exercise induced). Discussing each of these confounding issues in detail is beyond the scope of this focused review, however, the reader is directed to reviews which have addressed each of these issues at length , the complexity of the cognitive task(s) completed, previous experience of participants, hydration status, the definition of heat stress , simple task performance (vigilance) improved but complex task performance  was compromised. However, in a later study, it was shown that passively heating individuals up to 39.05°C did not affect short or long term memory, verbal logic problems, and numerical subtraction performance , independent of any rise in Tc, may be responsible for any heat induced cognitive deteriorations  and a reduced thermal comfort  in the heat, whereby subjects reported more negative feelings , were responsible for the reductions in complex task performance, which again were independent of any change in Tc  has been shown to preserve some complex cognitive functions  may be effective in maintaining complex cognitive function (and consequently safety) in passively experienced thermally stressful environments.It is generally accepted that simple task performance is less vulnerable to heat stress than complex task performance, a viewpoint that has been supported by recent literature reviews Hancock, . Complexattention network test (ANT) and functional magnetic resonance imaging (fMRI) to provide an insight into brain blood flow alterations upon exposure to heat stress, and how these changes affect aspects of the attention network  or Tc (peak ~38.5°C). A plausible explanation for these behavioral changes is that the increase in plasma serotonin  witnessed during passive heat stress  5-HT plays a major role in these heat stress induced cognitive alterations, and (2) if plasma (human) and/or brain  5-HT increases in response to an elevated Tsk and/or Tc differentially. To our knowledge, this relationship is yet to be examined.Recent investigations have utilized the KEY CONCEPT 1Attention NetworkNeuroscientific studies suggest that specific attentional functions are carried out by several interconnected brain networks. The attentional functions and related networks go under different names, but a classification into the three networks of alerting, orienting, and executive control is common. It is now understood that under many circumstances these networks interact and influence each other.KEY CONCEPT 2Functional Magnetic Resonance ImagingThis method highlights differences in brain activity by measuring related blood oxygenation levels. It yields information regarding relative differences in brain activity when comparing two or more experimental conditions and thus offers useful insight as to which brain areas are selectively active during certain mental processes.tyrosine  may be the primary factor mediating heat stress induced cognitive disturbances  may also combat the negative side effects of heat stress on complex cognitive functioning. However, results to date have not wholly supported this notion. For example, a recent study has shown that ingestion of menthol lozenges had no such effect  and athletic (winter sports) settings . Similar augmentation of cognitive function was observed following the use of caffeine, although this was during exposure to multiple stressors  significantly deteriorated many aspects of cognitive function, including complex attention, executive function, and cognitive flexibility  displayed decreased activation in a number of brain regions  as well as reduced performance during complex cognitive tasks (working memory) when compared to their sea level counterparts  is progressively associated with duration of stay at high altitude and is strongly correlated with elevated homocysteine in plasma.in vivo via plasma S100β quantification , future research should explore these subtleties (as they are currently not clear) to optimize interventional techniques and provide further mechanistic evidence relative to the content of this Focused Review.There also appears to be a lack of reliability data in the majority of studies utilized within this review. Reliability statistics, including the change in mean, coefficient of variation, intraclass correlation coefficient, and typical error for these cognitive tests  should be overtly reported, as to ensure that the true experimental effects can be correctly disseminated, and to demonstrate the reproducibility of the cognitive tests used. There also appears to be heterogeneity among dependent measures  used between studies, making them difficult to compare and thus draw meaningful conclusions. It is recommended that future researchers utilize the ANT in such studies, as this test is simple to implement, and can directly measure the efficiency of the three major attention networks . Moreover, rigorous familiarization for the cognitive tests  utilized will reduce learning effects which were likely evident in at least some of the previous work outlined within this review; increasing the reliability that the change in cognitive function is caused by environmental exposure and not poor experimental design. For example, experienced workers appear to be less vulnerable to the effects of heat stress than inexperienced workers because of task familiarity Hancock, . Thus, aIf adhered to, these guidelines could lead to greater knowledge and understanding of the cognitive decrement that often occurs during passive exposure to extreme environments. In turn, this may lead to the development of further interventional techniques, and thus ultimately enable practitioners to reduce the decline in cognitive function during extreme environmental exposure. These outcomes could prove life-saving when applied to many occupational settings.This review has highlighted the detrimental effects of passive exposure to environmental extremes of heat, cold, and hypoxia on cognitive function in simple and complex tasks. A decline in cognitive function can be attributed to a number of mechanisms, dependent on the environment to which the individual is exposed. It should be noted that such declines, across all the environmental conditions, will have some aspect of inter and intra-individual variation.Alterations in blood flow and sensory displeasure Gaoua, , hyperhoA variety of interventional techniques can be implemented to potentially combat the negative effects of exposure across the aforementioned paradigms. The use of cooling interventions (Nunneley 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.


Major depressive disorder (MDD) is characterized by a dysfunctional processing of autobiographical memories. We review the following core domains of deficit: systematic biases favoring materials of negative emotional valence; diminished access and response to positive memories; a recollection of overgeneral memories in detriment of specific autobiographical memories; and the role of ruminative processes and avoidance when dealing with autobiographical memories. Furthermore, we review evidence from functional neuroimaging studies of neural circuits activated by the recollection of autobiographical memories in both healthy and depressive individuals. Disruptions in autobiographical memories predispose and portend onset and maintenance of depression. Thus, we discuss emerging therapeutics that target memory difficulties in those with depression. We review strategies for this clinical domain, including memory specificity training, method-of-loci, memory rescripting, and real-time fMRI neurofeedback training of amygdala activity in depression. We propose that the manipulation of the reconsolidation of autobiographical memories in depression might represent a novel yet largely unexplored, domain-specific, therapeutic opportunity for depression treatment. Depression is a chronic and devastating mental disorder with an estimated lifetime prevalence of 11.1–14.6% worldwide  and is aConsolidated memories were once thought to be persistent and resistant to disruption . HoweverAutobiographical memories frame and shape our emotional life and provide input for planning and facing our everyday challenges. These memories define who we are and generate an updated sense of self , thus coThe overarching aims of this review are (1) to provide an overview of autobiographical memory disturbances in depression from a cognitive perspective; (2) to review neuroimaging studies of brain networks disturbed in depression that are also believed to support autobiographical memory processing; and (3) to review emerging evidences of psychotherapeutic techniques targeting autobiographical memory disturbances in depression. We speculate that mechanisms of memory reconsolidation may be explored as a novel target for the modification of dysfunctional autobiographical memories in MDD.