Persistent organic pollutants (POPs) bioaccumulate in the food chain and have been detected in human blood and adipose tissue. Experimental studies demonstrated that POPs can cause and promote growth of breast cancer. However, inconsistent results from epidemiological studies do not support a causal relationship between POPs and breast cancer in women. To identify individual POPs that are repeatedly found to be associated with both breast cancer incidence and progression, and to demystify the observed inconsistencies between epidemiological studies, we conducted a systematic review of 95 studies retrieved from three main electronic databases. While no clear pattern of associations between blood POPs and breast cancer incidence could be drawn, POPs measured in breast adipose tissue were more clearly associated with higher breast cancer incidence. POPs were more consistently associated with worse breast cancer prognosis whether measured in blood or breast adipose tissue. In contrast, POPs measured in adipose tissue other than breast were inversely associated with both breast cancer incidence and prognosis. Differences in biological tissues used for POPs measurement and methodological biases explain the discrepancies between studies results. Some individual compounds associated with both breast cancer incidence and progression, deserve further investigation. Persistent organic pollutants (POPs) are a group of chemical substances of synthetic origin used for industrial, agricultural or domestic purposes, that persist in the environment and bioaccumulate in the food chain due to their lipophilic properties ,2. POPs Given the abundance of adipose tissue in the human breast, mammary epithelial cells exposure to POPs sequestered in breast adipose tissue may promote carcinogenesis and progression of mammary cancers . In factAlthough experimental studies demonstrate that POPs can cause and promote growth of breast cancer, several observational studies conducted in humans yielded inconsistent results regarding the implication of POPs in women breast cancers ,24,25,26A systematic review was conducted following a pre-established protocol and according to the general methodology of Cochrane reviews . ConsideAn electronic search of the following databases was performed, from inception to December 2018: MEDLINE (via PubMed), EMBASE and CENTRAL . Search strategies were developed for each of these databases with text words and index terms referring to POPs, breast cancer risk and breast cancer prognosis, and excluding animal studies . No langAny observational or intervention study that evaluated the association between POPs and breast cancer risk, survival or a meaningful breast cancer prognostic factor, whatever the design was eligible for inclusion. No restrictions were applied regarding language or type  of publication. Women included in the studies before or after breast cancer diagnosis, regardless of age, menopausal status, breast cancer type, disease stage and treatment regimen, were eligible. No participants were excluded based on ethnicity.Studies that measured exposure to any lipophilic POP, in a lipid rich biological human sample , whatever the method of measurement, were eligible.Breast cancer risk, measured by breast cancer incidence, prevalence or breast mammographic density (a recognized breast cancer risk factor) and breast cancer survival, including overall survival , breast cancer-specific survival , and breast cancer-free survival (breast cancer recurrence), were the primary outcomes. Studies that assessed the association of POPs with meaningful breast cancer prognostic factors  were also eligible.The references identified by the search strategy were reviewed by one author (K.E-I.) in a two-step process. First, the title and abstract of each study were screened to exclude obviously non-eligible studies and second, the full text of retained articles was examined and subjected to evaluation using the predefined eligibility criteria. Whenever required, a second review author (C.D.) was consulted. When required, further information was sought from the authors by email.Data extraction was performed using an exhaustive standardized form designed for this review. Information about study design , participants and tumors characteristics at diagnosis , exposure assessment , measured outcomes and reported results  were collected. For observational studies, special attention was paid to distinguishing between adjusted and unadjusted results, and to the variable selection method used in multivariate analyses. Studies definition of each characteristic or variable retained was recorded. In the case of multiple publications related to the same study, the publication reporting the outcomes of interest to the present review or the one with the longest follow-up of these outcomes was considered as the reference, and information was supplemented by secondary publications as required. Abstracts with insufficient information and data to permit inclusion were excluded from the qualitative synthesis . Data weBased on the “STrengthening the Reporting of OBservational studies in Epidemiology.” (STROBE) statements , and theAssessment of the risk of bias was performed twice by a review author (K.E-I.), both for the risk of bias in each study and for the overall risk of bias across studies. When required, a second reviewer (C.D.) was consulted.Differences between studies, including study design, participant characteristics , tumor characteristics , exposure measurement  and different levels of risk of bias were considered for exploring possible sources of heterogeneity. Given that high heterogeneity between studies was expected, quantitative synthesis of data was not considered appropriate. A systematic qualitative synthesis of study characteristics and results was performed for risk, mortality, and prognostic factors associations with POPs exposure, and separately for each type of tissue sample. The results were considered adjusted only when all important confounders were considered into the models. For breast cancer risk, authors should have considered at minimum age, body mass index or any other estimation of body fat, and breastfeeding or parity as potential confounders. For breast cancer mortality, authors should have adjusted at minimum for age. In addition, studies of breast adipose POPs should have considered breastfeeding or parity as potential confounders. A positive association was defined as an observed higher risk or mortality with higher POPs exposure whereas a negative association was defined as an observed inverse association.n = 81) whereas studies of breast cancer prognosis included five cohort studies for mortality and nine cross-sectional studies for breast cancer prognostic factors. Overall, POPs were measured in peripheral blood in 63 studies, in breast adipose tissue in 32 studies, in adipose tissue other than breast in five studies and in breast tumors in four studies .Characteristics of the 61 studies that examined associations between peripheral blood POPs and breast cancer risk are summarized in Characteristics of the 26 studies that examined associations between breast adipose tissue POPs and breast cancer risk are summarized in Four studies examined associations between POPs in breast tumors and breast cancer risk, of which three included breast tissue surrounding malignant tumors for cases. Two studies compared malignant tumors of cases to benign tumors of controls whereas the two other studies compared malignant tumors of cases to normal tissue of controls. All these four studies were hospital-bases case-control studies with hospital controls, in which cases were on average 50 to 60 years old in the two studies that reported age at diagnosis. One study included exclusively invasive cancers, whereas the three other studies did not report proportion of invasive cancers. No study reported proportion of menopausal patients or the proportion of ER-positive breast cancers .Two studies examined associations between POPs in buttock adipose tissue and breast cancer risk. The recent one was a cohort-nested case-control study with incidence density (risk-set) sampling and included 409 postmenopausal breast cancer patients aged 58 years old in average, of which 78% had ER-positive breast cancers. The proportion of invasive tumors was not reported. The other study was a hospital-based case-control study with community controls including 265 breast cancer patients aged 62 years old in average. The proportions of postmenopausal patients, invasive tumors and ER-positive tumors were not reported .Characteristics of the 14 studies that examined the association between POPs and breast cancer prognosis are summarized in Six studies examined mortality outcomes, with three measuring POPs in peripheral blood, one measuring POPs in breast adipose tissue and two measuring POPs in adipose tissue other than breast. Patients were aged between 58 and 66 years old in average with only two studies reporting the proportion of postmenopausal women (66% and 100% respectively), and two studies reporting proportion of invasive cancers (71% and 86% respectively). The proportion of ER-positive breast cancers varied between 72% and 78% in the three studies that have reported patients ER status .Ten studies examined breast cancer prognostic factors, with three measuring POPs in peripheral blood, six measuring POPs in breast adipose tissue and one measuring POPs in adipose tissue other than breast. Patients were aged between 52 and 65 years old in average with varying proportions of premenopausal and postmenopausal women and none with at least 80% of postmenopausal patients. The proportion of invasive cancers varied between 85% and 100% and the proportion of ER-positive breast cancers varied between 50% and 86% with only two studies including at least 80% of ER-positive breast cancers .Overall, studies reporting associations between peripheral blood POPs and breast cancer risk ranged from moderate to critical risk of bias, whereas studies reporting associations between adipose tissue POPs and breast cancer risk were more likely to be at serious or critical risk of bias.Overall, studies