The spread of antibiotic resistance is currently a major threat to health that humanity is facing today. Novel multidrug and pandrug resistant bacteria are reported on a yearly basis, while the development of novel antibiotics is lacking. Focus to limit the spread of antibiotic resistance by reducing the usage of antibiotics in health care, veterinary applications, and meat production, have been implemented, limiting the exposure of pathogens to antibiotics, thus lowering the selection of resistant strains. Despite these attempts, the global resistance has increased significantly. A recent area of focus has been to limit the spread of resistance through wastewater treatment plants (WWTPs), serving as huge reservoirs of microbes and resistance genes. While being able to quite efficiently reduce the presence of resistant bacteria entering any of the final products of WWTPs , the presence of resistance genes in other formats  has mainly been ignored. Recent data stress the importance of transduction in WWTPs as a mediator of resistance spread. Here we examine the current literature in the role of WWTPs as reservoirs and hotspots of antibiotic resistance with a specific focus on bacteriophages as mediators of genetic exchange. Staphylococcus aureus (MRSA/VRSA), and pandrug resistant Acinetobacter baumannii  and the “F-factor” (sex pili) , noticinWhile several attempts have been made to reduce the use of antibiotics, prescribing less antibiotics for seemingly minor infections, the global discrepancy of antibiotic usage, both for human usage and for meat production, has limited the impact of such approach . The negThough likely being the most often thought of hotspot for antibiotic resistance spread, hospitals and healthcare systems are not the only spot where high amounts of bacteria, viruses, and resistance genes are concentrated into small compartments. A recently recognized main player in the spread of resistance genes is wastewater treatment plants (WWTPs) with hundreds of original articles and reviews published during the last decade only , and witThe WWTPs serve the purpose of making polluted water suitable for usage again through different mechanisms depending on the quality of the wastewater  and the technology employed in the plant. Many WWTPs also take advantage of the high nutritional value of the biomass leading to sludge used both as biofertilizer in agriculture and as biogas formation during anaerobic digestion. Several national and international organizations regulate the quality of the effluent water and byproducts of WWTPs. However, on a global scale, the inclinations and economy to implement these quality controls vary .The WWTPs have recently started to be considered one of the main hotspots for spreading of antibiotic resistance ; the maiThe presence of resistant bacteria in WWTPs has been recognized for some time, and means to reduce their quantity in effluent water is a high priority for the plants. Due to the association of many microbes with solid particles in wastewater, filtration efficiently removes a high portion of bacteria in the water, and more recent usage of high-efficiency membranes have decreased that amount even further . However8 gene copies/g sludge , why this is of necessity to investigate. Historically, focus has been on removing resistant bacteria, not specifically removing resistance genes, whether existing as free nucleic acids or in phage capsids  thus using bacteriophages as a proxy for pathogenic viruses . This ap5-8 plaque forming units (pfu)/L /L . Through (pfu)/L . While c (pfu)/L , applica (pfu)/L , indicat (pfu)/L . While c (pfu)/L . However (pfu)/L . The imp (pfu)/L .7-9 bacterial/phage interaction .Further adding, and contributing, to the problematic nature of an increased incidence of transduction events in WWTPs is the continuous exposure of environmental stresses for the bacteria. Sub-clinical levels of antibiotics, UV-radiation, toxic substances, and heavy metal ions present in wastewater will lead to an induction of prophages , furtherronments . Furtherronments ,b. SpreaWhile current technologies implemented in WWTPs are efficient in removing most bacterial species and lessen the resistance load among those microbes, it is evident that bacteriophages survive the process; able to infect the microbiota, inject resistance genes, and establish a reservoir of antibiotic resistance genes – a veritable smorgasbord for pathogens and the general microbiota. Membrane bioreactors, ultrafiltration, and the attachment of phages to biosolids within the reactor hold promises to control not only resistant bacteria, but also bacteriophages , 2016. TRL drafted the initial manuscript. RL, GE, and BM constructively advised on improvements concerning the science and general outline of the review. All authors read and approved the final version of the manuscript.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 classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings.Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA.A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2  establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3  provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum.There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios , and provide a foundation for future collaborative work. The term posterior cortical atrophy (PCA) was coined by D. Frank Benson and colleagues to describe a series of patients with early visual dysfunction in the setting of neurodegeneration of posterior cortical regions  Fig. 1)Fig. 1). Several single-center groups of researchers have proposed diagnostic criteria for the syndrome ,15 or deHowever, the extant detailed descriptions of PCA are based on clinical experience at single centers and have not been deliberated or validated more widely. Present-day PCA criteria were also formulated before the development of Alzheimer’s disease (AD) pathophysiological biomarkers, and although recent AD criteria include PCA, the clinical phenotype is not described in detail and such criteria naturally do not encompass individuals with the PCA syndrome who are negative for AD pathophysiological biomarkers. Some inconsistencies exist among the core features described, with the Tang-Wai but not Mendez criteria excluding individuals with early Parkinsonism or hallucinations, while Mendez but not Tang-Wai stipulates the relative preservation of verbal fluency ,15. SuchThe present study describes the formation and deliberations of a PCA working party that aimed to establish a consensus opinion regarding the PCA syndrome. The goal of the work was to review, revise, and complement existing single-center diagnostic criteria to represent multidisciplinary and multicenter experience and knowledge. In light of the problems outlined previously and the challenges facing the PCA research field, a multilevel PCA classification framework is proposed for use in a number of different research contexts.Atypical Alzheimer’s Disease and Associated Disorders Professional Interest Area (PIA) was subsequently constituted subsequently under the auspices of the International Society to Advance Alzheimer’s Research and Treatment. In June 2014, an online survey of Working Party and PIA members was conducted. Participants were requested to estimate the frequency of symptoms, signs, and features . Participants were also asked to rate their level of agreement with a series of statements regarding the conceptualization of PCA . The survey was completed by 36 experienced group members with backgrounds in neurology, psychology, pathology, psychiatry, gerontology, and neuroscience . The results of the survey , a PCA rvey see  and theiA three-level classification framework for PCA is described in As defined in the perspective article which followed the first consensus meeting, “PCA is a clinico-radiological syndrome characterized by progressive decline in visual processing and other posterior cognitive functions, relatively intact memory and language in the early stages, and atrophy of posterior brain regions” The clinical and exclusion criteria constrain the definition of PCA to individuals with a neurodegenerative condition. The semi-arbitrary stipulation of three or more cognitive features is designed to ascertain evidence of a cluster of posterior cognitive deficits and reduce misclassifications based on overinterpretation of a single complaint or abnormal test score. The stringency of this stipulation is also mitigated by the extensive list of potential features which fall broadly into the domains of basic visual, visuoperceptual, visuospatial, literacy, numeracy, praxis, and higher sensory functions. Many of these posterior cognitive deficits may have a pronounced impact on activities of daily living.A critical element of the PCA cognitive profile is the contrast between the posterior cortical dysfunction and the relative sparing of other cognitive domains. This is aimed at distinguishing PCA from typical (amnestic) AD (episodic memory), logopenic-variant primary progressive aphasia , frontotemporal dementia and the AD phenotype variously labeled frontal variant AD, behavioral variant AD, or dysexecutive AD . The concept of “relative sparing” is intentionally flexible to accommodate different assessment settings and tools. Operationalizing these criteria with recommended sets of brief and detailed cognitive tasks is a future objective of the working group, but the main principle is to reduce the impact of core deficits on assessment of these functions. For example, accurate testing of anterograde memory in people with PCA requires tests that avoid not only explicit visual demands  but also more implicit visual demands on visually mediated processes such as mental imagery .18F-labeled fluorodeoxyglucose positron emission tomography or single-photon emission computed tomography) abnormality in the occipital, parietal, and/or occipito-temporo-parietal cortices as supportive of the clinico-radiological syndrome. The inclusion of neuroimaging evidence of posterior cortical atrophy or dysfunction as an optional, supportive feature rather than obligatory component of the syndrome-level description is consistent with previous criteria. This issue generated considerable debate, but maintaining the optional status was justified on both clinical  and practical grounds . Where for practical reasons neuroimaging evidence cannot be obtained, research studies should specify the evidence used to support the classification of PCA. Another issue is that individuals with the visual variant of Creutzfeldt–Jakob disease typically decline rapidly such that obvious focal atrophy is not easily demonstrated )Biparietal  variant: This subtype has been described as “a biparietal variant defined by the presence of early, predominant, and progressive difficulty with visuospatial function, features of Gerstmann syndrome, of Balint syndrome, limb apraxia, or neglect” . This IWOccipitotemporal  variant: The biparietal variant of PCA has been contrasted with a more ventral occipitotemporal variant defined by the presence of an early, predominant, and progressive impairment of visuoperceptive functions or of visual identification of objects, symbols, words, or faces’  variant: Arguably even rarer than the biparietal or occipitotemporal syndromes is a more caudal primary visual syndrome characterized by primary visual failure, impairment of basic perceptual abilities, and bilateral occipital atrophy ,47,53,54Dominant parietal variant: The presentation of visual