∗.” Only articles published in English were considered. Articles were considered for inclusion based on overall methodological quality. Relevant meta-analyses were also included.For this narrative review, we performed a comprehensive search of Pubmed/MEDLINE and PsycInfo electronic databases from inception to October 10th, 2014. Search terms were “autobiographical memory,” “memory reconsolidation,” “neuroimaging,” “psychotherapy,” “cognitive behavioral therapy” cross-referenced with “depressSeveral decades of research indicate that individuals with mood disorders remember their past differently from healthy never-depressed controls . The autSummary of Terms and Definitions Employed in This ReviewSpecific Memories. These memories refer to autobiographical memories that can be localized in time and space and often do not last longer than 24 hours.Extended Memories. These memories refer to autobiographical memories that extend over long periods of time.Categorical Memories. Autobiographical memories that reflect a repeated event .Semantic Autobiographical Memories. These refer to memories that form the general knowledge about oneself .Episodic Memories. These autobiographical memories are characterized by a particular self-reflective mental state, referred to as autonoetic consciousness, which implies that the individual recollects or imagine his/her personal events with a sense of (re/pre) experiencing by mentally “travelling in time,” whether in the past or in the future.Strictly Episodic Autobiographical Memories. These memories are not only spatiotemporally unique autobiographical memories but are also accompanied by subjective (re/pre) experiencing phenomenological details .Conceptual-Self. This theoretical mental attribute is stored in the semantic memory system in the form of personal beliefs, values and attitudes, self-knowledge of personality traits, and judgments on a number of categories related to our abstract self-representation.Prospection. Imagining ourselves in the future, or prospection, plays a crucial role in planning, allowing one to select strategic behaviors to engage in successful goal pursuit. Some theorists have argued that remembering and future-oriented thinking may reflect a single mental (brain) process.Navigation. Topographical orientation refers to the capacity to navigate spatial environments imagining one's current position, the desired endpoint, and possible routes using both egocentric and allocentric perspectives.Theory of Mind. A key aspect of social behavior refers to the capability of understanding  that the behavior of others is motivated by inner states, such as thoughts, emotions, and values. The possession of a theory of mind is necessary to understand our peers .Default-Mode Network (DMN). The pattern of brain activations observed during rest conditions had been called the default mode of brain function and may represent stimulus-independent thought or mind-wandering. The DMN may set the stage for self-projection or scene construction.The disturbed processing of autobiographical memories is a trait-like cognitive manifestation of depression that may contribute to the onset –25 and dOne striking clinical feature of patients during a major depressive episode is the pervasively negative tone when they refer to their past. In depression, a systematic autobiographical bias favoring negative experiences is a replicated finding , 28, witThe recall of emotionally positive memories has been identified as a core adaptive emotion mechanism to counteract sad mood , 33. In Another evident feature of autobiographical memories in depression is the propensity to recollect categorical memories. In contrast to specific autobiographical episodes, these overgeneral recollections comprise themes related to repeated events, which present a consistent pattern across many past personal experiences. There is now a large evidence base showing that this overgeneral processing pattern overrides the recall of specific time and place details  , 41, 42.A possible explanation why categorical autobiographical retrieval is so exuberant in depression relies on cognitive theories of depression with their emphasis on the activation of underlying negative schemata in this disorder, which arguably consist of well-consolidated negatively valenced categorical themes . A previ neuroticism  have the tendency to retrieve negatively biased and overgeneral autobiographical memories [ neuroticism is one of the most consistently replicated personality features to be associated with a higher risk for depression [ neuroticism may mediate the relationship between the dysfunctional processing of autobiographical memory and the onset of depression.There is now compelling evidences that the impairment experienced by depressive individuals to recollect specific autobiographical memories is consistently associated with a worse prognosis . There memories , 47. Imppression , 49. ThuThe recall of emotional autobiographical memories is in certain circumstances a painful process. Explicit and implicit psychological mechanisms to avoid or suppress the assessment of negative past memories and/or the emotions often linked to these memories seem to be more common in depression , 51. HowMental avoidance mechanisms may operate in those with depression in the retrieval process of emotional memories. These mechanisms seem to be particularly prominent when those memories are recalled as mental images instead of verbal narratives . DepressEfforts to avoid unwanted autobiographical memories and the adoption of an observer perspective may spur ruminative processed focused on the memories themselves or on relating those memories to depressogenic categorical themes through “mental traveling” . brooding [ capture mechanisms are exacerbated by ingrained functional avoidance (FA) of specific details of distressing autobiographical events, which in turn leads to the processing of an autobiographical representation at the categorical level. The ability to counteract these dysfunctional processing mechanisms is compromised as a function of the limited executive (X) control, which is a consistent feature present in individuals with depression even in remitted states [The CaR-FA-X model  proposedbrooding . Such cad states , 59.The neurobiological substrates related to autobiographical memory retrieval have been extensively investigated in healthy human individuals through functional neuroimaging studies. Six published meta-analyses have synthesized the main findings related to autobiographical memory retrieval in healthy never-depressed individuals –64. OverSvoboda and colleagues performed the first of these meta-analyses  and foun per se. Nevertheless, this model has some limitations. For example, a reciprocal communication between the CMS and the PTS was not accounted for, while the lack of fine anatomical resolution is a significant shortcoming. However, the model may have heuristic value as it might provide a framework to investigate the role of different brain networks subserving the DMN in the recollection of autobiographical memories.Interestingly, Spreng and collaborators  synthesi episodic memories (the authors further studied “strictly” episodic memories), semantic memories, and the conceptual-self , previous exposure to antidepressant drugs, as differences in experimental paradigms across studies. nucleus reuniens and the medial prefrontal cortex [Finally, overgeneral processing of information might be related to two distinct processes: either a decrease in pattern separation or an increase in pattern completion. Pattern separation refers to the capability to dissociate similar stimuli conveyed from the external world in distinct nonoverlapping neuronal representations, while pattern completion enables the proper generalization of similar stimuli conveyed from the external world in the case of a partial sensory input , 84. Conl cortex . HoweverTaken together, the precise neurobiological substrates subserving autobiographical memory dysfunction in MDD remain unknown . Furthermore, studies investigating brain activation patterns following the retrieval of autobiographical in depression (which may likely reflect reconsolidation mechanisms) are lacking in the literature.Moscovitch and Nadel proposed a theory for memory reconsolidation referred to as multiple trace theory (MTT) . AccordiSchwabe and Wolf  attempte episodic  memories and the semantic memory system [Lane and colleagues recently proposed an integrative model suggesting that essential changes across diverse psychotherapeutic modalities involve the following: (1) reactivating old (sometimes painful) memories; (2) engaging in new emotional experience that is incorporated to these reactivated memories through reconsolidation; and (3) reinforcing the integrative memory structure by practicing a new way of behaving and experiencing the world in a variety of contexts . This moy system –94. Given = 23); this RCT also included a 2-month followup [Memory specificity training (MEST) is designed for participants with depression to increase the retrieval of specific past memories, counteracting the recollection of overgeneral autobiographical memories described above. Raes and colleagues  developefollowup , which aThese preliminary yet promising results of the MEST approach may rest on reconsolidation mechanisms, through the updating of overgeneral memories with incorporation of specific information. Thus, we can speculate that its efficacy might be improved with the exploration of some aspects of memory reconsolidation. For example, the total duration of the protocol and/or the cued reactivation of autobiographical memories could be adjusted depending on specific characteristics of the retrieved memory. For instance, it is known that the age and strength of the memory influence whether reactivation induces destabilization followed by reconsolidation , 97. FurThe impact of recalling positive memories may be enhanced through processes aiming to enrich these memories with affective, visual, and sensory details . For insThe method-of-loci (MoL) is an ancient mnemonic method that relies on memorized spatial relationships