reporting associations between POPs, measured in peripheral blood or in adipose tissue, and mortality outcomes were at serious risk of bias, whereas studies reporting associations with prognostic factors ranged from serious to critical risk of bias.Among the 61 studies that examined associations between peripheral blood POPs and breast cancer risk, 30 reported a positive association with at least one POP, six reported a negative association with at least one POP, and 20 reported no association. Cohort-nested case-control studies with cumulative density (exclusive) sampling, population-based case-control studies not nested in a defined cohort and hospital-based case-control studies with both community- and hospital-controls were more likely to observe an association. Studies that included at least 80% of postmenopausal patients were more likely to observe an association whereas studies that included less than 80% of postmenopausal patients were more likely to observe no association. Studies that included at least 80% of invasive cancers and those with non-reported proportions of invasive breast cancers were more likely to observe an association. Studies with non-reported proportions of ER-positive breast cancers were more likely to observe an association whereas studies including less than 80% ER-positive breast cancers were slightly more likely to observe no association .Among the 26 studies that examined associations between breast adipose tissue POPs and breast cancer risk, 10 reported a positive association with at least one POP, two reported a negative association with at least one POP, and seven reported no association. Studies reporting the proportion of invasive breast cancers were slightly more likely to observe an association. Studies with non-reported proportions of ER-positive breast cancers were more likely to observe a positive association. The four studies of POPs in breast tumors did not report minimally adjusted estimates of risk .The two studies that examined associations between POPs in buttock adipose tissue and breast cancer risk reported negative associations .All three studies that examined peripheral blood POPs reported positive associations with both breast cancer all-cause and specific mortality, of which one study also reported a negative association with all-cause mortality . The onlAmong the three studies that examined peripheral blood POPs and breast cancer prognostic factors, one study reported a positive association with tumor size and lymph-node involvement. Among the six studies of breast adipose tissue POPs, three studies examined associations with meaningful breast cancer prognostic factors but none of them reported minimally adjusted estimates. The only study of buttock adipose tissue POPs and breast cancer prognostic factors did not report minimally adjusted estimates .One to 71 individual POPs were measured in studies of breast cancer risk (median = 9). Organochlorines were measured in 69 studies, of which 43 in blood, 21 in breast adipose tissue, two in adipose tissue other than breast and three in breast tumor. Polychlorinated biphenyls (PCBs) were measured in 57 studies, of which 38 were in blood, 16 in breast adipose tissue, one in adipose tissue other than breast and two in breast tumors. Dioxins were measured in four studies, of which two in blood and two in breast adipose tissue. Perfluoroalkyl substances (PFAS) were measured in three studies in blood. Bisphenol A (BPA) was measured in two studies in blood, polybrominated flame retardants (PBBs and PBDEs) in one study in blood and one study in breast adipose tissue whereas mono-ethyl phthalate (MEP) and parabens were measured in blood in one study respectively . One to 35 individual POPs were measured in studies of breast cancer prognosis (median = 25). Organochlorines were measured in five studies of breast cancer mortality, of which three were in blood, one in breast adipose tissue and two in adipose tissue other than breast, whereas six studies measured organochlorines in relation to prognostic factors, of which three were in blood, four in breast adipose tissue and one in adipose tissue other than breast. PCBs were measured in four studies of breast cancer mortality, of which three were in blood, one in breast adipose tissue and one in adipose tissue other than breast, whereas four studies measured PCBs in relation to prognostic factors, of which two in blood, four in breast adipose tissue and one in adipose tissue other than breast . ParabenThe magnitude of the reported associations between POPs and breast cancer risk and mortality are summarized in p,p’-Dichlorodiphenyldichloroethylene , total or not specified DDE, β- Hexachlorocyclohexane (β-HCH), Dieldrin, PCB 118, PCB 138, PCB 170, PCB 180. Three individual POPs were consistently positively associated with breast cancer risk in breast adipose tissue: p,p’-DDE, total or not specified DDE, PCB 105. When considering POPs positively associated with breast cancer risk in at least one study and no reported negative associations, six individual POPs were positively associated with breast cancer risk in both blood and breast adipose tissue: p,p’-DDE, total or not specified DDE, Hexachlorobenzene (HCB), β-HCH, PCB 118 and PCB 180 , Dieldrin, PCB 174, PCB 177. Total PCBs and three individual POPs were positively associated with breast cancer mortality in breast adipose tissue: PCB 118, PCB 153, PCB 167  and when non-collapsible effect measures such as odds ratios are used . The biaThe strengths of the present systematic review include the use of the Cochrane Reviews rigorous methodology, the extensive and highly sensitive search strategy to retrieve as many relevant studies as possible, the use of a pre-established protocol, the assessment of the risk of bias, and the systematic analysis of results, in addition to considering sources of heterogeneity between studies results. Limitations include the lack of high-quality evidence inherent in observational study designs and the overall critical risk of bias in included studies. Finally, although the present systematic review has identified some individual POPs associated with both breast cancer risk and prognosis that deserve further investigation, it should be emphasized that different POPs have different metabolic profiles and can have synergistic or antagonistic effects, and that proportions of different POPs may vary from one person to another. Thus, approaches considering the simultaneous exposure to different POPs may be more relevant than the isolated analysis of individual POPs. Over the past three decades, numerous epidemiological studies have attempted to assess the association between exposure to POPs and breast cancer. Despite the apparent inconsistencies between studies, which were mainly due to methodological biases and to differences in the biological sample used for exposure measurement, when considering all studies  and all outcomes together (risk and prognosis), there was a trend toward a positive association between exposure to POPs and breast cancer that deserves further investigation. Future studies need to use rigorous methodology by including the relevant study population, using an appropriate biological sample for POPs measurement, controlling properly for confounding and assessing combined effects of POPs.


Skin damages are defined as one of most common lesions people suffer from, some of wounds are notoriously difficult to eradicate such as chronic wounds and deep burns. Existing wound therapies have been proved to be inadequate and far from satisfactory. The cutting-edge nanotechnology offers an unprecedented opportunity to revolutionize and invent new therapies or boost the effectiveness of current medical treatments. In particular, the nano-drug delivery systems anchor bioactive molecules to applied area, sustain the drug release and explicitly enhance the therapeutic efficacies of drugs, thus making a fine figure in field relevant to skin regeneration. This review summarized and discussed the current nano-drug delivery systems holding pivotal potential for wound healing and skin regeneration, with a special emphasis on liposomes, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, nanofibrous structures and nanohydrogel. Skin, the largest organ of human body, functions as a pivotal barrier featured with immunologic, sensorial and protective capability. Owing to its exposure to the external environment, skin is vulnerable to a variety of external factors which result in different types of skin damage and injury. It should be noticed that the prevalence of people suffering from chronic wounds has risen sharply in recent years, due to the dramatically increasing incidence of obesity and chronic diseases such as diabetes, venous and arterial insufficiency . It is eThanks to the innovative and impressive development of nanotechnology, numerous nano-drug delivery systems (nano-DDSs) were invented and introduced into the areas relevant to skin regeneration. It is universally testified that nano-DDSs evidently accelerate wound healing and improve the healing quality for the several prominent advantages they enjoy: (1) Nano-DDSs are found to be non-toxic, perfectly compatible with skin and favorably create a beneficial moist environment for activation and acceleration of wound healing process. (2) Some specific nano-DDSs are equipped with ability of entering into the cytoplasmic space across cellular barriers or activating specific transport mechanisms to improve the drug retention . (3) WheThis review mainly introduces the wound healing process, the current wound treatment and their limitations, and the state of the art in nano-DDSs that holds a promising potential for future application, with a special focus on liposomes, polymeric nanoparticles, lipid nanoparticles, nanofibrous structures and nanohydrogel.Wounds are defined as the breakage or disruption of skin caused by trauma or medical/physiological conditions. Under such circumstance, damage to skin anatomical structure and the loss of skin physiological functions occur frequently. The wounds generally fall into two categories: acute wounds often result from mechanical