complaints is a core feature of both the proposed consensus and existing single-center diagnostic criteria. However, not all PCA patients refer explicitly to visual problems among their primary complaints and may present with predominant impairment of other posterior cortical functions, such as calculation, spelling, and praxis ,30,55–57Naturally, there are multiple ways of classifying clinical heterogeneity within the PCA spectrum. An alternative way to discriminate putative subphenotypes would be to refer exclusively to the organization of the visual system . Certain presentations may also merit the combination of different types of descriptive terminology . It is anticipated that descriptions of PCA variants may be relevant to brain-behavior studies, phenotype characterization work , and examinations of phenotype progression . Descriptions of PCA variants may also be useful in the design and use of nonpharmacological interventions, aids, and strategies which are geared toward helping individuals with PCA cope with or ameliorate problems associated with a specific aspect of cognitive function . However, it should be stressed again that these descriptions are preliminary characterizations of positions within a spectrum of continuous variation.We have proposed a PCA classification framework with both syndrome- and disease-level descriptions for use in a number of different research contexts. The strong agreement over the features which constitute the core clinico-radiological syndrome (classification level 1) re-affirmed the Working Party’s original aim of offering a consensus statement refining and advocating specific uses and adaptations of the term PCA rather than any wholesale alteration or redescription of the syndrome. Accordingly, the working party regard classification levels 2 (PCA-pure/PCA-plus) and 3  as extensions to rather than replacements for the previous single-center diagnostic criteria, aimed at increasing the utility and specification of the PCA concept in a variety of research settings.The three-level classification system provides a standard against which clinicians, academics, reviewers, and editors may evaluate and compare study populations and inclusion/exclusion criteria across previous publications and future studies. Although the proposed core features permit of heterogeneity within the syndrome consistent with the amassed clinical experience, reducing the variability between sites and studies caused by inconsistencies of terminology and diagnostic criteria will benefit a variety of future studies. Refining study populations and minimizing clinico-pathological “noise” through both tighter diagnostic criteria and in vivo biomarkers is particularly important in the context of a relatively rare disorder such as PCA in which sample sizes are often limited.A number of challenges remain for the PCA research field. A primary challenge is to understand sources and drivers of phenotypic heterogeneity among individuals with a common underlying pathology. For example, members of the atypical AD PIA have contributed to the largest analysis to date of genetic risk factors for PCA, yielding evidence of both an altered risk profile across known AD risk factors and possible novel loci some of which are associated with visual system development . The curSecond, although the relationships between syndrome and pathology are indubitably less complex than among, for example, the frontotemporal dementias, the boundaries between PCA, and related syndromes  require further clarification through quantitative investigation. For example, motor impairment  has been found in 30% of a series of 44 patients all meeting the existing clinical criteria for PCA . VisuospThird, a further practical objective is to establish a common framework for cognitive screening, neuropsychological examination, and selection of cognitive outcome measures for trials involving individuals with PCA. There is a particular need for clarity regarding the evaluation of episodic memory in PCA . As noteThe proposed classification framework will not resolve these issues directly but may improve our ability to interpret findings across studies, increase the quality of clinical trials for AD, and provide a foundation for future collaborative work. There is a need to validate the reliability, sensitivity, and specificity of the proposed criteria, particularly to establish the quantitative relationships between the different levels of classification. The classification system will also likely require updating and revision, particularly based on emergence of new biomarkers and clinical evidence of PCA attributable to non-AD and mixed pathologies.


The rapid increase in metabolic diseases, which occurred in the last three decades in both industrialized and developing countries, has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as a consequence of a high dietary sugar intake. Animal models of high sugar consumption, in particular fructose, have reported AGE accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agents when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidence also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and the brain, affecting not only metabolic control, but global health. Indeed, the most recent reports on the effects of high sugar consumption and diet-derived AGEs on human health reviewed here suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities. An increase of the daily energy intake of 505 kcal, corresponding to 25%, from 1970 to 2010 [stimated .In addition, clinical evidence suggests that sugar-sweetened foods create psychological dependence . Indeed,On the other hand, results from experimental models confirm that the consumption of sugar-added foods is associated with increased risk for obesity , as wellHowever, sugar added to foods and drinks adds considerable calories without any benefits and may take the place of other nutrient-dense foods in the diet. Thus, many of the clinical and epidemiological observations indicating that excess glucose and fructose intake exacerbates metabolic complications in different tissues are possibly due to the increased calories intake. At present, there seems to be reliable evidence of results obtained from experimental models about the negative effects of high dietary sugar intake, but no clear reliable evidence indicating daily caloric thresholds for sugar intake to exert negative health effects in human.Sucrose, formed by 50% fructose and 50% glucose joint by a glycosidic bond, has been the most easily consumed sweetener in the last decade. The introduction of corn-derived sweeteners, in particular of high-fructose corn syrup (HFCS), which is provided with high sweetening power, organoleptic properties, the ability to confer a long shelf life and to maintain a long-lasting hydration in industrial bakeries, together with its low cost, has rapidly reduced the use of sucrose in many industrial preparations . The fruSome epidemiological studies show an association between fructose-containing sweeteners intake and body weight gain ,18. MoreDietary sugars, including glucose and fructose, are absorbed in the small intestine, but the absorptive capacity for fructose is lower than for glucose or sucrose. However, the addition of glucose, as in case of HFCS-added foods, facilitates the absorption of fructose . After aAGEs are toxic compounds deriving from non-enzymatic glycoxidation reactions of reducing sugars with proteins, which then result as being structurally and functionally compromised . ProteinIt has been a long time since studies started to investigate the glycative potential of different monosaccharides by in vitro incubations with physiologically relevant proteins such as haemoglobin and serum albumin ,33. The d-aldohexose, exists in solution as a stable ring structure. Since only the open chain form of sugar can react with an amino group in protein to form a Schiff base, the high reactivity of fructose may reflect its higher quote of existing as an open chain in solution than glucose [The papers reporting a different kinetic in AGE formation from glucose and fructose have attributed it to the different forms in which the two sugars exist in physiological conditions. Glucose, a  glucose ,33. The  glucose . A secon glucose .There are differences between glucose and fructose also concerning the glycating process, since the rearrangement of the Schiff base derived from fructose generates Heyns products that are quite different from the Amadori products formed by glucose, for they undergo a more rapid conversion to irreversible AGEs . HoweverIn recent years, several studies have highlighted some dietary aspects that can influence extra- and intra-cellular accumulation of AGEs.First, the high-temperature and long-time cooking of foods can generate AGEs that are exogenously introduced with the diet . A relevSecond, emerging evidence indicates that high dietary simple sugars consumption can represent a substantial source of endogenous AGEs . In lighIn addition to the effects attributed to the excess of calorie intake induced by high sugars consumption on metabolism, the sugar-derived AGEs have been shown in animal models to contribute to the development of pathological metabolic conditions through the interference with several protein functions and the activation of pro-inflammatory signals ,53, as iSeveral studies have demonstrated that excessive fructose consumption is associated with increased ectopic lipid deposition in liver and skeletal muscle both in experimental models and in humans ,49,54,55Besides the alterations of plasma lipid profile, fructose is suggested to be an important risk factor for the development of NAFLD . The patThe fructose-induced ectopic lipid deposition has been attributed to the activation of the transcription factor SREBP1c, which regulates the expression of several enzymes responsible for fatty acids de novo synthesis . In studThe same mechanism has been proposed to enhance intramyocellular lipid deposition in the skeletal muscle of high-fructose consuming mice . InteresThe deregulated enhancement of the de novo lipid synthesis can have relevant repercussions on the overall lipids metabolism. Recently, alterations of the sphingolipid metabolism have been evidenced in obese and diabetic patients, with increased plasma levels of ceramide and sphingosine-1-phosphate, which are hypothesized to elicit an inflammatory condition ,64. In aSince the last few years, there has been strong evidence for a causative association between central  obesity and the development of type 2 diabetes and cardiovascular complications, though the mechanisms are not fully understood. However, in this context, a low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy in metabolic tissues including adipose, liver, muscle, pancreas, and brain, has been defined as a causative factor underlying metabolic dysfunctions development and related comorbidities .Besides indications that a high fructose intake is also associated with the onset of a generic inflammatory response in several tissues, recent studies have addressed the specific activation of the NLRP3 inflammasome complex in models of a high-fructose diet ,53,72. IMitochondrial dysfunction and oxidative stress are strictly interconnected events representing the common features of metabolic disorders and chronic inflammatory diseases. It has been reported that a high intake of dietary sugars can evoke a mitochondrial overload in tissues with a high rate of energy metabolism, such as liver and cardiac and skeletal muscle, leading to enhanced mitochondrial respiratory chain activity and oxidative stress ,86,87. IIn addition, further recent findings highlighted in models of high-fructose intake the impairment of the transcriptional activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), a central player in the regulation of many antioxidant enzymes, including glyoxalase-1, the main enzyme responsible for AGE detoxification ,92,93, sAs mentioned above, the glycation induced by dietary sugars, through interference with many cell functions and signalling pathways, may contribute to the development of tissue damage and organ disease. However, most research studies on the pathogenic role of endogenous sugar-derived glycation have been performed in animal models, often through the employment of very high doses of sugars, particularly of fructose, not comparable to the general human nutrition.