between loci that are used to arrange and recollect episodic memories . The bas per se, MBCT aims to enhance affective executive control over mental life  through the practice of meditation skills that promote the ability to “step back” from painful  mental content [Mindfulness-based cognitive therapy (MBCT) may be an effective therapeutic modality for depression . Althoug content . The psy content .The practice of MBCT requires a highly trained psychotherapist . Thus, rn = 14) or the horizontal segment of the intraparietal sulcus  and instructed to contemplate positive autobiographical memories to raise the level of a bar representing the hemodynamic signal of the brain region of interest to a target level. Participants in the experimental group upregulated their amygdala responses during memory recollection [Previous studies showed that blood oxygen-level-dependent (BOLD) activity in the amygdala increased in response to both positive and negative emotional stimuli in healthy individuals . A functllection . SignifiThis review indicates that autobiographical memory dysfunction  is a constant neuropsychological correlate of depression. Furthermore, compelling evidence indicates that these disturbances may represent trait-markers for the disorder. Discrete brain regions integrating separate networks mediate the retrieval of autobiographical memories. These networks are distinctly activated during the recollection of autobiographical memories in depression, although a consistent pattern of activation in comparison with healthy individuals did not emerge. Finally, this extensive review indicates that promising therapeutic strategies specifically targeting autobiographical memory dysfunction in depression have been developed. However, these techniques are based on a solid preliminary research base, and more well-designed trials are needed to establish the effectiveness of these interventions before incorporating them in the routine care of depressive patients. We hypothesize here that the retrieval of autobiographical memories in depression would render the memory trace labile and susceptible to change through the process of reconsolidation. Furthermore, ongoing research on biobehavioral mechanisms of memory reconsolidation in humans may provide valuable insights to apprimorate psychotherapeutic strategies targeting autobiographical memory disturbances in MDD.Our review also opens important directions for further research. For example, additional studies are needed to elucidate brain networks subserving autobiographical memory dysfunction in depression. Despite drug therapies targeting the reconsolidation of autobiographical memories being abundant in posttraumatic stress disorder (PTSD) . The recently proposed National Institute of Mental Health research domain criteria (RDoC)  state th


There is general agreement that the central nervous system in rodents differs between sexes due to the presence of gonadal steroid hormone during differentiation. Sex differences in feeding seem to occur among species, and responses to fasting , gonadal steroids , and diet  vary significantly between sexes. The hypothalamus is the center for controlling feeding behavior. We examined the activation of feeding-related peptides in neurons in the hypothalamus. Phosphorylation of cyclic AMP response element-binding protein (CREB) is a good marker for neural activation, as is the Fos antigen. Therefore, we predicted that sex differences in the activity of melanin-concentrating hormone (MCH) neurons would be associated with feeding behavior. We determined the response of MCH neurons to glucose in the lateral hypothalamic area (LHA) and our results suggested MCH neurons play an important role in sex differences in feeding behavior. In addition, fasting increased the number of orexin neurons harboring phosphorylated CREB in female rats (regardless of the estrous day), but not male rats. Glucose injection decreased the number of these neurons with phosphorylated CREB in fasted female rats. Finally, under normal spontaneous food intake, MCH neurons, but not orexin neurons, expressed phosphorylated CREB. These sex differences in response to fasting and glucose, as well as under normal conditions, suggest a vulnerability to metabolic challenges in females. There is general agreement that the central nervous system in rodents differs between sexes due to the presence of gonadal steroid hormone during differentiation  neurons in the LHA (Bittencourt et al., Since orexin neurons are also involved in feeding (Broberger et al., We hypothesized that MCH neurons respond to nutrition-related feeding, but the feeding-related activity of orexin neurons is not evident unless hunger is accompanied by a bad emotion, such as that caused by fasting Figure . Thus, tThe 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.


Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here, we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that: (1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs and (2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals. All visual information leaving the eye is conveyed in the spiking activity of retinal ganglion cells. Given the limited dynamic range of these cells and the dramatically varying statistics of visual stimuli in the natural world, efficient encoding of visual information requires processing that responds to the statistics of the visual input. Contrast gain control is a prominent mechanism used by the visual system to meet the challenge of encoding visual information in diverse visual environments. Contrast gain control refers to the nonlinear receptive field property whereby a neuron’s gain and temporal dynamics are dependent upon stimulus contrast. Specifically, the response gain of neurons in the early visual system, including the retina, LGN, and V1 decreases as stimulus contrast increases, causing contrast response functions to saturate at contrasts below 100%. Additionally, as stimulus contrast increases, these same visual neurons become more responsive to stimuli with high temporal frequencies, and they exhibit a contrast-dependent phase advance (CDPA) in their responses to periodic stimuli. Although contrast gain control is first established within the retina, an open and unresolved question is how contrast gain control is enhanced between the retina and the LGN.The axons of retinal ganglion cells target several central structures, including the lateral geniculate nucleus (LGN) of the thalamus which in turn provides monosynaptic excitation to primary visual cortex (V1). Although the response properties of retinal ganglion cells and LGN neurons are generally quite similar  is lower for LGN neurons than for their individual retinal afferents. Further analysis suggests that this effect relies on the integration of multiple retinal inputs by individual LGN neurons. Our results also reveal that CDPA—a hallmark of contrast gain control—is significantly greater for LGN neurons than for their individual retinal afferents. To probe the underlying mechanism responsible for the CDPA changes, we applied a model of ISI-based filtering to recorded retinal spike trains. Results from this effort reveal that an ISI-based filtering mechanism of retinal spikes can produce CDPA in target neurons. Taken together, these results indicate that the LGN is more than a simple relay station, as it adjusts both the sensitivity and timing of visual signals en route from retina to cortex.To determine the influence of stimulus contrast on retinogeniculate communication and visual processing in the retina and LGN, we made simultaneous recordings from monosynaptically connected retinal ganglion cells and LGN neurons in the anesthetized cat and measured neuronal responses to drifting sinusoidal gratings that varied in stimulus contrast. Consistent with predictions from past studies . If physiological monitoring indicated a low level of anesthesia, additional thiopental was given and the rate of continuous infusion was increased. A midline scalp incision was made and the cortical surface above the LGN was exposed through a craniotomy which was filled with agarose. The lateral margin of each eye was dissected and each sclera was glued to a rigid post mounted on the stereotaxic frame. These posts secured the eyes and facilitated the introduction of a trans-scleral guide tube for retinal recordings. The nictitating membranes were retracted with 10% phenylephrine and flurbiprofen sodium drops were administered (1.5 mg/h) to prevent miosis. The eyes were refracted, fitted with appropriate contact lenses, and focused on a tangent screen located 172 cm in front of the animal. The positions of area centralis and the optic disk were plotted by back-projecting the retinal vasculature of each eye onto the tangent screen. Once all surgical procedures were complete, animals were paralyzed with vecuronium bromide  and mechanically respired.Six adult cats of both sexes were used in this study. All surgical and experimental procedures conformed to NIH guidelines and were carried out with the approval of the Animal Care and Use Committee at the University of California, Davis. Anesthesia was induced with ketamine  and thiopental sodium . Animals received a tracheotomy and were placed in a stereotaxic apparatus where the temperature, electrocardiogram (ECG), electroencephalogram (EEG), and expired COA multielectrode array  was used to record from individual LGN neurons from seven independently positioned