damage or exposure to extreme heat, irradiation, electrical shock or corrosive chemicals. Such wounds heal in a relatively short period of time if supported by appropriate wound management . ChronicAccording to wound depth, the wounds can be classified as three kinds: superficial wounds (only lose a part of epidermis), partial thickness wounds  and full thickness wounds (subcutaneous fat and deeper tissue are disrupted) .Wound healing is a complex and dynamic physiological process involves with various cells, mediators, extracellular matrix (ECM) components, growth factors, and proteinases . As showThe inflammatory phase often lasts 2 to 5 days after skin damage. When an injury occurs, the hemostasis is initiated immediately by intravascular platelets to form a clot and stop bleeding . FurtherThe proliferative phase generally takes 3 days to 2 weeks after injury, featured with cell proliferation and migration . FostereRe-epithelialization and remodeling phase varies from 3 weeks to 2 years post-injury. The collagen III in newly-synthesized ECM is gradually replaced by collagen I and the new born collagen fibers evolve into a more organized lattice structure, augmenting tensile strength of healed skin , 25. RemThe ultimate goal of the wound management is to prevent serious infection, accelerate wound healing and reduced scars and pain for patients. Currently, a set of strategies are available for wound management mainly including debridement, autografts and application of therapeutic agents. In addition, some burgeoning new therapies such as stem cell therapy, gene therapy, photothermal and photodynamic therapy, are playing an increasingly vital role in some complicated wound treatment.Conventional debridement removes the necrotic or infected tissue that may prolong the inflammatory phase and impede wound contraction as well as re-epithelialization, fostering a better wound bed for healing process . DebrideThe use of autografts and allografts remains the gold standard for skin regeneration. Autografts and allografts approaches mainly harvest full-thickness fascia from a donor site of patients or other donators and graft it over the target region . AutograApplication of topical drugs, which mainly focuses on promoting healing process and preventing infection, still plays an indispensable role in treatment for all types of wounds. Hence, a large demand still exists in exploring novel therapeutic agents for topical wound therapy. Topical therapeutic agents consist of growth factors and antimicrobial agents being crucial for the wound treatment and skin regeneration. Growth factors are biologically active polypeptides which regulate cell growth, differentiation, and migration and exert an impact on all stage of wound healing. It has been confirmed in some clinical researches, growth factors exert amazing effects on wound healing promotion and skin function restoration without any obvious side effects. The clinical used growth factors are listed in Table Owing to infection being a leading cause of mortality and horribly delaying the wound healing, antimicrobial agents are generally administrated both topically and systemically. The choice of antimicrobial agents strongly depends on the microbiological analysis for species and susceptibility of microorganisms. The most commonly used antimicrobial agents are listed in Table Nano-DDSs hold immense potential in enhancement of drug therapeutic efficacy for their capability of preventing drug degradation and sustaining drug release. Numerous nano-DDSs carrying therapeutic agents are springing up unprecedentedly and adopted in promoting wound healing and skin regeneration, mainly including liposomes, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, nanofibrous structures and nanohydrogel –38 Fig.. Recent Liposomes are bilayer vesicles built by amphiphilic molecules such as phospholipids, emerging as one of promising nano-carriers for topical drug delivery . They arPresented as a new generation of liposomes, deformable liposomes, also called transfersomes, mainly consist of phospholipids and an edge activator  , bringinNevertheless, liposomes also exhibit some demerits in application: drug leakage in liposomes sometimes can be unavoidable and rapid , 51; thePolymeric nanoparticles are biocompatible colloidal systems drawing increasing attention in both biomedicine and bioengineering fields . When emEscherichia coli and induced promoted cell migration while lifting no effect on proliferation of keratinocytes. In full thickness excisional wound model, PLGA-LL37 NP-treated group exhibited advanced granulation tissue formation, characterized by significant higher collagen deposition, re-epithelialized composition and neovascularization. Furthermore, it improved angiogenesis and modulated the inflammatory wound response by up-regulation of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Dave et al. [Staphylococcus aureus and Pseudomonas aeruginosa. Therefore, it was considered to hold a broad prospect in treating burn-induced infections.Many researches focus on developing polymeric nanoparticles encapsulating antimicrobial agents. Chereddy et al.  reportede et al.  preparedTo reduce high cytotoxicity of Amphotericin B and improve the patient appliance, Sanchez et al.  incorporPerformance of nanoparticles also exceeds expectation in gene therapy related to skin regeneration. To overcome the setbacks of insufficient expression of angiogenic factors and low cell viability after transplantation, biodegradable nanoparticles were developed to deliver hVEGF gene to human mesenchymal stem cells and human embryonic stem cell-derived cells . hVEGF pInorganic nanoparticles refer to nanoparticles deprived from inorganic materials, including the metallic nanoparticles, carbon based nanoparticles, ceramic nanoparticles etc. . BenefitJun et al.  investig2 nanoparticles by co-precipitation method. This kind of nanoparticles is an efficient inorganic material with antibacterial properties. ZnO2 nanoparticles had good antibacterial activity for pseudomonas aeruginosa and aspergillus isolated from wound infected tissues of burn patients. The results of histopathological evaluation confirmed that ZnO2 nanoparticles could accelerate the healing of skin wounds in animal models in vivo.Ali et al.  designed2O3) nanoparticle were fabricated and its therapeutic effect were evaluated via application on an incisional wound model [Thrombin is a widely used drug for topical hemostasis and wound healing. With the aim of overcoming the weak stability of drug, a thrombin-bounded maghemite  [Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were representatives of lipid nanoparticles introduced to overcome the limitation of liposomes. Lipid nanoparticles were generally prepared with physiological lipids or lipid molecules and their preparation process requires no involvement of any potentially toxic organic solvents . Their nRimpler) .Gainza et al.  reportedS. aureus and E. coli compared with the group treated with LL37 or A1 alone.Fumakia et al.  fabricatIn another related study, andrographolide-loaded lipid nanoparticles were developed, optimized, then successfully incorporated into a chitosan-HA scaffold . This scNanofibers are fabricated from natural and synthetic continuous polymer chains which are able to subsequently act as nanofibrous sheets or 3D-scaffolds applied in tissue engineering , 76. TheAdeli-Sardou et al.  electrosCombined with stem cell therapy, Ramasatyaveni et al.  attached2 hydrosol was designed for better skin repair. The results of physicochemical properties revealed the good permeability and stability, which offer a humid environment for wound healing and met the requirement of wound coverage protection. Due to the embedment of nano-TiO2, the scaffold strongly inhibited the growth of Staphylococcus aureus and induced red blood cell aggregation to stop bleeding. In another study, magnetic iron oxide nanoparticles were incorporated into three-dimensional fibrous scaffolds to form a novel formulation and its physicochemical properties and cell biocompatibility in vitro were investigated [In some cases, nanofibrous structures were simultaneously integrated with other nano-formulations to achieve a synergic impressive effect on skin regeneration. Zulkifli et al.  fabricatstigated . It turnNanohydrogel is the three-dimensional polymeric networks considered as ideal formulation for wound management: the porous three-dimensional structure endows it with the ability of aqueous fluid absorption , preventA gellan-cholesterol nanohydrogel embedding baicalin was introduced to speed up wound healing process . CharactBesides, the versatile administration of nanohydrogel has received considerable interest, with the special focus on injectable nanohydrogel. Giriraj et al.  reportedThe treatment of chronic wounds or ulcers remains a thorny and daunting challenge because current therapies mostly failed to provide favorable outcomes of wound healing. Nevertheless, the progressive expansion of nano-DDSs in recent years has brought new insight for skin regeneration of wounds: these drug carriers prolong drug release, protect drug from degradation and improve skin retention, so as to realize augment of the therapeutic power of biological and synthetic molecules . Moreover, various combinations of nano-DDSs are served as synergistic platforms for delivery, some of which even mimic and offer perfect physiological environment for the healing process. Despite the enormous potential of nano-DDSs, these systems also have exposed some limitations in researches such as lack of international standards and evaluation methods on their toxicology, biocompatibility and targeting efficiency, as well as the undeniable restriction of industrial production for their complicated preparation procedures. However, it is an inevitable and unstoppable trend for researchers to further exploit the full potential of nano-DDSs, overcome the technical difficulties and bring tangible benefits for the patients suffered from wounds, nano-DDSs are bound to constitute the most promising and cost-effective therapies to boost the wound healing and skin regeneration.