-/-), which are prone to consume excessive calories and develop obesity and insulin resistance, high levels of CML were trapped by the adipose tissue, while the deletion of RAGE reverted CML accumulation in adipose tissue, increasing its plasma levels, indicating a RAGE-dependent mechanism underlying endogenous AGE-induced obesity [Notably, in animals, the metabolic outcomes of a caloric restriction were attenuated by the diet enrichment with methyl glyoxal, demonstrating that dietary AGEs can induce oxidative stress, insulin resistance, and profibrotic conditions independently from total calorie amount . In addi obesity .On the other hand, epidemiological and observational studies in humans have not univocally demonstrated a relation between high sugar intake and organ diseases, such as liver steatosis, cardiac impairment, or neurodegeneration, so far. Excessive soft drink consumption has only been associated with increased risk for metabolic disorders such as obesity and insulin resistance ,99, but Nevertheless, the involvement of endogenous glycation in dietary sugar-induced dysmetabolism is far from being demonstrated in humans. Though, the reduction of dietary (exogenous) AGEs in type 2 diabetes or obese patients, without modification of the total calories intake, has also been demonstrated to be effective in amelioration of insulin sensitivity, with reduction of inflammatory markers and restoration of AGEs detoxifying systems and mitochondrial metabolism regulators ,105. In Moreover, endogenous and exogenous AGEs have been related to cognitive decline and impaired memory in two different studies, indicating that serum levels of methylglyoxal in elderly individuals were directly correlated with dietary AGE intake and cognitive decline assessed by the Mini Mental State Examination ,108.Recent cross-sectional studies from DeChristopher and colleagues indicated that the consumption of HFCS or fructose-sweetened beverages is associated with asthma and bronchitis in adults and to asthma in children ,110,111.In the present review, we provide experimental data and epidemiological observations indicating the negative effects of excessive intake of sugar-added foods and beverages, particularly of fructose. The data here reported also suggest that the glycation process following high sugar intake may play a central role in the development of metabolic disturbances by interfering with many cell signaling pathways and influencing the pro-inflammatory and pro-oxidant status that contributes to tissue injury and organ dysfunction.However, these mechanisms need to be deepened through animal models trying to mimic the real human sugar consumption and aimed to clarify the significance of dietary sugar-derived AGEs in metabolic diseases and increase the transferability to the human nutrition.Nevertheless, it is difficult to definitely establish limits for sugar intake above which risks for human health are increased. The guidelines to limit sugar addition in foods are not always free of conflicts of interest between public health and the food industry. Thus, since to date it is not possible to discriminate in human nutrition the contribution of different monosaccharides and the general calorie excess to protein glycation, high quality clinical trials are needed to evaluate the sugar daily intake, particularly of fructose, that can represent a feasible risk for human health, through the design of appropriated dietary interventions.


A systematic characterization of compulsivity in pathological forms of eating has been proposed in the context of three functional domains: (1) habitual overeating; (2) overeating to relieve a negative emotional state; and (3) overeating despite aversive consequences. In this review, we provide evidence supporting this hypothesis and we differentiate the nascent field of neurocircuits and neurochemical mediators of compulsive eating through their underlying neuropsychobiological processes. A better understanding of the neurobiological mechanisms that lead to compulsive eating behavior can improve behavioral and pharmacological intervention for disorders of pathological eating. Compulsivity, defined as a strong, irresistible internal drive to perform an action, typically contrary to one's will, is a transdiagnostic construct present in numerous psychiatric conditions. Compulsive eating behavior is observed in pathological forms of feeding behavior, such as binge eating disorder (BED), certain forms of obesity, and the recently proposed “food addiction” ; and the outcome/reward no longer motivates the action  and dorsal regions. While the NAc plays a key role in the reinforcing effects of food and drugs, the dorsal striatum is thought to contribute to the development of habits  decreased reward function, caused by within-system neuroadaptations and (ii) withdrawal-induced negative affect, caused by between-system neuroadaptations , and dysfunctions in cortico-striatal circuitries are thought to underlie compulsive eating behaviors , and Trace Amine-Associated Receptor 1 (TAAR1) , Sigma 1 receptors  initiative by The National Institute of Mental Health is concentrating efforts into the identification of key domains of function common to multiple disorders (The National Institute of Mental Health, Under this perspective, a better understanding of the construct of compulsive eating is warranted. Within the preclinical field, development and use of appropriate animal models that adequately model these functional domains is critical. Modeling complex behavioral constructs, such as those as presented in this review, may lead understanding of the development and progression of underlying neurobiological processes of the elements of compulsive eating behavior. Knowledge of the vulnerability factors, neuroadaptive mechanisms, and their interactions that lead to compulsive eating behavior has the potential to significantly improve behavioral and pharmacological intervention for millions of people.All authors made substantial contributions to conception and design of this review. CM drafted the manuscript. VS, GK, and PC substantially and critically revised it for intellectual content. All authors gave final approval for its submission.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.


Recent studies have claimed that processing of negative emotional information is modulated by the attentional demands of the task , negative pictures  interfered with letter search performance. Processing of these pictures activated several emotion processing brain areas such as visual cortex, anterior insula, amygdala, and orbitofrontal cortex and simultaneously decreased BP. In contrast, when less attention was available for processing distractors (high-load) these reactions were attenuated or diminished. Furthermore, high perceptual load (relative to low-load) boosted activation in attentional processing brain areas . These results are parallel with the theories of selective attention emphasizing the role of attention in regulating behavioral and neural responses to processing of irrelevant emotional information  mediated by the baroreceptors, enhancing stress, and emotional reactivity to negative information. This suggests that baroreceptor feedback pathway works when the level of BP is low. In Okon-Singer et al.'s  study BPIt has been suggested that the neuroanatomical bases for the CNS inhibitory effect of the baroreceptors comprises a central feedback pathway arising from the nucleus of the tractus solitarius (in the medulla oblongata) spreading to the reticular formation, hypothalamus, thalamus, central nucleus of the amygdala, ventral hippocampus, the periaqueductal gray, medial-lateral prefrontal, anterior insular, and anterior cingulated cortexes (Delgadoa et al., RG has written the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tursiops truncatus. Two-dimensional landmarks were recorded on the dorsal, ventral, lateral, and occipital views of the skull, and on the lateral view of the left and the right mandible of 104 specimens from the Mediterranean and the North Seas, differing environmental condition and degree of interspecific associations. Landmark configurations were transformed, standardized and superimposed through a Generalized Procrustes Analysis. Size and shape differences between adult males and females were respectively evaluated through ANOVA on centroid size, Procrustes ANOVA on Procrustes distances, and MANOVA on Procrustes coordinates. Ontogenetic allometry was investigated by multivariate regression of shape coordinates on centroid size in the largest homogenous sample from the North Sea. Results evidenced sexual dimorphic asymmetric traits only detected in the adults of the North Sea bottlenose dolphins living in monospecific associations, with females bearing a marked incision of the cavity hosting the left tympanic bulla. These differences were related to a more refined echolocalization system that likely enhances the exploitation of local resources by philopatric females. Distinct shape in immature versus mature stages and asymmetric changes in postnatal allometry of dorsal and occipital traits, suggest that differences between males and females are established early during growth. Allometric growth trajectories differed between males and females for the ventral view of the skull. Allometric trajectories differed among projections of skull and mandible, and were related to dietary shifts experienced by subadults and adults.Feeding adaptation, social behaviour, and interspecific interactions related to sexual dimorphism and allometric growth are particularly challenging to be investigated in the high sexual monomorphic Delphinidae. We used geometric morphometrics to extensively explore sexual dimorphism and ontogenetic allometry of different projections of the skull and the mandible of the bottlenose dolphin  Ziphius cavirostris), the killer whale (Orcinus orca), the narwhal (Monodon monoceros), or the fossil ziphiids [Since Darwin  sexual dziphiids , 29, 30.ziphiids , 34, 35.ziphiids , 26, 36.ziphiids , 26, 37.ziphiids . Specifiziphiids . As a coziphiids  but alsoziphiids . Thus inT. truncatus (Montagu 1821), using two-dimensional geometric morphometrics of the skull and the mandible. Although some authors reported differences in the number of teeth and height of the braincase of males and females of the bottlenose dolphin T. truncatus [We specifically aimed to explore the evolutionary and ecomorphological significance of sexual dimorphism, ontogenetic allometry, and their interaction in the widespread bottlenose dolphin runcatus , 43, 44,We particularly focused on the following questions: 1. Is sexual size monomorphism a constant trait of this species? 