microelectrodes. The locations of receptive fields measured using the array were used to guide the placement of the retinal electrode. To record from retinal ganglion cells, a tungsten-in-glass microelectrode was introduced into the posterior chamber of the eye through a guide tube and positioned using a custom-made manipulator. Neural responses were amplified, filtered and recorded to a personal computer with a Power 1401 data acquisition interface and the Spike 2 software package . The spikes from individual neurons were isolated using template matching and parametric clustering.2. Receptive fields were mapped in space and time using a binary white-noise stimulus and reverse-correlation analysis  and presented on a gamma-calibrated Sony monitor with a mean luminance of 38 cd/mX and Y cells were distinguished on the basis of receptive field size, response latency, and time course of response  was used to fit each cyclic histogram with the positive-only rectification of the following sinusoidal equation:To determine the amplitude and phase of responses to drifting gratings, spike times were expressed relative to the phase of the sinusoid cycle, producing a cyclic histogram for each contrast. A constrained nonlinear optimization procedure (MATLAB function: R(t) is the magnitude of the cyclic histogram at time t, A is the response amplitude at the modulation frequency, ω is angular frequency of the drifting stimulus in radians per second, t is time in seconds, θ is the response phase determined by the vector sum of phases for all spikes in the cyclic histogram, and the baseline (b) indicates the value below which the sinusoid is rectified. The baseline was constrained to range between –A and 2 * A. For each spike train, cyclic histograms were fitted sequentially from low to high contrast with the additional constraint that b was monotonically decreasing. This procedure was found to produce more useful estimates of the modulated response amplitude and response phase, independent of contrast-induced changes in rectification, than a standard Fourier decomposition algorithm available in MATLAB (fft), and is analogous to estimation of the F1.where fminunc; The Mathworks, Natick, MA, USA):For each spike train, the contrast response function was fitted with a hyperbolic ratio  is the response for a given contrast C, maxR is the maximal response amplitude across contrasts, the exponential n reflects the sensitivity of the response function, 50C is the contrast corresponding to 50% of the maximal response, and b denotes baseline and was set as the response to the lowest contrast (1%).where 50C for all curves.As contrast increased, response phase was often observed to advance progressively earlier in the stimulus cycle. This phenomenon will be referred to as CDPA to distinguish it from absolute phase advance relative to the stimulus. In order to quantify CDPA, a first-order polynomial was fit to the curve of phase vs. log (contrast) over the middle six contrasts presented  was used to determine p values for all pair-wise statistical tests.Unless otherwise indicated, population data is summarized by the mean and standard error of the mean. Wilcoxon’s signed-rank test . The 50C is therefore a good metric for contrast gain control as it tends to be lowest for neurons that exhibit greater contrast saturation. Across our sample of connected cells, LGN neurons typically had significantly lower 50C values than their simultaneously recorded retinal input , indicating that LGN neurons display greater contrast gain control than their retinal counterparts.Simultaneous recordings were made from 10 pairs of monosynaptically-connected retinal ganglion cells and LGN neurons in order to study the influence of stimulus contrast on neuronal responses across the retinogeniculate synapse . As shown in Figures 50C between the two classes of retinal spikes (p = 0.23). Thus, it seems unlikely that the difference in 50C values between retina and LGN can be attributed to the selective filtering of spikes generated by the simultaneously recorded retinal ganglion cells.To determine whether the decrease in 50C between retinal ganglion cells and LGN neurons, we divided the spikes generated by each LGN neuron in our sample into two categories: those evoked (or “triggered”) by the simultaneously recorded retinal ganglion cell, and those evoked from other sources (“non-triggered”), including other retinal ganglion cells. Across our sample of cells, 50C values were significantly lower for non-triggered LGN spikes compared to triggered spikes . This finding is consistent with the idea that an LGN cell’s contrast response function is shifted in the direction of its most sensitive input which, because of convergence, is likely to be an input other than the simultaneously recorded retinal ganglion cell.Estimates indicate that individual LGN neurons in the cat typically receive monosynaptic input from approximately 2–5 retinal ganglion cells . In general, this exponent can be taken to quantify the linearity of the contrast response function, with small exponents indicating a relatively linear curve, and larger exponents indicating nonlinear expansion below the inflection point and compression above it. Consistent with Duong and Freeman (n > 1) was present for all of the Y-type retinal ganglion cells and LGN neurons in our sample. However, we did not find a significant difference in the exponent term n between pre- and postsynaptic neurons, suggesting that this feature of the contrast response function is passed on, unaltered, from retina to LGN . It is worth noting that the single outlier in Figure We next examined whether the exponent “ Freeman , we founCDPA is another hallmark of nonlinear processing in the early visual system. As contrast increases, neurons in the retina, LGN and visual cortex are reported to respond progressively earlier relative to the phase of the stimulus , suggesting that the increase in CDPA from retina to LGN relies, in part, on a selective filtering of retinal spikes. Across our sample of cell pairs, there was not a significant difference between CDPA values calculated from triggered and non-triggered LGN spikes , suggesting that signals from simultaneously recorded and non-recorded retinal ganglion cells experienced comparable levels of CDPA.Consistent with previous reports, our sample of Y-type retinal ganglion cells exhibited an average phase advance of ~55° over the 2.78–35.94% contrast ranges  has a strong influence on the generation of postsynaptic responses in the LGN, as retinal spikes following short ISIs (<30 ms) are significantly more likely to evoke a postsynaptic spike than retinal spikes following longer ISIs . While the magnitude of this effect was less than what was found in the original data , this result suggests that temporal filtering indeed plays a significant role in the increased CDPA that occurs across the retinogeniculate synapse.We next quantified the relationship between ISI and the efficacy of retinal spikes in evoking postsynaptic responses for each retinogeniculate pair of simultaneously recorded neurons in our sample. Similar to previous results  is significantly lower for LGN neurons compared to their simultaneously recorded retinal input, indicating that contrast gain control is enhanced by the LGN and that LGN responses begin to saturate at lower contrasts than their retinal inputs. Further analysis suggests that this decrease in 50C relies, at least in part, on convergence of multiple retinal inputs onto individual LGN neurons. With convergence, LGN neurons receive input from an ensemble of retinal ganglion cells that have a range of sensitivity profiles, and the most sensitive of these inputs will be those that influence LGN activity under low contrast conditions, thereby shifting 50C values toward lower contrasts. Because individual LGN neurons are estimated to receive convergent input from approximately 2–5 retinal ganglion cells, our recording configuration was unlikely to include the most sensitive retinal input, a view consistent with the finding that non-triggered retinal spikes (spikes evoked from other sources) have lower 50C values than spikes triggered by the simultaneously recorded retinal ganglion cell.Here, we compared the responses of monosynaptically connected Y-type retinal ganglion cells and LGN neurons in the cat as a function of stimulus contrast. Consistent with the view that nearly all spikes in the LGN are triggered by retinal action potentials  increased sensitivity to low-contrast stimuli and (2) CDPA, were both greater for individual LGN neurons compared to their simultaneously recorded retinal inputs. Further analyses suggests that increased sensitivity is achieved via spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals. Taken together, these results reveal a breadth of processing strategies, both spatial and temporal, employed by the thalamus to transform visual signals en route from retina to cortex.DLR contributed to experimental design, data collection, data analysis, and manuscript preparation. HJA contributed to data analysis and manuscript preparation. DKW contributed to data analysis and manuscript preparation. WMU contributed to experimental design, data collection and manuscript preparation.This work was supported by National Eye Institute Grants EY 13588, EY12576, and T32 EY15387, and the German ministry for education and research (BMBF) 031 A 308 and 01GQ1002.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.