The notion that specific cognitive and emotional processes arise from functionally distinct brain regions has lately shifted toward a connectivity-based approach that emphasizes the role of network-mediated integration across regions. The clinical neurosciences have likewise shifted from a predominantly lesion-based approach to a connectomic paradigm—framing disorders as diverse as stroke, schizophrenia (SCZ), and dementia as “dysconnection syndromes”. Here we position bipolar disorder (BD) within this paradigm. We first summarise the disruptions in structural, functional and effective connectivity that have been documented in BD. Not surprisingly, these disturbances show a preferential impact on circuits that support emotional processes, cognitive control and executive functions. Those at high risk (HR) for BD also show patterns of connectivity that differ from both matched control populations and those with BD, and which may thus speak to neurobiological markers of both risk and resilience. We highlight research fields that aim to link brain network disturbances to the phenotype of BD, including the study of large-scale brain dynamics, the principles of network stability and control, and the study of interoception . Together, these findings suggest that the affective dysregulation of BD arises from dynamic instabilities in interoceptive circuits which subsequently impact on fear circuitry and cognitive control systems. We describe the resulting disturbance as a “psychosis of interoception”. Bipolar disorder (BD) is a relatively common disorder with a substantial illness burden and high risk of suicide , 2. The Fluctuations in mood, affect, and motivation are a cornerstone of human experience, allowing us to anticipate and adjust our social interactions according to context . In BD, Classic theories of brain function focus upon cognitive and emotional function in segregated, functionally specialized regions . The notIn this paper, we view BD through the prism of connectomics. We first review the basic definitions of brain connectivity theory and their application to neuroimaging data. We then highlight the body of work on structural, functional and effective connectivity disturbances in BD and high risk (HR) cohorts. We finally discuss recent developments in connectomics and computational neuroscience more broadly: we use this body of work to propose that BD reflects a loss of stability in large-scale brain network dynamics, and more specifically, those which subserve physiological homeostasis and interoception .Connectomics rests upon a branch of mathematics known as graph theory whereby complex systems are represented as networks of elements (nodes) and their interactions (edges) . Since tThe notion of a brain “node”, as a functionally and structurally distinct and homogenous entity depends upon clustering contiguous neural tissue into discrete parcels , 47. TheMany biological networks, including the human connectome, contain highly-connected hubs  further support the presence of disturbances in prefrontal, limbic and subcortical areas in BD . For exaa priori selection as a region of interest), reduced functional connectivity in BD has also been observed to involve other regions—between the IFG and the ACC  and mean diffusivity (MD), or by applying tractographic techniques to reconstruct whole-brain structural networks and then subjecting these to graph theoretical analyses Fig. . Of the Substantial “DTI-based” research has thus contributed to the notion of structural dysconnectivity amongst limbic and prefrontal regions in BD . HoweverRather than focusing on local white matter properties, tractography performed upon dMRI data allows examination of large-scale brain networks, with the “connectivity” of these networks typically corresponding to the streamline density. Mirroring the morphological disturbances in the corpus callosum, analyses of tractography also supports a disturbance to the integration of inter-hemispheric structural connectivity Fig.  100, 1001. The aAs with functional connectivity, graph metrics can also be applied to tractography both at the whole-brain  and nodal-level (to examine the network environment of specific brain regions). Such an approach has revealed local structural network changes largely in prefrontal and limbic areas, namely, the hippocampus, IFG, anterior insula (AI) and superior frontal gyrus , 141. ThApplication of graph-theoretical tools to whole-brain networks has yielded a more nuanced picture: slight decreases in network integration have been observed in BD   which usWhile few in number, these studies of effective connectivity are important steps toward identifying the neural mechanisms of phenotype and treatment response in cognitive and emotional networks in BD. They demonstrate, for example, that interactions amongst key brain regions  are indeed disturbed during the perception of facial affect.Several limitations beset studies of BD: the confounding effect of different classes of medication , comorbidity, and the possible secondary effects of illness expression. Waiting for the expression of a manic episode to confer the diagnosis also misses the opportunity to mitigate the secondary harm  if the illness could be averted. Addressing these important issues can be achieved through the study of unaffected HR cohorts. BD has a strong familial association and hence offers the potential for disambiguating risk endophenotypes –157 and A recent study of structural connectivity compared a young HR cohort  to matched control and BD cohorts . ApplicaOlder HR individuals, who have passed the peak age for BD onset, also represent a unique study population. Whereas young HR groups are a mix of risk and resilience, older HR cohorts more likely express neurobiological patterns that reflect resilience , 23. A sThe majority of structural connectivity studies in BD and HR cohorts have been derived from streamline-based approaches. As with the earlier use of FA, the extent to which streamline counts correspond with the intra-axonal “fibre density” is debatable. Recent streamline-filtering approaches provide more biologically accurate measurements , but reqAs with structural connectivity in BD and HR cohorts, the large-scale network topology of resting-state functional connectivity in HR cohorts also appears to be largely conserved , 129.Reported disturbances are again confined to specific subsystems of the brain: increased functional integration (i.e. increased participation index) has been observed within default-mode regions in an older HR cohort (mean age 32) but not matched control or BD individuals . In the Task-related functional connectivity has been probed in HR cohorts using psychophysiological interactions (PPI) , a methoResting-state functional connectivity can also be used to examine whether task-related effects persist beyond the context in which they were observed. In this vein, the left ventromedial IFG, whose engagement in an emotional ‘go-nogo’ task was reduced in young HR individuals (average age 23 years) , also shThe left IFG, particularly the ventro-lateral and ventro-medial portions, have thus been implicated in task-related hypo-activation as well as reduced functional and structural connectivity in both young and older HR individuals Figs. a–c, 3c. A DCM study of effective connectivity in an older HR cohort  reported significantly increased effective connectivity between the inferior occipital cortex and the fusiform gyrus during perception of emotionally salient faces . This inHence, there are patterns of structural, functional and effective connectivity that are unique to HR cohorts when compared to BD, as well as shared patterns. Disturbances of the connectivity and functional involvement of IFG in broader prefrontal-limbic circuitry appear to be more prominent in those at risk than those with the disorder. Functional under-activation of the IFG and the surrounding VLPFC during emotional and cognitive control are common to both HR and BD populations, as are distributed disturbances such as in somatosensory and higher visual cortex.Integrating the connectomic findings in HR individuals is challenging, given the small number of studies that exist and their cross-sectional nature. In addition, these studies have been conducted on HR individuals at different developmental stages of risk for BD. As we argued above, young HR individuals are at a critical cognitive and affective developmental period. Disturbances to the IFG and its affective and cognitive connectivity in young HR cohorts may reflect an endogenous risk that changes upon illness expression in those whom convert to BD. Alternatively, unique differences in older HR individuals may also represent early compensatory responses that confer resilience , 169 in In sum, viewing BD through the lens of connectomics positions earlier studies of functionally localised disturbances into broader circuit and network mechanisms that integrate cognitive control, affective and reward-systems of the brain. Some connectivity disturbances are common to both BD and HR groups; these speak to a shared risk of affective dysregulation. Other connectivity disturbances are unique to BD, reflecting illness expression and possible medication effects. Several changes are unique to HR cohorts: in the younger of these, unique effects may reflect a mix of risk and resilience, whereas resilience may figure more highly in older HR groups. When interpreting these effects, however, it should be recalled that the actual inherited risk of a first-degree relative is far from uniform and varies sporadically and with the severity of the affected relative (e.g. a higher risk is associated with an early age of onset of BD). Thus, unaffected older first-degree relatives may have a lighter genetic load, as reflected in the absence of structural connectivity differences  or a strThe first expression of BD typically occurs during the final neurodevelopmental stages of brain development and co-occurs with fundamental changes in inter-personal functioning, role, and self-identity . LongituAlthough the potential utility of brain network analyses to identify future psychosis  in high-Longitudinal studies which integrate imaging assays with genetic risk variants for BD may also help disentangle aetiological mechanisms. Patient carriers of genetic risk variants for BD (CACNA1C and ANK3) show abnormal effective connectivity in facial processing networks . PotentiSeveral clear observations emerge from the growing body of BD connectomics research. The over-arching picture is that, compared to the pernicious “small world” and rich-club effects in SCZ, disturbances in BD and HR populations appear to be confined to specific fronto-limbic subsystems, most notably those associated with the perception and regulation of emotionally salient material. Whereas large consortia investigations have revealed that all major white-matter bundles are impacted to some