2. Is there any shape dimorphic trait of the skull or the mandible that could be related to any differential behaviour or adaptation of females and males? 3. Is there any geographic variation in sexual dimorphic traits that could be related to intra- or interspecific interactions? 4. Is there any allometric pattern that could be related to any adaptive shifting during growth?We investigated 104 sexed specimens of bottlenose dolphins  from ten European museum collections .Most specimens were strained along the coasts of the Mediterranean Sea  and the North Sea . These largest samples were respectively characterized by monospecific (North Sea) or interspecific (Mediterranean Sea) associations , 46. TheLandmark coordinates were digitized from images using TPSDig (version 2.17)  and thenWe first tested the effects of sex and association on skull shape variation of adult specimens. Sexual dimorphism was then further investigated through allometric growth trajectories of males and females subadults and adults. SSD was evaluated by univariate analysis of variance on log CS using the software PAST version 2.17c (Hammer and Harper 1999–2013). Shape variation was explored by Procrustes ANOVA and by multivariate analyses of the Procrustes coordinates with a Bonferroni correction , using MProcrustes ANOVA was run considering effect of sex, association, and their interaction. The sample included 31 specimens  from North Sea and Baltic Sea , 26, 45,Sexual dimorphism was then further investigated through allometric growth trajectories of males and females subadults and adults. Ontogenetic allometry was explored by multivariate regression of shape coordinates on log CS in all projections of the skull and the mandibles  in the lANOVA on log CS revealed no significant differences in the size of the skull between males and females of bottlenose dolphins , confirmPCA and Procrustes ANOVA on shape variables of adult males and females revealed a significant distinction between populations of bottlenose dolphins living in mono- and multispecific associations , and no A more detailed analysis of shape differences for the dorsal, ventral and occipital projections was then performed separately for the two largest populations of adult specimens living in monospecific and interspecific associations, i.e. respectively the North Sea  and the Mediterranean Sea . ANOVA, Procrustes ANOVA, and MANOVA of Procrustes coordinates confirmed a significant difference between sexes in the occipital projection of the North Sea population living in monospecific association . Specifip-value = 0.0123).Regression of shape coordinates of the North Sea sample onto log CS was significant for all of the projections, and shape variance predicted by size varied from 7.5% for the occipital view to 24.1% for the right lateral view of the skull .The first two PC scores of shape coordinates showed a clear distinction of adults and sub-adults along PC1 for the occipital and the dorsal views , while PFrom sub-adults to adults the skull undergoes an extension of the rostral and the nasal bones, a shortening of the braincase and an enlargement of the right frontal bones. Specifically, the braincase increases in height and becomes more curved in the posterior part. These changes are accompanied by a dorsal-ventral compression, a shrinking of the occipital area, and the development of the zygomatic processes  and the base of the braincase (included the cavity housing of tympanic bulla), that is more stressed in males. Furthermore, the allometric trajectories of the ventral traits, i.e. the feeding apparatus, showed a more paedomorphic final shape in males . PaedomoPeculiar allometric growth patterns were detected in the lateral view of the skull and in the mandible of the bottlenose dolphins, irrespective of sex. Sub-adults showed a ‘morphological stasis’ in the lateral skull shape until they reach a CS value of 60, followed by sudden morphological changes when approaching the adult stage (CS from 60 to 80). These sharp changes were marked by an enlargement of the braincase, evidenced by the expansion of the parietal and sub-occipital bones. In contrast, the growth of the mandibles was characterized by step clines and highly variable shape changes.In general, the shape of the mandible showed an increase in its complexity, from an almost linear bar to a more complex shape involving the expansion and increase of the corpus, and a relative narrowing and curvature of the ramus see . A positAs the shape of the dolphin mandible is also influenced by hearing functionality , 108, itWe are aware that our results only represent a first insight into the sexual dimorphism and growth patterns of such complex and highly derived mammals as the Delphinidae, and that further data are needed to support any ecophyisiological hypothesis relating growth and sexual dimorphism with trophic resource exploitation and intra- and interspecific interactions.S1 Appendix(DOC)Click here for additional data file.S1 Dataset(ZIP)Click here for additional data file.


The potential of marine natural products to become new drugs is vast; however, research is still in its infancy. The chemical and biological diversity of marine toxins is immeasurable and as such an extraordinary resource for the discovery of new drugs. With the rapid development of next-generation sequencing (NGS) and liquid chromatography–tandem mass spectrometry (LC-MS/MS), it has been much easier and faster to identify more toxins and predict their functions with bioinformatics pipelines, which pave the way for novel drug developments. Here we provide an overview of related bioinformatics pipelines that have been supported by a combination of transcriptomics and proteomics for identification and function prediction of novel marine toxins. Little Multi-omics studies using next-generation sequencing (NGS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) technologies advanced considerably, leading to more sensitive and efficient research of venoms ,11. ThesIn this review, we access the current state of knowledge regarding marine venoms, in particular how toxin databases can be correctly utilized in order to accurately predict function of marine toxins.http://www.snakebd.com/) provide expert annotations on sequences and 3D structures of general venomous animals [There are two kinds of toxin databases, generalist and toxin-centered. In generalist databases such as Genbank , it is difficult to extract the toxin sequences or their structure data due to a lack of annotations as toxins or the redundancy of similar sequences ,14. Larg animals ,20,21,22 animals ,24.A complete and well-annotated sequence provides the ultimate resource for venomics approaches; however, this relies on the accuracy of toxin sequences from a given database in order to predict if the sequence is a toxin or not. Toxin sequences share many similarities in their sequences, further increasing the difficulty in accurately annotating the sequences.After a brief survey of related publications and these above-mentioned public databases, we found that unlike the databases for venom terrestrial animals , there is no such unique toxin database or dataset for marine venomous species except cone snails (ConoServer Database), which is a major drawback in the research of marine venoms . DespiteOur in-house toxin database is a comprehensive dataset of all public toxin sequences, which enables the discovery and annotation of toxin genes. There were 4455 toxin sequences identified from venomous marine animals, 87% of which were from cone snails . ConsideDue to the dramatic decline of the cost for NGS sequencing, there are a large number of transcriptomes available for snakes, spiders, scorpions and many other terrestrial venomous animals. Except for the identification of novel biological active toxins, evolution/diversities of toxin families and discovery for drug precursors are also included in the hottest research fields ,27,28.Related transcriptomics analysis can identify all the toxin genes transcribed under certain biological circumstances or certain ecological environments. Transcriptomes can also provide insights into the mechanisms and the diversity of toxins, venom synthesis and secretion, and the biological functions of venoms. Meanwhile, comparative transcriptome analysis allows parallel examination of the dynamic expression of all genes in a holistic manner. This contributes to understanding the unique biological functions of the venom glands. A recent study undertaken on the venom glands of fish shows that the glands most likely originate from the skin and the secretions from the skin are speculated to play an important part in the skin recovery and immunity .The method for the transcriptome analysis of venom glands is summarized in Conus bullatus and C. consors) [Illumina sequencing platforms are the most widely used due to their high outputs and long reads . Transcrconsors) ,37, one consors) , one spiconsors) , a honeyconsors)  and paraconsors) . For the majority of venomous marine species, the parameters for assembly software should be carefully scrutinized. Generally speaking, the assembling strategy will vary for different species, since the guanine-cytosine (GC) content, N50, and the mean length for evaluating the quality of assembly will always be various in different species. Different assembly softwares and parameters are often comparable and their performances are often assessed on the basis of annotation results. While looking into the results of annotations, we always find that toxin precursors can be aligned to several highly divergent superfamilies, which might be confusing for our subsequent analysis. We previously observed that fish toxins belonging to any novel gene superfamily are difficult to identify using sequence similarities due to the remote phylogenetic relationships between our examined fish and those species in the public databases. Reported studies have shown that hundreds of thousands of toxins may originate from only a few primitive genes ,43. SchoSimilar to those approaches for terrestrial species ,52, protTraditional proteomics relies largely on the use of automated Edman degradation and amino acid composition analysis, followed by the confirmation of molecular weights. This approach enables confident assignment of peptide sequences; however, it suffers from both low throughput and a large amount of sample demand. However, there are typically hundreds of different peptides in the venom of a specific venomous species , and theUntil recently, the studies of toxic peptides from marine venomous animals have been mostly limited by the isolation and biochemical characterization of toxins of medical importance. Little or no attention was paid to the related genes, cellular machinery, and other important processes involved in assembly of the final products expressed in the venoms. Marine animal venoms were generally screened in medium- to high-throughput assays against targets of therapeutic interest, and then “hit venoms” were chromatographically fractionated and the individual fractions were re-screened in order to isolate peptides responsible for bioactivity. In some cases, incomplete sequence information acquired via MS/MS and/or Edman degradation has been used for designing primers to amplify transcripts encoding the toxin of interest from a venom gland cDNA library. This method has the