Background and objectives: Maternal stress can depress birth weight and gestational age, with potential health effects. A growing number of studies examine the effect of maternal stress caused by environmental disasters on birth outcomes. These changes may indicate an adaptive response. In this study, we examine the effects of maternal exposure to wildfire on birth weight and gestational age, hypothesising that maternal stress will negatively influence these measures.Methodology: Using data from the Australian Capital Territory, we employed Analysis of Variance to examine the influence of the 2003 Canberra wildfires on the weight of babies born to mothers resident in fire-affected regions, while considering the role of other factors.Results: We found that male infants born in the most severely fire-affected area had significantly higher average birth weights than their less exposed peers and were also heavier than males born in the same areas in non-fire years. Higher average weights were attributable to an increase in the number of macrosomic infants. There was no significant effect on the weight of female infants or on gestational age for either sex.Conclusions and implications: Our findings indicate heightened environmental responsivity in the male cohort. We find that elevated maternal stress acted to accelerate the growth of male fetuses, potentially through an elevation of maternal blood glucose levels. Like previous studies, our work finds effects of disaster exposure and suggests that fetal growth patterns respond to maternal signals. However, the direction of the change in birth weight is opposite to that of many earlier studies. A growing body of work considers the effects of maternal exposure to stressors on fetal health, principally in terms of birth weight and gestation length, with an increased incidence of both low birth weight (birth at <2500 g) and prematurity (birth at <37 weeks gestation) being documented in populations exposed to major stressors during gestation . PretermMaternal stress is likely linked to lower weights and shorter gestations because the physiological stress response creates an energetic cost that adds to the metabolic load of gestation. An evolutionary perspective suggests that this greater load encourages reduced maternal metabolic investment in the fetus in order to aid the mother’s own chance of survival and thus her future reproductive potential . Theoretet al. [et al. [et al. [Consistent with this evolutionary theory, natural experiments demonstrate that maternal exposure to stress is associated with reduced birth weights and gestational age . For exaet al.  and Danc [et al.  find dec [et al.  find inc [et al. .et al. [Likewise, Oyarzo et al.  find an et al.  who findet al. . Similaret al. , 38.Notably, there are some exceptions to the overall trend of decreases in birth weight and gestational age. In addition to the trend of lighter and earlier neonates following the 2010 earthquake in Chile, increases in the incidence of macrosomic infants were also found and were attributed to underlying gestational diabetes mellitus (GDM) and maternal obesity . Similarin utero, as well as in early life [From an evolutionary perspective, it is also understood that stress-related differentials in maternal investment exist depending on the sex of offspring . Sex difrly life .In this study, we examine patterns in average birth weights and gestational ages following the 2003 Canberra Wildfires in the Australian Capital Territory (ACT). Wildfires expose populations to both physiological and psychosocial stressors. Some such stressors include experiences of extreme heat and poor air quality, both of which have independent effects on pregnancy , 50. PsyOn 18 January 2003, the Canberra fires burnt part of the southern and western suburbs of Canberra, Australia’s national capital, located in the ACT. The Canberra fires were the northern most tip of an 800 km fire line known collectively as the Australian Alps fires. The Canberra fires killed four people, injured 489 people, destroyed ∼500 homes and triggered the evacuation of 5000 residents. A further 50 000 residents lost essential services, representing around 15% of Canberra’s total population .Following ethics approval from The Australian National University Human Research Ethics Committee and the ACT Government Human Research Ethics Committee’s Low Risk Sub-Committee, and approval of data access by the ACT Chief Health Officer, the study used unit record data managed by the ACT Government Health Directorate Epidemiology Section  to examine birth weights and gestational ages in the ACT between 2000 and 2010.Clinical birth records in Australia are collected and administered for almost all births by hospitals and midwives . Birth rIndigenous status was recoded into a binary variable as either ‘Indigenous’  or ‘not Indigenous’. Similarly, plurality was recoded as either ‘singleton’ or ‘multiple’, with the latter category including all multiples. Lastly, divorced, separated and widowed mothers were combined in the analysis of the influence of marital status, due to small cell sizes. ‘Married’ mothers included those in common law or same-sex relationships. Maternal smoking in all analysis refers to reported smoking at any point during gestation.Three levels of fire exposure were defined using the mothers’ reported Statistical Local Area of residence at the time of birth. Mothers’ reported location of residence was used as a proxy measure of disaster exposure. The three levels of exposure we used were: ‘severely affected’, which included mothers who were resident in areas where both deaths and property damage occurred; ‘moderately affected’, which included mothers from areas where property damage (only) occurred and ‘least affected’, which was the remainder of the residential areas of Canberra, where no fire damage occurred.Because disaster impacts can be difficult to define geographically and people outside the affected zones may also experience substantial stress, the analysis included inter-year comparisons of the same areas as well as intra-year comparison between levels of disaster exposure. This allows births in each region to be compared to those in the same region in pre- and post-fire years.Analysis of variance (ANOVA) was used to examine the influence of residential location on birth weight and gestational age in the year of the fire (2003), with the three previous years (2000–02) and seven following years (2004–10), while also considering the influence of maternal age, maternal smoking during gestation, maternal Indigenous status, maternal marital status, baby’s plurality, and maternal previous pregnancy status (i.e. primigravida versus multigravida). Research indicates that multiple births, older maternal age, positive maternal Indigenous status, maternal smoking and single marital status have a depressive effect on birth weight , 54. SecBirths in 2002, 2003 and 2004 were divided into quarters to allow the effects of timing of exposure to be examined more closely, using approximate trimesters of exposure. Because previous studies indicate some sex differences in stress responsivity , 55 thisP < 0.003, df = 2), 18 g heavier in the severely affected area in 2005 , 47 g heavier in the severely affected area in 2008  and 56 g lighter in the severely affected area in 2010  when compared to those reported in the moderately affected area.ANOVAs for each year showed that average male birth weights were 197 g heavier in the severely affected area in the year of the fire (2003) , 117 g greater in the severely affected area in 2009  and 160 g greater in the severely affected area in 2010  when compared to those reported in the moderately affected area.ANOVAs for each year also showed that average female birth weights were 163 g greater in the severely affected area in 2008 . A further ANOVA which included data from all years indicates that exposed male neonates were heavier throughout 2003 than males born to mothers residing in the same areas in the previous and following years , as well as being heavier than males born elsewhere during 2003  showed that being in the severely affected area in the year of the fire was only significant for male offspring  or reported as single mothers  had babies with lighter mean birth weights [P < 0.001, df = 1) and primigravida mothers had lighter offspring than multigravida mothers  [P = 0.01).Other significant factors detected in the 2003 ANOVA on birth weight were consistent with the literature: those mothers who smoked during gestation  . Older mP = 0.02, uncorrected P = 0.01) with the largest difference occurring in individuals born between 4501 and 5000 g  and between October and December 2003 (i.e. those exposed very early in the first trimester or conceived in the fire aftermath). This positive relationship was not seen in neonates born between April and September 2003 (i.e. those exposed in the first and second trimesters). Accordingly, the relationship between birth weight and gestational length appears disrupted. While infants who were in the third or late second trimester at the time of the fire show a consistent relationship between gestational length and birth weight, the strength of this relationship declines over the remainder of 2003 (i.e. children exposed earlier in gestation or conceived in the fire aftermath) before becoming more consistent again from early 2004 onwards.P = 0.81). Similarly, there were no significant differences in the prevalence of pre-existing maternal diabetes mellitus across the three levels of fire exposure (P = 0.99).Because of the unusual pattern of higher birth weight, we explored the presence of other maternal conditions with a known relationship to birth weight disruptions including gestational diabetes and maternal smoking. Chi-square tests found no significant differences in the prevalence of GDM between the three defined areas of fire exposure in 2003 among mothers of male neonates (P < 0.001), but these declines were concentrated outside the severely affected area.Although maternal smoking was controlled for in the analysis, unreported smoking was considered as a possible relevant factor. Maternal smoking declined sharply in the ACT during the first 6 months of 2003  had a significant effect on the birth weights of exposed male fetuses, resulting in a pattern of higher birth weights with only a partially corresponding and non-significant increase in gestational length, largely in those fetuses exposed in the later stages of gestation. Because birth dates were only known by month and year, it is not possible to be more specific on the effects of exposure timing. The absence of a significant increase in gestational length suggests accelerated While we accounted for the effects of reported maternal smoking, this analysis cannot include unreported maternal smoking. During 2003, there was a decline in reported maternal smoking but this was concentrated outside the severely affected area. Assuming that unreported smoking follows similar patterns to reported smoking, changes in actual maternal smoking