extent in SCZ , 188, thAs noted above, these connectivity differences reflect the over-arching distinction of the phenotypes: the bivalent and episodic nature of BD contrasts with the core and enduring perceptual and cognitive deficits that characterise SCZ. Hence, even though the networks of structural, functional and effective dysconnectivity in BD do “hang off” important brain hubs such as the AI, IFG, DLPFC and ACC, the connectivity amongst other distributed core-regions remains relatively preserved. However, the degree of disturbance in those networks that are affected in BD is quite substantial. That is, the disorders may differ in their core topological reach, but not in the depth of the perturbation on the networks where they do impact.Unfortunately, most prior connectomic studies of BD and SCZ patient groups are typically careful to exclude each other, clinical practise suggests a less distinct continuum of phenotypes that reflects the shared genetic architecture . Given tOn the topic of differential diagnoses, the need to detect BD during its initial depressive episodes is crucial to early and targeted interventions. The potential utility of neuroimaging markers to differentiate bipolar from unipolar depression has been highlighted by the few connectomic studies that include both BD and unipolar (UD) depression cohorts , 191. DiIn addition to multi-disorder studies, successful clinical translation rests upon replication in large, independent studies . This apComputational models of brain activity suggest that the structural connectome forms a scaffold that shapes complex, multiscale neuronal dynamics , 199–202The emergence of computational psychiatry approaches  has shifDynamics lie at the heart of BD: On short time scales, fluctuations in arousal and motivation are a core aspect of everyday life . When apWhat network mechanisms might cause this? Insights could derive from the application of network control theory, that is, quantifying how inputs to individual nodes or subnetworks potentially change the state of the whole network , 229. ThCurrently, such applications are grounded in linear network control theory. While linear approximations may be sufficient to capture state-to-state transitions, future developments in the more elusive nonlinear network control theory may reconcile this approach with the richer dynamics present in empirical data , 234.It finally remains to be seen how and why the networks implicated in BD play a role in the (dys)regulation of mood. For this purpose, we highlight recent developments in computational psychiatry that reconcile a ‘William Jamesian’ mapping between physiological states and emotion with predictive coding accounts of perception and inference , 236.Emerging frameworks of emotional experience and psychopathology have repositioned brain function in light of its interactions with internal body systems , 235. ThFollowing Bayesian ideas, contemporary models of active perception rest upon hierarchical representations of sensory signals encoded as prediction signals in agranular cortices, namely the AI, ACC, subgenual cortex (SGC), and also the orbitofrontal cortex Fig.  11, 239239–242. We conclude by considering how this framework can be used to integrate the various connectomic disturbances in BD and HR cohorts. To this end, it is notable that the agranular cortices proposed to embed interoceptive predictions comprise the prefrontal and limbic areas , 246 repUnder predictive coding accounts, the psychotic features in SCZ are framed as disturbances to hierarchical inference in exteroception : symptomThe disturbed subnetworks in BD suggest broad patterns of network dysfunction involving all levels of the interoceptive hierarchy: the symptomatic expression of BD may reflect fronto-limbic dysfunction, that has figured prominently in this review, and which leads to unstable and maladaptive internal representations of the social world. Given the aberrant precision or weighting afforded towards incoming interoceptive signals, features of the external milieu may be consequently perceived in BD patients as increasingly salient, rewarding or threatening , 255. DiIn closing, we propose BD as a type of “psychosis of interoception”, with unstable neuronal dynamics in corresponding hierarchical systems. The ensuing dysregulation yields the fluctuations in mood at the core of the disorder. The traditional fear circuitry, that include regions such as the amygdala, may not be a primary target of the disorder, but may be maladaptively recruited as a result of misperceptions of threat. This proposed model of abnormal interoceptive inference accommodates the larger-scale patterns of network dysfunction reviewed in this manuscript, and suggests the need for future imaging studies that integrate appropriate emotionally salient tasks with concurrent physiological recordings.


CYP19, have also provided critical insight into how aromatase affects brain function in a possible sex-dependent manner. A better understanding of how AIs, used to treat breast cancer and other clinical conditions, may detrimentally affect neurobehavioral responses will likely promote development of future therapies to combat these effects. Herein, we will provide a critical review of the current knowledge of sex differences in aromatase regulation of various neurobehavioral functions. Although many species have been used to better understand the functions of aromatase, this review focuses on rodent models and humans. Critical gaps in our present understanding of this area will be considered, and important future research directions will be discussed.Aromatase is the enzyme responsible for converting testosterone to estradiol. In mammals, aromatase is expressed in the testes, ovaries, brain, and other tissues. While estrogen is traditionally associated with reproduction and sexual behavior in females, our current understanding broadens this perspective to include such biological functions as metabolism and cognition. It is now well-recognized that aromatase plays a vital lifetime role in brain development and neurobehavioral function in both sexes. Thus, ongoing investigations seek to highlight potentially vital sex differences in the role of aromatase, particularly regarding its centrally mediated effects. To characterize the role of aromatase in mediating such functions, effects of aromatase inhibitor (AI) treatments on humans and animal models have been determined. Aromatase knockout (ArKO) mice that systemically lack the enzyme have also been employed. Humans possessing mutations in the gene encoding aromatase,  Cyp19/CYP19 gene) is the rate-limiting enzyme responsible for the unidirectional conversion of androgens to estrogen (E2) in gonadal and extra-gonadal tissues (Aromatase (encoded by the  tissues . It is r tissues . In mammCyp19) and pharmacologic  means. However, species comparisons of aromatase function pose problems due to sometimes stark inter-species differences. For example, rodent species exhibit short gestational period and tend to be polygynous, whereas, humans have long pregnancy duration and most societies are monogamous and biparental; this makes investigation of the precise role of aromatase during gestation difficult. Even so, early post-natal brain development in rodents resembles the critical window for human fetal brain development that occurs during the third trimester  mice (bred on the C57Bl6 background) have been developed that constitutively lack aromatase activity throughout all stages of development. This has been a useful animal model to discern the role of aromatase in physiology and behavior of both sexes . There aPharmacologically, AI  can be administered to down-regulate aromatase activity. AI are primarily used as adjuvant hormone therapy in pre- and post-menopausal women with breast cancer and in less frequent cases of male metastatic breast cancer but are also employed in the treatment of other hormonal conditions . In boysCYP19/Cyp19 is widely expressed in the central nervous system (CNS) of both sexes, as well as in different neuronal cell types, with levels of mRNA expression being greatest in regions associated with sexual differentiation and corresponding closely with expression of E2 receptor alpha (ESR1) and beta (ESR2), as well as androgen receptors (AR)  . PredomiCyp19 expression in rodent brains and varies by region. Cyp19 gene expression in the amygdala, bed nucleus of stria terminalis (BNST), and pre-optic area, while no sex differences were observed in the dorsal hippocampus and cingulate cortex  have higher aromatase activity in specific micro-dissected sub-regions of the hypothalamus and amygdala compared to females, while other subsections displayed no sex differences , but that study did not investigate sex differences in aromatase expression in those two brain regions , castration decreases aromatase expression in the hypothalamus but not in the amygdala  were gonadectomized at 98–103 days gestation and were surgically removed from the uterus at 120 days of gestation , aromatase may also affect brain regions not typically associated with sexual differentiation, such as the hippocampus, cortex, and amygdala. These areas also must be programmed at critical windows of time. For instance, in sheep which typically have a 147–150 day gestation period, the brain is sculpted between 60 and 90 gestational days; whereas in non-human primates with a 165 gestational period, this occurs at 40–60 gestational days . These eestation . In the estation . Convers females . This stCyp19 mRNA expression in the BNST and hypothalamus during the peripubertal phase (PND 20–60)  . In sheeD 20–60) . Taken tSociosexual behaviors such as lordosis, mounting, and preference for non-volatile pheromones  assists in mate selection and reproduction in several mammalian species. These behaviors may be regulated by aromatase. In rodents, olfaction detection and perception are considered socio-cognitive behaviors in that odor recognition of same and different sex individuals guides subsequent socio-behavioral responses, i.e., fighting or mating behaviors. Two olfactory systems exist in rodents and likely mediate diverging purposes . The maiWhen examined separately, Kiss1) and kisspeptin neuronal activity were reduced in both ArKO males and females, seemingly contradicting the previous findings by In a separate but supporting study using the same mouse model, However, further examination of the GnRH/LH system by Pharmacological manipulation of aromatase has also been utilized to examine the effects of the removal of E2 during gestation on later adult sexual behaviors. Cyp19 expression in the olfactory bulbs of 21-day old female rat pups whose mothers were fed a methyl-donor deficient diet throughout gestation  that are monogamous and demonstrate biparental care. Conflicting parenting results have been obtained in prairie voles treated with AI, which are likely due to when the animals were