advantage of providing useful information about the signal and pro-peptide regions of the toxin precursors as well as the sequences of transcripts encoding paralogs (and even orthologs in related species) . Most of the known toxin sequences were predicted from RNA sequences with six frame-translating or open reading frame (ORF)-finding tools. Consequently, the majority of toxins cataloged in public databases do not have any experimental support (at protein or activity levels) for their production in venoms. For instance, there are 1873 mature toxins recorded in Conoserver, while only 379 toxins have experimental evidence. However, supports for mature toxin sequences are increasing rapidly with evidence from modern proteomic experiments.Throughout the course of evolution, venom peptides and proteins from both vertebrates and invertebrates have been optimized to target specific receptors with high affinity and often exquisite selectivity, making them excellent pharmacological tools and drug leads ,60,61. TOver the past few years, there has been a rapid development in transcriptomics and proteomics research for toxins on the basis of a combination of NGS and MS. The multi-omics analysis on a venom gland (i) can reveal the toxin genes under certain biological conditions or ecological environments; (ii) can provide useful information for the scale and mechanism of the variety of toxins; (iii) and can provide solutions to those biological questions concerning toxin functions, the process of toxin synthesis and the secretion of toxin peptides. Meanwhile, there is a special significance for the research targets that have never been studied before with transcriptomics analysis, which can provide evidence for the identification of peptides and the protein mass spectrum from MS sequencing. Additionally, the comparative analyses can verify the special biological functions between the venom glands and other tissues , and thus we can learn more about the process of venom synthesis.The integration of transcriptomic and proteomic/peptidomic approaches  using biOur recent combination of transcriptomics and proteomics analyses for the Chinese Yellow catfish  and the Comparative Genomics of Fish Venoms, which will greatly enrich our marine toxin databases so as to overcome the obstacles from lacking reference sequences. Improvements in technologies, such as sampling strategies, nanoscale nuclear magnetic resonance (NMR) for structure determination, full-length chemical synthesis, data opening and exchange, and collaborations between research groups, are all crucial for the successful development of marine toxins as drug leads. However, a high degree of innovation in the field of marine toxins will generate a new wave of new drug research and development in the coming future. Interdisciplinary research using new technologies will be essential for the future success of marine toxins as new therapeutic chemical entities that can make significant contributions to the cure of human diseases. Through the combination of transcriptomics and proteomics, the contribution of marine toxins to the future pharmaceuticals seems to be more promising.Venomous marine animals have been revealed to be an important resource for pharmacological tools with promising biological activities. These compounds not only have novel chemical structures but also new functions and/or functional mechanisms. In order to conduct preclinical and clinical trials and further develop a promising lead into a marketed drug, a sustainable supply of these toxins is necessary and challenging. For venomous fish, we are glad to launch the Fish T1K program  with a p


The follow-up of patients who are discharged from intensive care units followsdistinct flows in different parts of the world. Outpatient clinics orpost-intensive care clinics represent one of the forms of follow-up, with morethan 20 years of experience in some countries. Qualitative studies that followedup patients in these outpatient clinics suggest more encouraging results thanquantitative studies, demonstrating improvements in intermediate outcomes, suchas patient and family satisfaction. More important results, such as mortalityand improvement in the quality of life of patients and their families, have notyet been demonstrated. In addition, which patients should be indicated for theseoutpatient clinics? How long should they be followed up? Can we expect animprovement of clinical outcomes in these followed-up patients? Are outpatientclinics cost-effective? These are only some of the questions that arise fromthis form of follow-up of the survivors of intensive care units. This articleaims to review all aspects relating to the organization and performance ofpost-intensive care outpatient clinics and to provide an overview of studiesthat evaluated clinical outcomes related to this practice. In addition, post-discharge evolution of thesepatients presents with frequent hospital readmissions and with the use ofmany health resources, along with a high consumption of financialresources related to health.The quantity-28 In its conception, the main objective of theoutpatient clinic was to improve the cost-effectiveness ofcare.,29Follow-up outpatient clinics (or clinics) for ICU survivors were proposed as a way tofollow up survivors after hospital discharge to treat the numerous morbidities priorto admission to the unit and to diagnose and treat those acquired duringhospitalization in intensive care. and current UKguidelines recommend that ICU survivors be reviewed 2 to 3months after discharge. This evaluation focuses essentially on the diagnosis ofmotor and neuropsychological disorders to refer patients to specialized units whenthey are stricken by a problem  peer support ; (3) frequent contacts of the ICU staff to addressdoubts through phone calls "telemedicine" programs; and (4) scheduled singleor multiprofessional consultations.,26,30Over the years, various follow-up strategies for patients from the ICU have beentested - some still in their very beginning and others with a body of evidence, notalways favorable, but more robust, namely: (1) ICU team integration with primarypublic health;,30 In the UK, most outpatient clinics are funded bythe ICU itself, which allocates a preset monthly resource for monitoring thesepatients.,30,32 In Brazil, these outpatient clinics are not part ofthe health policy strategies and, when they occur, are basically performed asclinical research stations in rare services.The need for professionals and the size of the action defined by them is veryexpensive for the health system. In this context, there is a strong participation ofthe financing model in the form of organization of post-ICU outpatientclinics.,28,30 The greater the range ofprofessionals, the higher the cost of the operation.Depending on the model adopted and available resources, outpatient clinics canprovide aid ranging from clinical to information services to ICU survivors andtheir families. Depending on the services available, the following may beoffered: functional evaluation, physical therapy evaluation, medical evaluation,pharmaceutical evaluation, medical consultation, psychosocial support, andrehabilitation therapy, among others. One-third of the outpatient clinics had accessto psychotherapy services, and one-third had access to the physical therapyservices. Specialized medical services were usually not routinely provided. Insome outpatient clinics, a home physical therapy rehabilitation program wasoffered in addition to ambulatory patient appointments.In a study published in 2002 in the UK, outpatient clinics were primarily run bynurses or doctors.,31,34-60 However, most authors suggest that post-ICUoutpatient follow-up should only occur in patients requiring mechanicalventilation ≥ 48 hours or ICU ≥ 2-5 days. It does not seemcost-effective to follow up all cases that have beendischarged.,34 Approximately 15-20% of patients admitted tothe ICU meet these criteria, but less than 20% of these patients adhere to theprogram and are effectively followed up by outpatientservices. This low attendance may possibly only mean thatthis model is not suitable for all patients. Our experience shows that the mostdependent patients are unable to access the outpatient clinic due to the risk ofnot being transported safely. In our opinion, home visits could correctthis problem, with results possibly similar to those in post-ICU outpatientclinics.The type of patient referred to (or invited) to the post-ICU outpatient clinicsvaries according to the referred study . isaimed only at the diagnosis of the functional and cognitive sequelae of patientsand at the verification of family psychological and organizational problemsalready installed due to the lack of previous guidelines by the health team.Furthermore, missing the possibility of guiding these patients and their familymembers/caregivers would be very large, since approximately 25% of patients whowere discharged from the ICU are either readmitted or die in the first monthsafter discharge from the ICU.,11,13,15Post-ICU outpatient follow-up studies vary greatly regarding time of initiationof follow-up . Van der,14 and that up to 1year after hospital discharge, family members and caregivers presentpsychological and psychiatric symptoms related to the psychological loadsuffered in the ICU.We are not aware of recommendations on how long patients, family members, andcaregivers should remain in follow-up in post-ICU outpatient clinics. Data fromthe literature suggest that up to 10 years after hospital discharge, patientsstill present problems related to ICU admission, However, mostauthors agree that a structured collection based on parameterized manual orelectronic instruments can facilitate the interpretation of data aposteriori and can reduce costs related to personnelcosts.The literature does not provide information to define which instruments should beused in the evaluation of outpatients after ICU discharge. This difference in the findings of thequantitative studies, in relation to the qualitative ones, is likely due to theneed: (1) to apply, in quantitative studies, instruments not validated for thispopulation , (2) toself-complete many of the questionnaires (in patients with cognitivedysfunction); and (3) that patients exaggerate to please health care providersin qualitative interviews . In our view, rather than classifying these results as discordant,we consider them complementary, since qualitative studies should be viewed ashypotheses that generate and provide detailed information on survivors'experience, while quantitative ones try to translate these experiences intographical or measurable forms.As shown in ,14,15 cognitive dysfunction,,17depression,,19 anxiety, posttraumatic stress disorder (PTSD),and sexual dysfunction.,21 Objectively, up to the present time, muchwas measured, but little was obtained regarding the reduction of post-ICUdischarge sequelae with actions performed in post-ICU outpatient clinics  in patients undergoing follow-up by outpatientclinic teams; however, there were no reductions in the other domains ofpatients' quality of life.In the follow-up of patients discharged from the ICU, some clinical outcomes arevery relevant and very prevalent. These patients often experience physicalmorbidities , clinics .