are unlikely to explain the increase in birth weights observed and nor would maternal smoking necessarily provide an explanation for the sex differentiation of the effect.Because macrosomia poses important health risks to both mother and neonate, potential causes of macrosomia deserve close attention. In the short term, macrosomia is associated with higher birth risks, including unplanned caesareans, assisted delivery, shoulder dystocia, newborn asphyxia and perineum tears . Over thet al. [et al. [in utero [et al. [et al. [Three studies have previously reported secondary patterns of higher birth weights or lengthened gestation following disasters: Oyarzo et al.  after a et al. , and Mar [et al.  followin [et al. . Disastein utero . Such ps [et al.  suggest  [et al.  suggest The presence of macrosomia indicates a dysregulation of maternal glucose levels. While we excluded diagnosed GDM through our analysis, it is important to note that GDM is usually screened for only once during gestation (at around 25–26 weeks) in otherwise low-risk pregnancies and has few obvious symptoms. Although high birth weights were recorded both in babies exposed to the fire before screening and in babies exposed after screening, the absence of a GDM diagnosis does not necessarily indicate the absence of any blood glucose elevation. Maternal glucose and fetal weight correlate in non-diabetic mothers, indicating that persistent increases in maternal blood glucose can increase fetal weight, even when blood glucose levels remain below those required for GDM diagnosis , 60. We Normal pregnancy triggers the action of placental steroid hormones, including corticotropin-releasing hormone  and placStress-related increases in cortisol levels would be predicted to increase circulating blood glucose via accelerated gluconeogenesis or through the disruption of glucose metabolism . As suchAlso potentially disrupting glucose metabolism are changes in food intake and physical activity. Both increased food intake and increased consumption of low-nutrition but high-calorie foods have been documented as a behavioral response to stress during pregnancy , 67. IncAlthough little is known about physical activity patterns of pregnant women during wildfires, official advice to stay indoors (due to smoke and heat) or to relocate to an evacuation centre would both have the effect of reducing normal physical activity. If reductions in physical activity occurred these would also likely alter glucose metabolism.Maternal body weight, and weight gain in pregnancy, are also good predictors of macrosomia . We wereThe Hypothalamus–Pituitary–Ovarian axis can act to upregulate steroid hormone production when nutritional energy is abundant . This inIt is well documented that male fetuses are more responsive to maternal stress than female fetuses, often measured through rates of early pregnancy loss , 68 or cIncreases in body size, particularly an increase in fetal fat reserves, could act adaptively in that they provide the infant with greater nutritional reserves when a stochastic external environment is signaled through maternal stress markers. This male responsivity indicates greater environmental sensitivity and potentially greater need for nutritional buffering due to larger average body size at birth. For example, one recent study finds that male fetal growth is accelerated under conditions of mild stress . HoweverHowever, it is equally likely that increase male macrosomia simply reflects the confluence of established male sensitivity and stress effects on maternal glucose. This response may further interact with the influence that fetal sex appears to have on maternal glucose regulation. Recent research shows that mothers of male fetuses have greater odds of developing GDM  than those carrying females. Carrying a male also further increases the effect size of usual GDM risk factors, such as older maternal age (>35 years) and non-White ethnicity .Notably, the timing of the greatest effect differs in this work from that of several previous studies. Previous studies find that prenatal stress is most impactful in early pregnancy , 5, 34, We find a pattern of fetal macrosomia associated with maternal exposure to the 2003 Canberra wildfires among male neonates, which is contrary to other similar studies in that it finds a primary pattern of macrosomia accompanied by small increases in lighter births, rather than the inverse pattern found elsewhere , 37.The study has a number of limitations. First, the definition of disaster impact assumes both a relationship to geographical area and a causal link between disaster proximity and maternal stress. Although disaster impact is not necessarily geographically limited, no stronger method of defining disaster exposure is available when working within the constraints of public datasets and this approach is commonly used in the literature. Second, we are limited in the specificity of our estimates of the timing of fetal exposure to the fire, as birth dates were only identified by month and year, limiting the specificity of that measure. Lastly, we are unable to directly test our hypothesis regarding maternal blood glucose elevation. This is an area which we hope to examine more closely in future work.Nevertheless, the findings of the study indicate a risk of macrosomia to exposed male infants. Fetal macrosomia poses immediate health risks to mother and child, as well as longer term health risks to the child. Our analysis finds that neither changes to maternal cigarette smoking nor changes to diagnosed rates of GDM in the population are good explanations for the observed pattern. However, elevations in maternal glucose can be sufficient to increase fetal weight without being sufficient to trigger a GDM diagnosis. Therefore, we propose that the maternal stress response precipitated an increase in maternal glucose levels that accelerated fetal growth in the more environmentally responsive male cohort. Disaster-related behavioral changes, such as a higher calorie diet and reduced physical activity, might have exacerbated this process.While our finding is contrary to the general trend of prematurity and lowered birth weights associated with disaster stress, this contrary finding does not necessarily imply that the underlying evolutionary features of the changes are similarly altered. Our findings accord with both theories of increased male frailty, as demonstrated through greater environmental responsivity, and that maternal stress acts as an indicator of future environmental quality. Potentially, higher birth weight is simply a consequence of maternal glucose rising in response to stress; however, it is also plausible that increased body weight is an adaptive response to expected future stress, albeit compromised by heightened immediate survival risks and downstream health risks.Although the timing of effects found here differs from previous work, we propose an underlying evolutionary explanation for the observed pattern. In late pregnancy, maternal investment is high and the risk of fetal loss low, because of the sunk costs of maternal investment thus far. Due to this high investment, mothers experiencing late pregnancy stress may opt for a ‘double or nothing’ strategy in which maternal investment increases to boost the chance of neonatal survival and consequent return on investment. While this strategy may disadvantage a small number of larger neonates by increasing their risk of macrosomia and its complications, for the majority such a strategy would provide an unproblematic increase in body weight which provides a buffer against environmental stress.Importantly, our results are consistent with previous findings in that they find an association between disaster exposure and changes in birth outcomes that threaten maternal and fetal health. Thus, the broader implementation of maternal stress management as an aspect of disaster response is lent further support by this work.


Gasterosteus aculeatus) populations. Although female sticklebacks often exhibit a preference for red male throat coloration, the possibility of sexual selection on female coloration has been little studied. Using sequential and simultaneous mate choice trials, we examined male mate preferences for female throat color, as well as pelvic spine color and standard length, using wild-captured threespine sticklebacks from the Little Campbell River, British Columbia. In a multivariate analysis, we found no evidence for a population-level mate preference in males, suggesting the absence of directional sexual selection on these traits arising from male mate choice. Significant variation was detected among males in their preference functions, but this appeared to arise from differences in their mean responsiveness across mating trials and not from variation in the strength  of their preference, suggesting the absence of individual-level preferences as well. When presented with conspecific intruder males, male response decreased as intruder red throat coloration increased, suggesting that males can discriminate color and other aspects of phenotype in our experiment and that males may use these traits in intrasexual interactions. The results presented here are the first to explicitly address male preference for female throat color in threespine sticklebacks.Sexual selection drives the evolution of exaggerated male ornaments in many animal species. Female ornamentation is now acknowledged also to be common but is generally less well understood. One example is the recently documented red female throat coloration in some threespine stickleback ( There is now abundant evidence that sexual selection underlies the evolution of exaggerated male ornamentation  in many animal species. PerhapsOne hypothesis to explain female ornaments is that they result from intersexual genetic correlation with sexually selected male traits. It is oGasterosteus aculeatus) has been studied as a model system of behavior and evolution, most recently with particular emphasis on speciation and sexual selection)One possible explanation for the absence of a male preference for female throat color in this study involves the operational sex ratio. The paternal care system of threespine sticklebacks’ means that males are investing heavily in each reproductive bout. Repeated periods of nest building, courtship, and egg guarding (and starvation due to not being able to forage) throughout a single breeding season can dramatically reduce the number of available males in the late breeding season. Therefore, if only in the late breeding period, the OSR could shift from male biased to female biased. A female biased OSR could encourage female-female competition for mates and males may stand to benefit by having some means to assess female quality. Observations by Kynard and MoriAn alternative explanation to the results of this study may involve the fact that fish were tested in clear water conditions, with ample illumination and a full spectrum of light, including UV. This was done so as to minimize the effects of environmental conditions on male perception of