exposed to the pharmaceutical agent. Female virgin prairie voles normally exhibit infanticidal behavior when exposed to pups, while virgin males exhibit normal parental behaviors  subjected to prenatal ATD exposure had decreased mounting activity but comparable responses were not observed in males subjected to similar AI exposure  or vehicle control . ATD-treexposure . Howeverexposure . Howeverexposure .Taken together, the above data provide mixed results as to the role of an early prenatal aromatase surge in guiding later sociosexual behaviors. The results are muddled by the fact that different AI and doses have been tested, variation in developmental exposure periods, and specific tests used to measure sociosexual behaviors. Moreover, the studies have used different animal models that demonstrate divergent reproductive strategies (polygynous vs. monogamous) that assuredly will influence the outcome. The ideal experiment should test the same AI dose at the same gestational period in rodent models displaying these two types of mating systems.Anxiety and depression are two of the most widely diagnosed mental illnesses today with women being more likely to be diagnosed than men . While aUsing the ArKO mouse model, Cyp19 mRNA expression were detected , and 233 control men and women. Consistent findings between those polymorphisms and both AD and MCI cases were observed, and significant interactions between select polymorphisms and sex were also noted. Remarkably, all associations between CYP19 polymorphisms and AD were identified exclusively in women  in the hippocampus of intact AI-treated mice ; an electrophysiological parameter of memory, in the hippocampus of 12-week old female C57Bl/6 mice, while treated males of the same age only experienced a 20% reduction in LTP after 7 days . SurprisCYP19 gene expression, and aromatase activity  and a systemic absence of E2 (as occurs in the ArKO model) . App/Cypactivity .Possibly the most limited area of research on sex differences in aromatase is in its effects on physical/locomotor activity. It is known from many rodent studies that intact females are significantly more active than age-matched males  and precFew studies have examined the mechanisms by which aromatase affects physical activity directly, so much of the available evidence includes secondary measurements of locomotor activity as assessed in association with another major outcome . One experiment conducted in an attempt to understand the role of E2 in schizophrenia discovered that female and male ArKO mice experienced reduced psychotropic drug-induced hyperactivity in an OFT after administration of apomorphine, MK-801, and amphetamine while WT counterparts were unaffected, although this effect was not as pronounced in male ArKO mice . Thus, tper se on sex differences in physical activity requires more investigation. Better understanding the sex-specific effects of aromatase on physical activity  may lend insight into the mechanisms driving physical activity, as well as potential side effects of aromatase inhibition in humans. Our current studies seek to examine for potential sex-differences in motivated physical activity using an ArKO mouse model.In contrast, a separate study showed that aromatase inhibition administered via subcutaneous injection had no effect on locomotor activity of neither male nor female middle-aged rats (15 months) when tested in the EPM, which measures both anxiety-like and exploratory behavior . SimilarSex differences in recovery following brain injury and ischemia have been reported . Rodent How aromatase may contribute to recovery from traumatic brain injury or stroke may depend on the level of aromatase expression in that particular brain region, as well as the cell type , as discussed earlier. Since astrocytes following brain injury or ischemia become reactive, aromatase activity by these cells in particular may mediate neuronal recovery from injury  Indeed, Cyp19, P450scc , and StAR (regulates cholesterol transport in the mitochondria) expression in the cerebellum of male and female Wistar albino rats at several days of early development . In both males and females, peak Cyp19 expression occurred at PND5, with males exhibiting higher expression than females at all ages. In females, an increase in aromatase at PND10 was sequentially followed by an increase in P450scc and StAR  of humans, which has not been identified in these brain regions of other species (While rodent models have provided insight into the role of aromatase in the brain and sex differences, there are potential drawbacks, including differences in gestational period, which might limit translation to humans. Non-invasive methods to image the human brain will aide in our understanding the role aromatase in various brain regions and sex differences. One rapidly evolving method to image in a non-invasive manner the human brain -imaging . Structuromatase . For insal areas . As ment species . In combFuture research with enhanced transgenic and imaging technologies will continue to improve our understanding of the relationship between aromatase and neurobehavioral functions. Such methodologies will help unveil the role of this enzyme in normal cognitive aging, mental illness, neurodegenerative disease, and even traumatic brain injury, and whether those relationships are sex specific. A better understanding of how aromatase contributes to the etiology of such cognitive diseases may lead to improved treatment strategies in men and women.DS, VV-P, and CR researched the area, wrote the original manuscript, and reviewed the final manuscript. DS and CR helped prepare the figure.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.


BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor , and PD-1 or PD-L1 , anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors , as well as MEK 1/2, and WEE1 inhibitors . Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 ( BRCA1/2) deficient tumour cells to poly (ADP-ribose) polymerase PARP inhibition have been demonstrated in 2005. Poly (ADP-ribose) polymerase (PARP) inhibitors have ultimately changed the way that patients with BRCA-related ovarian cancer are treated .Combination trials with PARP inhibitors and chemotherapy are reported in BRCA mutations and HR deficiency status, and to facilitate patient stratification for combined therapy. It is also challenging evaluation of the risk of adverse events, specifically in the combination strategies. With this regard, optimization of the treatment dose in order to be maximized the overall risk-benefit profile of a given combination, would be based on dose escalation studies that can however be expensive. Finally, high cost of therapy remains target for improvement of PARP inhibitors, both as single agents and in combination with other drugs. If we manage to address these issues, PARP inhibitors would move into the forefront of ovarian cancer treatment.The path forward for PARP inhibitor treatment in ovarian cancer is multifaceted. More research is warranted in order to deepen our understanding of DNA repair mechanisms, cancer biology, and targeted therapies. Resistance to PARP inhibitors also need to be further explored. Tumour biopsies on disease progression would be critical for the identification of mechanisms of drug resistance. Therapeutically, combinations of PARP inhibitors with drugs that inhibit HR might be an effective approach to sensitize ovarian cancers with de novo or acquired HR proficiency to PARP inhibitors. However, further studies are required in order to better define predictive biomarkers beyond


Cell death has a vital role in embryonic development and organismal homeostasis. Biochemical, pharmacological, behavioral, and electrophysiological evidences support the idea that dysregulation of cell death programs are involved in neuropathological conditions like epilepsy. The brain is particularly vulnerable to oxidative damage due to higher oxygen consumption and lower endogenous antioxidant defense than other bodily organ. Thus, in this review, we focused on the comprehensive summarization of evidence for redox-associated cell death pathways including apoptosis, autophagy, necroptosis, and pyroptosis in epilepsy and the oxidative stress-related signaling in this process. We specially proposed that the molecular crosstalk of various redox-linked neuronal cell death modalities might occur in seizure onset and/or epileptic conditions according to the published data. Additionally, abundance of polyunsaturated fatty acids in neuronal membrane makes the brain susceptible to lipid peroxidation. This presumption was then formalized in the proposal that ferroptosis, a novel type of lipid reactive oxygen species (ROS)-dependent regulatory cell death, is likely to be a critical mechanism for the emergence of epileptic phenotype. Targeting ferroptosis process or combination treatment with multiple cell death pathway inhibitors may shed new light on the therapy of epilepsy. Cell death is a biological process that is essential for embryonic development and tissue homeostasis. Fine tuning of cell death in neurons is especially important due to the limited self-renewal capacity in adult neurons. Aberrant neuronal death is involved in multiple human diseases including epilepsy. The role of neuronal death mechanisms in epilepsy has been debated for decades. Despite the possibility that isolated brief seizure may not induce cell death, severe and repetitive seizures can undoubtedly activate neuronal death process . And sei2+ level in mitochondria, resulting in ROS overproduction  in the extrinsic pathway of apoptosis causes lipid raft formation and Nox activation and ROS production  significantly protects neurons against seizure-induced hippocampal damage   . It suggnophagy) . Taken tnophagy) . And thenophagy) . Taken tEpilepsy is a highly complex neurological disorder, which is often accompanied with two features, namely, neuronal excitotoxicity and gliosis. On the one hand, neuronal hyperexcitation triggers ROS overproduction via enhancing calcium entry, finally leading to neuronal death. Neuronal ROS can also be transferred via neuron-glial gap junction, subsequently triggering neuroinflammation in glial cells (gliosis). On the other hand, following redox-related cell death, especially necroptosis, pyroptosis, and ferroptosis in neurons, the pro-inflammatory DAMPs are often released by the necrotic neurons and cause inflammatory responses in glial cells (gliosis). These two aspects both have an emphasis on the central roles of ROS and neuronal death mechanism in the development of epilepsy. Besides, we also give a proposal that ferroptosis, a recently identified regulated cell death mode, is involved in the etiology of epilepsy as we summarize the ferroptotic signs during epileptogenesis in X-YM and W-LJ designed the manuscript. X-YM wrote the manuscript. W-LJ and H-HZ revised 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.