(35-38)  Since the primary focus of post-ICU outpatientclinics is on the patient, few outpatient follow-up studies have focused on theneeds and morbidities of family members or caregivers. Although family membershave often been encouraged to participate in clinical consultations in theserare reports, efforts have not always been specifically directed at thediagnosis or management of the patient's symptoms. Still, familymembers can subjectively report positive experiences with follow-upclinics, but many of them do not show up for follow-upat outpatient clinics.Not only does an ICU stay have a lasting impact on the survivors, but it can alsoprofoundly affect the family members and/or caregivers of thesesurvivors. though the family members were invited toparticipate in the outpatient clinic, only one-third of them actually opted forthe service. Engstrom et al. included nine family members in theoutpatient evaluation, who reported that it had been a positive experience. In arandomized clinical trial, Jones et al. analyzed the psychologicalmorbidity in caregivers before and after clinical intervention . They documented PTSD symptoms in 49% of caregivers, anxietysymptoms in 58 - 62%, and depression in 22 - 31%, but found no effects of theintervention on any of these symptoms. These authors demonstrated that thefamily members reported that the experience of outpatient care was positive(subjective assessment). In this study, however, both groups participated in theclinical follow-up, with the addition of a manual and a rehabilitation programin the intervention group. Since the intervention was not directed specificallyto caregivers, it is difficult to assess whether the intervention would have animpact on the psychological morbidity of the caregiver.In the PRaCTICaL study,, a well-documentedphenomenon among ICU teams. Some authors argue that the professionalscan suffer less burnout if they feel their work is valued and important toothers. In analyzing narrativeinterviews with intensive care nurses, the researchersdemonstrated that nurses appreciated the experience of "seeing a healthyperson." In addition, they described that when patients and family membersvisited the ICU after discharge, this visit was "a learning experience."Currently, to our knowledge, there are no studies assessing burnout among ICUstaff members participating in post-ICU outpatient clinics.The experience of the ICU workers in caring for critically ill patients and theirfamilies leads to high levels of burnoutThere are numerous possible interventions to be performed on patients, familymembers, and caregivers that can be captained by a team dedicated to post-ICU care.Briefly, some were described below.handoverPRaCTICaL). Patients with diseases that do notshow signs of severity should be treated in the primary care network (primarysystem) and should be referred to referral services (of greater complexity) whenrequired. The ICU is situated at the apex of the complexity pyramid of thissystem. The need for technological resources and the high performance ofprofessionals has led to a reduction in the mortality of patients in theintensive care setting.In the flow of the health system patients , relevant information related to their healthmay be lost in a fragmented and inefficient care transfer model andlater to their homes, featuring a progressive escalation of the need for careand, theoretically, the need for vigilance. However, these survivors frequentlypresent new needs , and their family members and basic healthcare staff may not be prepared for their proper care. Therefore, there is a riskthat primary care physicians will be excluded from the clinical discussions andmanagement of these ICU survivors. randomized 291 sepsis survivors to bemaintained in the usual post-ICU care with their primary care physicians (n =143) or to undergo intervention (n = 148) in nine ICUs in Germany, whichconsisted of 12 months of periodic outpatient contact with patients (by trainednurses), training of primary care physicians and patients in specificsituations, support for clinical decision  for primary carephysicians, reference to specialists when needed, and prescription ofmedications when necessary. The main outcome of the study was the change inquality of life related to mental health on immediate discharge from the ICU and6 months after discharge from the ICU, measured using the SF-36 MentalComponent. The authors concluded that among survivors of sepsis and septicshock, the use of a team-based intervention focused on primary care comparedwith usual care did not improve the quality of life related to mental health 6months after discharge from the ICU.Schmidt et al. Because thetranslation of knowledge is notoriously slow, many family physicians may notknow of the existence of post-intensive care syndrome, rendering them even lesslikely to address survival issues. The result is that millions of criticalillness survivors are discharged into the community, unprepared and uninstructedabout what to expect from their recovery and how best to cope, adjust, andoptimize their possible recovery. Since the patient's motor andneuropsychological impairments are often not recognized and/or minimized, asubstantial burden usually falls on informal caregivers and family members -many of which can still be fighting their own emotional sequelae secondary tothe patient's experience in the ICU.Issues regarding "staying alive" are rarely addressed by ICU teams during thetime the patient is admitted to intensive care. The mutual support is based on mutual respect.Peer support is centered on the notion that survivors can help each other, shareproblems, and the will to overcome them. It is not a physician-centered model;however, it has the role of helping to provide a safe space in which survivorscan work. The potential benefits of this technique comefrom establishing a community that promotes health and well-being through sharedexperiences of disease and recovery. Potential benefits include mentalreassignment (hope and optimism), role modeling, sharing of information, andpractical advice that is not readily available to healthprofessionals. In addition, peer support has already proven tobe an effective technique in people with mental health disorders and substanceabuse problems, in the self-management of diabetes, and among cancersurvivors.Peer support is a strategy in which patients help patients and can be defined as"a process of empathy, which offers advice and share stories among ICUsurvivors". and because of the reluctance of health careproviders to engage in the spiritual aspects of illness andrecovery, these support groups can allow patients toexplore these aspects of recovery with greater fluidity.As survivors and their caregivers have firsthand experience with the challengesthey will face, these individuals are well-suited to educating and preparingother survivors for certain aspects of the recovery process. However,spirituality and religion seem to be very important in survivor supportnetworks, This form of screening can improve resourcesby detecting only those patients at higher risk of developing physical andneuropsychological disorders, that is, possible candidates for post-ICUoutpatient follow-up.A large part of the follow-up studies of ICU survivors was performed throughtelephone contacts and the application of validated and standardizedquestionnaires and instruments.The use of telemedicine in the follow-up of patients from the ICU can be aninstrument that facilitates communication between family physicians and criticalcare medical and non-medical specialists. In the future, this tool can alsoprovide real-time decision making for ICU survivors in any region of thecountry, bringing ICUs to cities other than capitals and making intensive caremore balanced in different regions of Brazil.,30 These patients are characteristically at highrisk when compared with other hospitalized patients; frequently, their continueduse medications are discontinued during hospitalization and are not - eitherintentionally or unintentionally - restarted after discharge from the ICU. Thereturn of the patient to the post-ICU outpatient clinic can be an excellentopportunity to review the medication in use, aiming at restarting, maintaining,or withdrawing drugs.,40A review of which medications will be required after ICU discharge is afundamental stage of post-ICU care often neglected by the teams of theseunits. Consultation inpalliative medicine in the context of post-ICU outpatient clinics translates theuse of an excellent opportunity to meet the patient's many needs, such aspsychological concerns, spiritual needs, and better physician-patient,physician-family, and family-patient communication.,41Currently, palliative care specialists encourage a broader view of theirspecialty, with a focus on symptom relief and the promotion of quality of lifefor individuals with chronic but lifelong illnesses.Undoubtedly, one of the great contributions that outpatient clinics can givepatients and their families is through standardized assessments to confirmpsychological, cognitive, or functional diagnoses that allow them to be referredfor specific evaluations and treatments in the health care network.,31,42 What is the most cost-effective model? Which modelis able to provide the service equitably to patients? Does regionalization of theUTI, more preferably concentrated in large cities, allow a single model of post-ICUcare? Is a single model of post-ICU care appropriate for functionally dependent andindependent patients? Which professionals are the most qualified to implement eachmodel of post-ICU care? Should the post-ICU outpatient clinic be uni- ormultidisciplinary?Currently, there is scant evidence as to which is the best follow-up model for ICUsurvivors.In this review, the importance of the ICU team in building and maintaining long-termrelationships with their patients has been emphasized. Some authors suggest that ICUstaff should continue to follow patients after they leave the ICU and hospital,especially those for whom we indicate and perform high-complexity and high-costinterventions.To date, the model of outpatient follow-up after ICU discharge does not seem toprovide significant benefits to patients and families and is not cost-effective.However, this limitation should not reduce the importance of the long-term follow-upof patients, family members, and caregivers. Patients feel confident with theparticipation of intensivists in their future therapeutic decisions since thecomplexity of their sequelae requires multidisciplinary and specialized follow-up.Relatives feel confident in clarifying their doubts and exposing their fears to theteam that treated them with respect and dignity during what was possibly the worstsituation in their lives. The use of an eventsdiary kept by the ICU staff and presented to patients after discharge seems to havebenefits in reducing the symptoms of PTSD.,63 Some colleagues have argued for a follow-upmodel that prioritizes the best use of technology, such as telemedicine andelectronic health records, aimed at better communication with primary careproviders, rehabilitation institutions, and experts responsible for specializedclinical assessments. Perhaps, and most likely, there is no single modelof monitoring of post-ICU patients, but several models which, when individualized,allow the "right care for the right patient".Therefore, our challenge is to develop and implement longitudinal models of care thatbegin the day the patient enters the ICU and continue for the rest of thehospitalization, and even after it. Our focus should start with the prevention ofmorbidity, early initiation of rehabilitation activities, and management ofdelirium, attitudes known to impact the long-term results.