female throat color . Additionally, females were presented in a stable, head-up position, with males often approaching from in front of and below the female. However, water from the upper-stream Little Campbell is tea-stained in color  and in natural mating encounters, males are likely to view females (and their throat color) from an array of perspectives and distances. Both of these factors, watercolor and the male/female spatial relationship, could have an effect on color perception . Once again, testing under more natural conditions (i.e. tea-stained water and full interaction) may prove beneficial in exploring this topic further.Since males display no preference for throat coloration in females, female throat color in this population may not be sexually selected. Instead, female throat color may arise through a genetic correlation with the phenotype under sexual selection in males. Having Males displayed no population level preference for female body size in sequential presentations . The lack of male preference for female body size is unexpected given the numerous examples of male preference for larger females across fish species. Studies with sticklebacks–60, mosqIn the absence of preference for female size, it is reasonable to question if the experimental design allows for males to properly assess relevant traits of presented fish. The conspecific male trials completed during the second year indicate that the design does permit such assessment. Males presented with a conspecific, same sex intruder responded differently relative to when females were presented in the same manner. Significantly more zigzags (indicating courtship) were directed towards females while the number of bites (which occur in both courtship and aggression) did not differ. Additionally, as intruder male standard length and throat color increased, male response (PC1) decreased. These results suggest that males were able to not only distinguish between males and females in the experimental set-up, but could also differentiate body size and color. It is also possible that power in this study was inadequate to detect preferences, but the significant results with regard to stimulus sex and male traits argue against this interpretation.Males displayed no population level preference for female pelvic spine coloration, in contrast to Nordeide, who fouUnlike throat coloration, the presence of pelvic spine color in females may not be as easily explained as a correlated response to sexual selection in males. Being that very few studies have addressed this trait specifically ,31,66, oWorking from the knowledge that red throat coloration in male threespine sticklebacks is often a sexually selected trait; the same ornament in females might be predicted to be under similar selective pressure. While natural observations and field studies can certainly help to further explore this hypothesis, the results of this study suggest that red throats in females are not under strong male mate preference. However, the existence of female coloration still poses an intriguing problem, especially since the trait has also been observed in females from other populations. Preference tests in other populations could help to further our understanding of the role sexual selection plays in this traits’ existence and assess the generality of our findings.S1 Fig(TIFF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


Epigenome-wide association studies (EWASs) provide a systematic approach to uncovering epigenetic variants underlying common diseases. Discoveries have shed light on novel molecular mechanisms of disease and enabled the application of epigenetic variants as biomarkers. Here, we highlight the recent advances in this emerging line of research and discuss key challenges for current and future studies. Many common diseases in humans are mediated by genetic and environmental factors. Genome-wide association studies (GWASs) have been instrumental in identifying common genetic variants associated with a multitude of complex traits including common diseases. By contrast, the systematic assessment of epigenetic variation has lagged behind. Epigenetic modifications of DNA and histone proteins are heritable (re-established) during cell division and can induce stable changes in the regulation of gene expression. Technological advances in high-throughput DNA analysis have facilitated the genome-wide examination of epigenetic modifications, primarily DNA methylation, enabling systematic, large-scale association testing with disease phenotypes et al.et al. achieved a substantial reduction of spurious association signals attributed to cellular heterogeneity. Conversely, the detected changes in cell type composition based on global epigenetic patterns between cases and controls may in some studies delineate disease pathogenesis or progression itself, thereby informing biomarker discovery  and endogenous  factors, as well as pathogenic  conditions, have an effect on cellular composition. Therefore, EWASs depend on analytical tools that determine epigenetic variation with respect to both confounding cellular heterogeneity and phenotype of interest. The importance of adjusting for the proportions of different cell populations was emphasised by Liu iscovery .Figure 1et al. found evidence of DNA methylation changes that precede clinical diagnosis, potentially contributing to the aetiology of overt type I diabetes. However, large prospective cohorts that enable the assessment of temporal origins of epigenetic changes are scarce, highlighting the need for alternative approaches. To this end, Dick et al. HIF3A gene locus, and the most significant MVP was found to have a larger impact on BMI than previously reported genetic associations at the well-studied FTO gene locus. Two genetic variants were identified upstream of HIF3A that showed an independent effect on DNA methylation levels. However, these genetic variants were not associated with BMI, suggesting that the increased DNA methylation levels at the locus are likely to be a consequence of increased BMI rather than a cause. The finding that these MVPs were associated with BMI in subcutaneous adipose but not skin tissue further strengthened this notion. Nonetheless, the identified non-causal epigenetic changes may still be meaningful as diagnostic or prognostic biomarkers. In addition to metQTL analysis, causal dependency can also be assessed by Mendelian randomisation that has been specifically adapted for EWAS Epigenetic variation can contribute to the development of a disease or be a consequence of it . Distinguishing between the two processes presents a major challenge for EWASs. In an early EWAS for type I diabetes, another common autoimmune disease, a longitudinal cohort consisting of individuals that were profiled both before and after disease diagnosis and treatment was analysed http://www.epitwin.eu/).The aforementioned EWASs for rheumatoid arthritis et al.et al.The study by Dick Taken together, in EWASs (and in stark contrast to GWASs) we advise caution with respect to the cellular heterogeneity of sample material and causal inference of the identified epigenetic changes. Nevertheless, we propose that an EWAS is a valuable approach for uncovering novel molecular mechanisms of disease, and identifying diagnostic and prognostic biomarkers.


Self-assembly of proteins and peptides into amyloid structures has been the subject of intense and focused research due to their association with neurodegenerative, age-related human diseases and transmissible prion diseases in humans and mammals. Of the disease associated amyloid assemblies, a diverse array of species, ranging from small oligomeric assembly intermediates to fibrillar structures, have been shown to have toxic potential. Equally, a range of species formed by the same disease associated amyloid sequences have been found to be relatively benign under comparable monomer equivalent concentrations and conditions. In recent years, an increasing number of functional amyloid systems have also been found. These developments show that not all amyloid structures are generically toxic to cells. Given these observations, it is important to understand why amyloid structures may encode such varied toxic potential despite sharing a common core molecular architecture. Here, we discuss possible links between different aspects of amyloidogenic structures and assembly mechanisms with their varied functional effects. We propose testable hypotheses for the relationship between amyloid structure and its toxic potential in the context of recent reports on amyloid sequence, structure, and toxicity relationships. The core of all amyloid fibrils adopt what is commonly known as the cross-β structure, named due to the arrangement in which β-strands that run perpendicular to the fiber axis form β-sheet ribbons or filaments that further associate to form amyloid fibrils.-E. coli produces curli that forms a layer of amyloid fibrils on the outside of the organism,In amyloid associated disease, amyloid fibrils are deposited in tissues, forming insoluble structures and sometimes replacing cells. For example, in lysozyme amyloidosis, much of the kidney can be replaced by amyloid deposits.These observations together with recent advances in the determination of the sequence and structural properties of amyloid fibrils raise an important question: Why are some amyloid assemblies toxic, while others are inert or tolerated, even to the extent that they may be evolved to perform useful biological functions, despite the fact that the end products of amyloid assembly share a common cross-β structural organization?The varied toxic potential of amyloid assemblies may involve several structural and assembly properties such as different levels of structural rigidity, stability , and surface protection of amyloid fibrils . These f42)  . We inve,Another property to consider is the stability of amyloid fibrils, and their reversibility and disassembly processes. The assembly process of amyloid is reversible, and this dynamic process is normally favored toward the formation of amyloid fibrils. Thus, fibrils that are thermodynamically and/or kinetically more stable will disassemble more slowly and, therefore, shed a lower population of potentially cytotoxic species,,-The surface properties of amyloid fibrils may also influence their toxic potential. For example, small oligomeric species and fibrillar fragments have all been shown to be able to disrupt lipid membranes.,,,Finally, a large area of synthetic biology has grown from the use of β-sheet structural growth, providing nanowires and hydrogels composed of amyloid-like structures.Ultimately, engineering synthetic amyloid as a novel and safe bionanomaterial will rely on the understanding of the structural factors that underpin toxic properties so that the toxic potential of designed amyloid materials can be minimized or avoided. In the same way, understanding the same underlying principles will be key in understanding amyloid disease so that the toxic potential of disease associated amyloid can be inhibited.