Fall prevention programs towards older adults are beneficial, however, drop-out rate among older adults in short-term fall prevention programs are relatively high (one out of three). With older adults dropping out, the programs benefit less for their target populations and achieve a lower level of cost-effectiveness as reported to funders. Literature review has revealed that previous studies on attrition frequently focus on longitudinal research, leaving the factors causing older adults to quit short-term  fall prevention programs understudied. This study aimed to explore the association between demographic factors, educational level, health status, fall history, and the completion of the short-term fall prevention program named A Matter of Balance. A total of 691 older adults  65 and older participated in the program were included and a Descriptive Discrimination Analysis (DDA) was conducted to analyze the multivariate relationship stated above. The results have identified that fall frequency, educational level, fear of falls, health status, perceived limitations due to fall, injury cases resulted from falls, and having arthritis are the most statistically significant factors that are associated with the completions among older adults for the short-term fall prevention program. The implications of this study include suggestions to modify future recruitment eligibilities in order to include the most suitable participants in certain programs, as well as adaptive modifications for short-term fall prevention programs that aim to serve larger aging populations with individualized conditions. Networking of evidence-based research outcomes should be shared for increased success of future programs.


Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is a form of cell-based therapy, which replaces the HSC in the patient's bone marrow but also serves as a T-cell therapy due to the Graft-vs.-leukemia (GVL) effect mediated by donor T cells transferred with the graft. Allogeneic HSCT provides one potentially curative option to patients with relapsed or refractory leukemia but Graft-vs.-Host-Disease (GVHD) is the main cause of non-relapse mortality and limits the therapeutic benefit of allogeneic HSCT. Metabolism is a common cellular feature and has a key role in the differentiation and function of T cells during the immune response. Naïve T cells and memory T cells that mediate GVHD and GVL, respectively, utilize distinct metabolic programs to obtain their immunological and functional specification. Thus, metabolic targets that mediate immunosuppression might differentially affect the functional program of GVHD-mediating or GVL-mediating T cells. Components of the innate immune system that are indispensable for the activation of alloreactive T cells are also subjected to metabolism-dependent regulation. Metabolic alterations have also been implicated in the resistance to chemotherapy and survival of malignant cells such as leukemia and lymphoma, which are targeted by GVL-mediating T cells. Development of novel approaches to inhibit the activation of GVHD-specific naïve T cell but maintain the function of GVL-specific memory T cells will have a major impact on the therapeutic benefit of HSCT. Here, we will highlight the importance of metabolism on the function of GVHD-inducing and GVL-inducing alloreactive T cells as well as on antigen presenting cells (APC), which are required for presentation of host antigens. We will also analyze the metabolic alterations involved in the leukemogenesis which could differentiate leukemia initiating cells from normal HSC, providing potential therapeutic opportunities. Finally, we will discuss the immuno-metabolic effects of key drugs that might be repurposed for metabolic management of GVHD without compromising GVL.Utilization of the adaptive immune system against malignancies, both by immune-based therapies to activate T cells  Quiescent immune cells use glucose, amino acids, and lipids to meet their bioenergetic demands. ATP, the key energy-transporting molecule, is generated in every cell during the breakdown of such nutrients by glycolysis and OXPHOS. Depending on the functional demands, cell metabolism can be shifted toward anabolic reactions leading to production of molecules involved in biosynthesis necessary for cell growth, or toward catabolic reactions leading to breakdown of macromolecules and the generation of byproducts, which are subsequently used for energy generation or for construction of anabolic pathways. A balance of these anabolic and catabolic processes is mandatory for maintenance of metabolism homeostasis .2 which are required for the donation of electrons to the electron-transport chain for OXPHOS.Glucose is the most abundant extracellular nutrient and, although ATP production during glucose catabolism by glycolysis is significantly lower compared to the ATP generated by OXPHOS reactions, it is faster and more efficient in increasing cellular ATP than mitochondrial metabolism. Glycolysis also supports cell growth because glycolytic intermediates provide a bridge to multiple biosynthetic pathways, including PPP that has an important role in building blocks necessary for nucleotide biosynthesis, rapid generation of metabolic intermediates, and cell growth , 3. AddiRapidly proliferating malignant cells preferentially use glucose to sustain their rapid growth in the hazardous TME . The preMetabolic aberration provides a key signature that differentiates malignant hematopoietic cells from normally differentiating hematopoietic progenitors that give rise to committed progenitors and mature myeloid cells . As in oMEM subsets have been found to sustain GVL function , while the metabolic phenotype of M2 macrophages parallels that of memory-like T cells (such as those inducing GVL). Thus, concomitant metabolic reprogramming of APCs and T cells will have an important role in the net outcome of GVHD and GVL and these outcomes might vary dependent on the metabolic polarization of one or both these immune populations. For instance, the preferential engagement of APCs and T cells in glycolytic metabolism will allow immune cells to sustain inflammatory GVHD-mediating functions by promoting the generation of GVHD-inducing M1 macrophages and effector-like T cells. Conversely, the metabolic shift of these cell populations toward oxidative phosphorylation might selectively promote the differentiation of GVL-inducing memory-like T cells while supporting M2 differentiation and resolution of inflammation thereby preventing or suppressing GVHD. Indeed, inhibition of FAO by etomoxir suppressed M2 polarization of macrophages  and TMEMt manner . It shouin vivo and attenuates GVHD in HSCT recipient mice (+ effector T cells are unable to expand and induce GVHD in vivo, while, in this context, Treg population increases, showing independence from Glut1 (EFF cells but enhanced the differentiation of CD8+ TMEM cells (MEM cell production and supported their survival (The central goal of post-transplant therapeutic immunomodulation is the prevention or treatment of GVHD, without diminishing GVL activity. As outlined in the previous sections, the distinct metabolic pathways in these processes point to potential new therapeutic targets. Although FAO and glutamine metabolism might have a role in the activation of GVHD-inducing alloreactive T cells, elegant work has provided evidence that glycolysis is the dominant metabolic pathway of alloactivated donor T cells and inhibition of glycolysis by targeting HK-2 or the rate-limiting PFKFB3 prevents alloreactivity ent mice . Blockinent mice . Thus, tom Glut1 . NotablyEM cells . Similarsurvival . Such moEFF, TMEM, and Treg cells. Inhibition of PI3K/AKT/mTOR with BEZ235, a dual PI3K/mTOR inhibitor, resulted in decreased T cell activation and diminished GVHD grade (MEM cell differentiation (MEM and Treg. Thus, rapamycin might be repurposed and used not simply as an immunosuppressant but also as an immunomodulator to alter metabolism-driven differentiation of T cell subsets in recipients of alloHSCT.Targeting PI3K/AKT/mTOR pathway has been explored in the context of alloHSCT, because this pathway is central to the activation, expansion and differentiation of THD grade . Importantiation . Becausentiation , such apin vitro, suggesting a Cpt1a-independent action (Utilization of mitochondrial F1F0-ATPase inhibitor, Bz-423, promotes apoptosis of alloactivated cells, thereby reducing GVHD rates and improving survival without impairing immune reconstitution . The Cptt action . Such Cpt action . Thus, tt action .Together, the results of targeting studies in various mouse models , 115–117EFF cells, which are mandatory for their function under conditions of stress and response to pathogens. Future work is required to identify and dissect the potential metabolic differences of pathogen-specific vs. host antigen-specific T cells that induce GVHD. Identifying pathways that dominate in each of these populations during their lifespan will allow the development of experimental approaches and clinical trials to implement and evaluate metabolic interventions in these distinct TEFF cell populations in parallel to studies dissecting the effects of such approaches on GVHD vs. GVL.A major challenge when targeting metabolism for therapy of GVHD, will be to preserve the metabolic properties of pathogen-specific TEFF cells are expected to suppress or eradicate leukemia cells, it is possible that the high degree of plasticity and metabolic adaptation of LSC may provide them the means to survive by shifting their metabolic preferences. Identifying LSC dominant pathways upfront and modulating them by metabolism-targeting interventions, together with chemotherapy, will be highly beneficial because will eradicate LSC, thereby minimizing the risk for relapse. It is particularly intriguing and hopeful to attempt achieving this objective, together with selective metabolism-driven differentiation of immune cell subsets, with the goal to minimize GVHD and enhance GVL after allogeneic HSCT.Metabolism is a rapidly growing subject in immunology and malignant hematology. LSC that survive under intensive chemotherapy are responsible for MRD and relapse. These LSC use both anabolic and catabolic pathways, depending on the environmental cues. Our knowledge regarding the metabolic features of leukemia cells in relapsed or resistant disease in patients who undergo allogeneic HSCT is limited because relevant studies are currently missing. Based on current data, relapsed or resistant leukemia cells display features of LSC, which are highly dependent on glycolysis, but also have the metabolic plasticity to adopt other metabolic programs for energy generation, including mitochondrial metabolism, FAO and autophagy. Thus, although therapeutic approaches to target glycolytic metabolism employed to suppress GVHD-mediating TNT-O: wrote the main body of the manuscript and prepared figures; TK: wrote several sections of the manuscript and provided relevant citations; H-TW: wrote sections of the manuscript and provided relevant citations; VB: supervised NT-O, TK, and H-TW and was responsible for the overall preparation of the manuscript. All authors read and approved the content 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.