Aggression is a costly behavior, sometimes with severe consequences including death. Yet aggression is prevalent across animal species ranging from insects to humans, demonstrating its essential role in the survival of individuals and groups. The question of how the brain decides when to generate this costly behavior has intrigued neuroscientists for over a century and has led to the identification of relevant neural substrates. Various lesion and electric stimulation experiments have revealed that the hypothalamus, an ancient structure situated deep in the brain, is essential for expressing aggressive behaviors. More recently, studies using precise circuit manipulation tools have identified a small subnucleus in the medial hypothalamus, the ventrolateral part of the ventromedial hypothalamus (VMHvl), as a key structure for driving both aggression and aggression-seeking behaviors. Here, we provide an updated summary of the evidence that supports a role of the VMHvl in aggressive behaviors. We will consider our recent findings detailing the physiological response properties of populations of VMHvl cells during aggressive behaviors and provide new understanding regarding the role of the VMHvl embedded within the larger whole-brain circuit for social sensation and action. Aggression is an innate social behavior essential for resource competition, settling disputes, defense, and protecting kin. It is a prevalent behavior across many species, including humans, and in a variety of species including cats, rats, chickens, and monkeys, electrical stimulation studies have demonstrated a causal role of the medial hypothalamus in expressing aggressive behaviors ; (2) the detection of aggression-provoking sensory cues (sensation); and (3) the initiation and execution of attack and aggression-seeking behaviors (action) ;  the deteUpon the intruder introduction, VMHvl activity quickly increases and is maintained at a high level. This elevation in spontaneous activity is not associated with any particular behavior and can account for ~50% of the total VMHvl firing rate increase , peaks at the onset of attack, sustains throughout the duration of attack, and quickly drops to the baseline level at the behavioral offset  during sexual behaviors. Mounting evidence now suggests that the response properties of VMHvl neurons are not fixed as would be in a “hard-wired” innate circuit, but instead are constantly updated. Recently, Remedios et al. used microendoscopic calcium imaging to examine changes in VMHvl cell activity over days as the recorded males encountered male and female intruders and obtained social experience   Levey, . The Mus) Levey,  and thus) Levey, . Interes) Levey, . When DR) Levey,  mediatedwww.brain-map.org, experimental ID: 75081001). In vitro slice recording showed that oxytocin can directly excite VMHvl cells when bath applied . Given that oxytocin can be released from not only axons but also dendrites . Tracing studies have revealed dense projections from the VMH surrounding regions to the VMH, suggesting a strong local control of the VMHvl activity by its surrounding zones  illustrated the exceedingly high strength of this projection: in the list ranking the tracing results according to the largest terminal fields produced within the PAG, the VMH appeared in 6 of the 10 topmost positions. The 4 other top positions were occupied by areas adjacent to the VMH, such as the tubular- and the lateral hypothalamic area, which all receive strong inputs from the VMHvl. Thus, VMHvl projections to the PAG, either directly or indirectly, are likely to have strong impact on the PAG cell activity.The attack initiation signal in the VMHvl ultimately needs to activate premotor areas to drive the motor execution of attack. Among all the downstream regions of the VMHvl, the periaqueductal gray (PAG) represents the most likely relay between the VMHvl and the motor neurons in the spinal cord. PAG is a midbrain structure located around the cerebral aqueduct. PAG neurons project to the nucleus raphe magnus (NRM) and pallidus (NRP), the ventral part of the caudal pontine, the medullary reticular formation  and is composed of multiple columns surrounding the midbrain aqueduct  (Bandler and Shipley, vice versa (Canteras et al., In addition to the PAG, there likely exist parallel pathways to generate attack, given that a large lesion that destroyed the entire PAG at one level only transiently impaired aggressive behaviors (Mos et al., in vivo recording have quickly advanced our knowledge regarding the neural substrates relevant for aggression. Beyond the VMHvl and associated regions mentioned above, including the MEA (Hong et al., After decades of relative quiescence, aggression research has regained its momentum. Recent studies using genetically precise, cell-type specific manipulation, tracing, and DL wrote the manuscript. YH and KH made the figures. KH commented and AF edited the manuscript.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.


Drosophila and male mammals. Furthermore, the discovery of mammalian OGSCs challenged the traditional opinion that the number of primary follicles is fixed in postnatal mammals, which is of significance for the reproductive ability of female mammals and the treatment of diseases related to germ cells. Meanwhile, it still remains to be determined whether the Hh signaling pathway participates in the regulation of the behavior of OGSCs. Herein, we review the current research on the role of the Hh signaling pathway in mediating the behavior of GSCs. In addition, some suggestions for future research are proposed.Germline stem cells (GSCs) are adult stem cells that are responsible for the production of gametes and include spermatogonial stem cells (SSCs) and ovarian germline stem cells (OGSCs). GSCs are located in a specialized microenvironment in the gonads called the niche. Many recent studies have demonstrated that multiple signals in the niche jointly regulate the proliferation and differentiation of GSCs, which is of significance for reproductive function. Previous studies have demonstrated that the hedgehog (Hh) signaling pathway participates in the proliferation and differentiation of various stem cells, including GSCs in  Drosophila and male mammals, the migration of OGSCs from the ovarian surface epithelium (OSE) to the ovary cortex, and the development of OGSCs in the ovary cortex of mammals.Stem cells have many possible applications based on their ability for differentiation. At present, advances in regenerative treatments with stem cells are progressing dramatically, bringing hope for individuals with certain complicated and refractory diseases, such as maculopathy and nerve injury , 2. GSCsDrosophila embryos; thus, the gene was named Hh [Shh, Dhh, and Ihh, homologous to Hh, were found in vertebrates. The proteins encoded by all of the above genes can activate the Hh signaling pathway, which can regulate the function of stem cells, repair damaged cellular tissue, and maintain cellular structure [In 1980, when Nusslein-Volhard and Wieschaus were screening genes that affected the growth of fly larvae, they found that a certain mutated gene caused hedgehog-like spiked protrusions on the ventral side of named Hh . Afterwatructure , 5.Hh encodes the Hh precursor protein, which turns into the Hh ligand protein after self-cleavage and palmitoylation. The Hh ligand protein acts on target cells through paracrine or autocrine modes of action with the help of the dispatched (Disp) protein [The classical Hh signaling pathway is composed of the Hh ligand, a membrane protein receptor complex of patched (Ptc) and smoothened (Smo) proteins, nuclear transcription factors, and target genes.  protein , 7. Inte protein , 9. In tβ (glycogen synthase kinase 3 beta) and is phosphorylated by PKA, GSK3β, and CK1. Then, Gli3 is recognized by the E3 ubiquitin ligase βTrCP (beta-transducin repeat-containing proteins). Meanwhile, the transcriptional activation region at the C-terminal end is removed, and Gli3 becomes a transcription repressor (GliR), which enters the cell nucleus and inhibits the transcription of target genes. When the Hh ligand is present, activated Smo mediates the phosphorylation of SuFu/Gli/Kif7 complexes that release Gli (mainly Gli1), which blocks the hydrolysis process of the transcriptional activation region at the C-terminal end. Then, the full-length Gli acts like GliA to promote the transcription of target genes. It has been proven that Hh, Gli1, Ptc, and Bmp are target genes for the classical Hh signaling pathway.Generally, nuclear transcription factors are divided into transcription activators (CiA/GliA) and transcription repressors (CiR/GliR) . In mammGSCs are restoring cells in the gonads that have the ability to differentiate into germ cells. They exist in a microenvironment (niche) in the gonads that contain somatic cells. These somatic cells cooperatively regulate the proliferation and differentiation of GSCs. GSCs are usually called spermatogonial stem cells (SSCs) in males  and ovarDrosophila gonads are located in a niche composed of SSCs, hub cells (HCs), and cyst stem cells (CySCs). In Drosophila, at the apex of the bilateral testicle, there is a cluster of HCs. One side of the cluster connects with the basement membrane of the testicle; the other side is the binding site for SSCs and CySCs. Usually, there are six to nine SSCs on one side of the testicle, and each SSC is isolated by two irregular-shaped CySCs. During spermatogenesis, SSCs divide asymmetrically into two daughter cells. One cell adheres to HCs to maintain self-renewal, while the other separates from the