Polyamines (PAs), low molecular weight aliphatic amines, are ubiquitous in all living organisms except the archaeal methanogens and halophiles. In marine macroalgae, commonly known as seaweeds, the diamine putrescine (Put), triamine spermidine (Spd), and tetramine spermine (Spm) are the major PAs, although some brown and red seaweeds reported to have nor-spermine and nor-spermidine PAs. In plants, PAs have been shown to modulate a diverse range of biological processes including cell growth, development, and responses to various biotic and abiotic stresses  in the green seaweed Ulva rigida. However, it was Prof. Rafael Robaina's group who first identified PA's induced changes in growth (higher cell division and elongation rate) and morphogenesis (transforming carposporelings into morphogenic cell masses) in the red seaweed Grateloupia doryphora  and nitric oxide (NO) generation. These compounds are generally associated with the regulation of cellular processes, such as enlargement of meristematic cells, cell elongation, embryogenesis as well as stress responses in plants  which is responsible for PA uptake in land plants. This finding emphasizes that for both prokaryotes and eukaryotes, PA transport is not just a passive mechanism, and selectivity could be achieved through specific recognition and translocation  in different red seaweeds  displays only tSpm synthase activity and tSpm plays a crucial role in regulating vascular development in Arabidopsis  expression is localized to a particular cell- or tissue-specific region such as sporangial and carposporangial cells in order to confirm its role in reproductive structure maturation and development. Knott et al. , and the influence of tSpm whether mediated via its oxidation or not during seaweed reproduction and development are both worthy of further examination. This may provide new insights into the role of PAs in metabolic pathways in response to developmental signals. Further, PA conjugates such as HCAAs (hydroxycinnamic acid amides-most abundant phenolic compounds in reproductive organs of plants) and their potential role in seaweed development is largely unknown.The potential function of Spm in seaweed development that has been reported so far, should actually be attributed to tSpm  rather to Spm. It has been found that tSpm is present throughout the whole plant kingdom, while Spm is found only in angiosperms , Chondrus crispus and Porphyra umbilicalis (red seaweed), provided a new suite of opportunities to investigate phytohormone signaling, and diverse cellular gene expressions under different conditions in these model organisms  or by using sense and antisense transgenic approaches may facilitate the identification of knockouts with genes of interest and/ or gene regulations using PCR-based techniques that need to be develop in the near future to manipulate PA metabolism. PAs biosynthesis involves relatively few enzymes, therefore genes coding for respective enzymes should be characterized and cloned in model seaweeds to gain better insights into their role in reproduction and morphogenesis. Recently, cloning of ornithine decarboxylase gene from the red seaweed Grateloupia imbricata (GiODC) and its expression studies throughout the reproductive process provide evidence for PA's involvement in seaweed reproduction  regulation during seaweed reproduction and development is also interesting as this gene has been suggested to be involve in tSpm synthesis. Moreover, Arabidopsis mutant smadc4 exhibits vascular tissue alterations that partially resemble the acl5 phenotype. Therefore, cloning and characterization of most of the genes involved in PA pathway and ET receptors in seaweeds may serve as an excellent model to test various hypotheses related to developmental processes in seaweeds derived from pathway manipulations. These breakthrough investigations are also equally important in establishing transgenic somatic embrogenic lines and studying PAs involvement in embryo development.It is apparent from the previous studies that PAs are involved in seaweeds in some reproductive stages such as carposporogenesis, sporulation, and tetrasporogenesis. However, due to lack of extensive genomic information in seaweeds and the absence of authoritative databases on molecular gene expression studies, it is hard to establish functions of PAs as phytohormone. No molecular information is available on the number of genes encoding each of the specific enzymes involved in PA synthesis. The recent genome sequencing of E. siliculosus, C. crispus, and P. umbilicalis together with protoplast and somatic emryogenesis protocols, will enable the use of reverse genetics, transgenic, proteomic, and functional genomic approaches to generate critical new knowledge in understanding the role of PAs in seaweed developmental processes. Researchers should consider projects aimed at cloning and transforming genes encoding PA biosynthesis in seaweeds. The manipulation of endogenous PA levels in transgenic algal plants using tissue-specific or inducible promoters will greatly help in exploring the PA's functionality associated with various developmental processes in seaweeds.The investigations conducted so far on PAs clearly show their potentials in regulating morphogenesis and developmental process in seaweeds. The opportunities that became available following whole genome sequences of 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.


A well-supported conclusion a reader would draw from the vast amount of research on Bayesian inference could be distilled into one sentence: “People are profoundly Bayesians, but they fail to solve Bayesian word problems.” Indeed, two strands of research tell different stories about our ability to make Bayesian inferences—our ability to infer posterior probability from prior probability and new evidence according to Bayes's theorem. People see, move, coordinate, remember, learn, reason and argue consistently with complex probabilistic Bayesian computations, but they fail to solve, computationally much simpler, Bayesian word problems.On the one hand, a first strand of research shows that people are profoundly Bayesians. Strong evidence indicates that the brain represents probability distributions and certain neural circuits perform Bayesian computations  cognitive abilities and biologically secondary  cognitive abilities Geary, . It coulWhich type of evidence should we call upon to help us decide whether people are Bayesians or not? Both implicit and explicit processes are relevant for assessing this ability. Having Bayesian eyes, hands and minds is arguably important for survival. Yet, our environment has changed dramatically in the Twentieth century—it became crowded with explicit aggregated statistical information. Learning from described aggregated information condenses the learning process compared with learning from experience. Imagine, for example, an experienced UK physician relocating to Nigeria. Her experience would provide her with an adequate knowledge of the disease base rates, sensitivity and specificity of medical tests within the UK population; however her experience may not be applicable or may even be deleterious in Nigeria given that those pieces of information may differ. The doctor would greatly benefit from reading explicit aggregated statistical information on base rates of diseases, sensitivity and specificity of medical tests in the local population to avoid making errors and the long learning process based on personal experience. Most importantly, she should be able to integrate this information into her diagnostic judgments when facing a given set of symptoms in a patient in Nigeria. More generally, in their probability-laden environment, all people (not just physicians) may come across a lot of problems similar to Bayesian textbook problems, of which cancer or prenatal screening are just examples , but it also offers alternative concepts enacting novel insights, different explanations and more elaborate models generating deeper understanding of Bayesian problem-solving. We outline three examples of such theoretical benefits in the context of facilitating Bayesian problem-solving.First, applying problem-solving concepts to Bayesian reasoning offers a novel and productive perspective. For example, we could think of Bayesian textbook problems in a problem-solving framework as a combination of insight and analytical problems. Typically, the problem-solving literature distinguishes two classes of problems: analytical and insight problems  women with cancer from our previous example.Third, recruiting problem-solving models offers a better understanding of well-known effects in Bayesian reasoning than we currently have, for example, the format effect. Statistical formats such as natural frequencies represent probably the most cost-effective (and the most discussed) tool to facilitate Bayesian problem-solving, given that visual aids offer mixed evidence of their effectiveness —not the numerical format by itself—may trigger a representation of the problem as nested sets, while a wording of the task with probabilities which conceal the nested set structure due to normalizing, does not. Such an explanation casts natural frequencies as a familiar format rather than a privileged one. Some authors view natural frequencies as a privileged format because they are processed by a specialized frequency-coding mechanism shaped by evolutionary forces (Gigerenzer and Hoffrage, According to the general framework of mathematical verbal problem solving (Kintsch and Greeno, Our environment is laden with statistical information and demands from people that they successfully solve problems that are exactly the same as, or similar to, classical Bayesian textbook problems. Although some brain function appears to implement Bayesian computations, people's abilities to solve Bayesian word problems could still be substantially improved. We should therefore strive to understand and improve people's performance with this kind of problems. We suggest thinking about the involved processes as processes akin to those engaged during problem-solving (see also Johnson and Tubau, 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.