HCs and forms a gonialblast (GB), which enters the differentiation stage. CySCs divide into two cyst cells, which surround the GB and regulate its proliferation and differentiation [SSCs in ntiation –15.In 1994, SSCs were first discovered in mammals in the basement membrane of the mouse testis seminiferous tubule, and they account for 0.02%–0.03% of the total cells in the testis . They arDrosophila are located in a niche composed of cap cells (CpCs), terminal filament cells (TFCs), and escort cells (ECs). The niche is located in the apex of the oviduct in the bilateral germarium. In general, there are two or three OGSCs in each germarium. They adhere to CpCs through the E-calcium adhesion protein. OGSCs can asymmetrically divide into two daughter cells: one cell turns into a new OGSC and continues to adhere to CpCs while the other one separates itself from CpCs and proceeds to becoming an oocyte latterly [OGSCs in latterly , 19. Furlatterly  first selatterly , 22, andlatterly  further latterly  purifiedDrosophila, the hedgehog signaling pathway regulates the proliferation and differentiation of SSCs via an indirect mechanism. Although SSCs are closely conglutinated with HCs, SSCs cannot express Ptc and Smo and fail to receive Hh signaling from HCs. Furthermore, the Hh ligand originating from HCs directly binds with Ptc in CySCs, which results in the upregulation of the transcription of target genes, including Hh and Bmp (bone morphogenetic protein) [bag-of-marbles (Bam), which encodes Bam (differentiation-associated factor), to sustain the undifferentiated status of SSCs [Drosophila spermatogenic cycle.In protein) . The inc of SSCs . Hence,  of SSCs . Hence, In mammals, the Hh signaling pathway regulates the proliferation and differentiation of SSCs in direct and indirect ways. Previous studies mainly considered that Hh signaling could indirectly affect the cellular behavior of SSCs through somatic cells in the niche. However, recent research revealed that SSCs could secrete Hh ligand and directly activate Hh signaling pathway in SSCs.In mice, SSCs directly adhere to adult SCs in the niche. During the adult SC period, the transcription and sustained expression of Dhh can be detected in SCs. After secreting Dhh, adult SCs accept Hh signaling and promote the expression of glial cell-derived neurotrophic factor (GDNF), bone morphogenetic protein (BMP), and stem cell factor (SCF). These proteins can further activate other signaling pathways in SSCs, such as BMP, PI3K-Akt, Src, and RAS/ERK1/2, which inhibit the differentiation of SSCs and sustain a certain amount of SSCs –29  and glass bottom boat (Gbb) (both belong to the Bmp family), in AECs [Dpp in CpCs. Eventually, BMP (Dpp) signaling in the OGSCs niche is intensified. As a result, Dpp suppresses the expression of Bam and inhibits the differentiation of OGSCs. As OGSCs differentiate, the expression of Fused (Fu), a positive regulator in the Hh pathway, is constantly increased. Moreover, Fu mediates the ubiquitination and proteolysis of thickveins  in OGSCs, which is beneficial for the differentiation of OGSCs [Hh signaling in the niche of OGSCs can suppress the differentiation of OGSCs in direct and indirect ways. Firstly, Hh signaling has been proposed to directly signal OGSCs and control the maintenance of OGSCs , A. Seco in AECs , 43. Hh of OGSCs , 44–47  derived but not CpC-derived Hh starts to participate in the differentiation process. It was discovered that maintaining the activation of the Hh signaling pathway and secretion of Hh ligand in PECs requires the presence of COP9  in ECs . Moreoveechanism  (Figure OGSCs in mammals are located in a single layer of epithelial cells with tight junctions in the OSE. In almost all species, it is not possible to observe obvious OGSC division in the normal OSE, and most research concerning OGSC function involves OGSC transplantation experiments. Thus, it is more reasonable to discuss the effect of Hh signaling pathway on OGSCs in normal OSE or in the ovary cortex after transplantation –52. MoreWe proposed a hypothesis that the special structure of the OSE restricts the activity of OGSCs, but Hh signaling could help OGSCs migrate into the ovary cortex. Under natural conditions, the outside of the OSE is covered by the peritoneum, and the underside of the OSE adjoins the ovary cortex –55. HoweHh, Ptc, and Gli are very low [Drosophila when Hh signaling stimulates other cells to secrete BMP protein.It is not clear whether somatic cells in the ovary cortex regulate the function of OGSCs through the Hh signaling pathway. During the initial forming period of the mammalian fetal ovary, the transcription levels of very low . After bvery low , inducinvery low –64. In tvery low , 65. Henvery low . Furthervery low . Then, tvery low  found thDrosophila? Grieve et al. [Can somatic cells in the ovary regulate OGSC development as in e et al.  found thAccording to the current research progress in this area, the following questions need to be thoroughly addressed in the near future.Drosophila, the JAK-STAT signaling pathway, whose functions overlap with those of the Hh signaling pathway, enhances the proliferation of SSCs and the overexpression of the antiapoptosis protein DIAPI in cells, which helps sustain the activity of SSCs [Currently, many studies have indicated that the Hh signaling pathway has a strong effect on the proliferation and differentiation of SSCs. What we are mostly interested is whether we can artificially alter the self-renewal or differentiation process via regulating Hh signaling in the SSC niche, thereby improving the reproductive ability of animals. For example, some animals with azoospermia cannot produce a sufficient number of sperm and lose their reproductive ability because of the dysfunction of SSCs or the low number of SSCs. A sufficient number of SSCs is a prerequisite for a normal spermatogenic ability in males. In 2014, it was determined in testicular biopsies that the ectopic expression of Shh results in the absence of spermatocytes and increased numbers of LCs in the testes . We disc of SSCs . Thus, tDrosophila ovary somatic cells, which eventually promotes the differentiation of OGSCs. Meanwhile, the Hippo-YAP signaling pathway has a negative regulatory effect on the generation and development of mammalian follicles [OGSCs are considered one of the possible cells in animals that can generate oocytes. Regulating OGSC function can be used to help those who wish to lengthen their reproductive life span or to treat animals or humans with germ cell dysfunction to restore their reproductive ability. Whether changing the Hh signaling pathway in OGSCs can affect the formation of primordial follicles in mammals and whether any effects on the proliferation and differentiation of OGSCs are caused by Hh signaling regulation still require further investigation. Previous studies have shown that Hh signaling can influence the development of TCs and hinder ovulation in mammals , but theollicles , which p


The Diptera (true flies) is one of the most species-abundant orders of Insecta, and it is also among the most important flower-visiting insects. Dipteran fossils are abundant in the Mesozoic, especially in the Late Jurassic and Early Cretaceous. Here, we review the fossil record and early evolution of some Mesozoic lower brachyceran flies together with new records in Burmese amber, including Tabanidae, Nemestrinidae, Bombyliidae, Eremochaetidae, and Zhangsolvidae. The fossil records reveal that some flower-visiting groups had diversified during the mid-Cretaceous, consistent with the rise of angiosperms to widespread floristic dominance. These brachyceran groups played an important role in the origin of co-evolutionary relationships with basal angiosperms. Moreover, the rise of angiosperms not only improved the diversity of flower-visiting flies, but also advanced the turnover and evolution of other specialized flies. The Diptera (true flies) is one of the most species-abundant orders of Insecta, and they are certainly one of the most ecologically ubiquitous and significant orders of insects . They arThe Cretaceous is a time of important developments in angiosperms that angiosperms rose to dominance during the Albian-Cenomanian, and become forest dominants during the Campanian-Maastrichtian . AlthougBrachyceran flies are quite abundant during Mesozoic, especially from the Middle-Late Jurassic to mid-Cretaceous. The middle Early Cretaceous to the early Late Cretaceous is a significant period for brachyceran flies, including the ecological success of some flower-visiting flies and extinction of several important groups, such as Eremochaetidae and Zhangsolvidae . The extFigure 1A; Tabanidae, normally called horse flies or deer flies, is an ubiquity family, and the most diverse family-level clade that has more than 4000 species distributed in 156 genera worldwide  is a quite diverse and widely distributed family of Asiloidea. It is a cosmopolitan group and a quite large family that comprising over 4500 described extant species around the world . The diversity of proboscis strongly suggests diverse plant hosts  are responsible for the origin of flowers and the diversity of angiosperms. In this review, we have only scratched the surface of the co-evolution of Cretaceous brachyceran flies with angiosperm, our knowledge of Mesozoic flies-angiosperm mutualisms should greatly expand with more and better preserved fossils and improvements in phylogenetic analysis.BW designed the project; QZ performed the comparative and analytical work, and wrote the manuscript.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.