Sleep is associated with all-cause mortality, cardiovascular disease, cognitive impairment, as well as daily social interactions and productivity. Studies often have focused on sleep duration only, lacking the ability to comprehensively understand the importance of age-related changes in varied facets of sleep health. Moreover, psychological and social factors that may be associated with sleep health in adulthood are still poorly understood. This symposium showcases contemporary endeavors towards understanding how diverse indicators of sleep health relate to psychological and social factors across adulthood. Paper 1 uses perceived job discrimination as a social stressor to test associations between perceived job discrimination and sleep health  among working women. Paper 2 examines the relationship between personality traits and self-reported and actigraphy-measured sleep health . Paper 3 uses daily diary data to examine the link between pain and sleep health  in older adults’ everyday lives and test moderating effect of social support. Paper 4 examines sleep health  as a mechanism linking physical activity and cognitive function. These papers use different project datasets that include diverse populations of middle-aged and older adults, such as the Sister Study, Midlife in the United States Study, and Daily Experiences and Well-being Study. At the end of these presentations, Dr. Buxton will discuss their theoretical and methodological contributions, and consider challenges and opportunities for future research.


N = 22) were community-based treatment-seeking daily smokers (≥5 cigarettes/day) who were also heavy drinkers . Twenty five percent of interested individuals were eligible after initial phone screen, and all randomized participants were retained through follow up. All skills demonstrated high acceptability , and a significant proportion of participants in each condition reported taking action to reduce cigarette smoking and/or alcohol use at 1-month post-quit. Three participants in each condition (27.3%) attained bioverified (CO ≤ 4 parts per million and cotinine ≤ 3 ng/mL) smoking quit at follow-up. Given the modified intervention's acceptability and flexibility, larger studies may help to elucidate this intervention's effects on readiness to change, smoking cessation, and alcohol reduction.Approximately 20–25% of regular smokers report heavy drinking. Abstinent smokers are five times as likely to experience a smoking lapse during drinking episodes. Current efforts seek to improve treatments for this subgroup of heavy-drinking smokers. This study tested the feasibility and acceptability of addressing alcohol use in a brief, single session smoking cessation intervention (SMK+A) compared to smoking cessation counseling only (SMK); these interventions were grounded in a motivational interview framework and included personalized feedback, decisional balance, quit day setting, and tailored skills building  to maintain abstinence. Descriptive outcomes included reported helpfulness of intervention skills, readiness to change scores, and feasibility of participant recruitment and retention. We also assessed 7-day point prevalence of smoking cessation, and smoking and drinking reduction at 1-month follow-up. Participants ( Despite overall declines, cigarette smoking remains prevalent with 15.1% of adults in the United States reporting regular smoking, defined as smoking at least 100 cigarettes during their lifetime and smoking at minimum several days a week –4, and aThe guidelines for smoking cessation counseling consistently describe the combined risks of smoking and drinking  and suggOne potential barrier for effective and broadly implemented treatments for heavy-drinking smokers is that smoking and drinking topics are often approached differently by treatment providers. Within primary care settings, physicians dedicate significantly greater amounts of time addressing smoking relative to alcohol effects on health , 15. ThiIn summary, heavy-drinking smokers represent a unique subgroup of smokers for whom the available interventions may not be optimal. Current efforts seek to improve upon the standard of care for this sizeable and hard-to-treat subgroup of smokers who drink heavily. Empirically validated brief behavioral interventions have demonstrated short-term efficacy in simultaneously reducing alcohol use and increasing smoking cessation rates among heavy-drinking smokers. No study to date, however, has consolidated these smoking cessation interventions that address alcohol use into a single session of counseling. Examining the impact of such an intervention on smoking and drinking outcomes may be important for two reasons. First, addressing substance use that frequently co-occurs increases ecological validity and relevance of smoking intervention content. Second, this single-session intervention may be informative for emerging and versatile brief smoking/alcohol treatments that can be delivered across multiple treatment settings by different types of providers , 23. SucTo that end, this pilot study tested whether addressing alcohol use during a brief, single session, smoking cessation counseling (SMK+A) would be feasible and acceptable among heavy drinking smokers as compared to smoking cessation counseling only (SMK). These interventions were grounded in a motivational interview framework and included personalized feedback, decisional balance, quit day setting, and tailored skills building, as such menu-based interventions are efficacious, acceptable, and feasible ; furtherN = 22) were treatment-seeking smokers recruited through community advertisements. These advertisements described an opportunity to participate in a study of smoking cessation counseling to help people quit. Interested individuals contacted the lab to complete an initial phone screening to assess substance use history and exclusionary medical and psychiatric conditions; 247 individuals completed this initial screening. Inclusion criteria were: (1) between 21 and 55 years old, (2) treatment-seeking smokers without quit attempts in the past 3 months and who were willing to set a quit date in the 30 days following the intervention visit, (3) daily smokers smoking at least five cigarettes per day, verified by carbon monoxide (CO) and cotinine levels, (4) current heavy drinking as defined by the National Institute on Alcohol Abuse and Alcoholism ] and the counseling session. Participants also completed the following assessments at this laboratory visit: 30-day Timeline Follow-Back for cigarette smoking and alcohol consumption (TLFB) ; and Alcn = 11; see Figure Eligible participants were randomly assigned to one of two counseling conditions: alcohol and smoking (SMK+A) condition or smoking only (SMK) condition (each condition The 50-min smoking cessation counseling (SMK & SMK-A) interventions included four components that were based on effective motivational interview-based smoking and alcohol interventions –36. FirsFor example, a participant in the SMK condition might have chosen the skills “Identify and Cope with Urges” and “Cigarette Refusal Skills,” in addition to the therapist's choice of “Medication Guide.” In this case, the therapist would begin the skills component of the intervention with information about abstinence- and cue-induced cravings, such as their temporary and undulating nature. The participant would have then been asked to identify recurrent situations in which they experienced craving. The therapist and participant would work to develop methods for coping with cravings, such as engaging in other activities, avoiding certain situations, or “urge surfing” . The therapist and participant then would move on to discuss the second chosen skill, “Cigarette Refusal Skills,” which included a discussion on how to effectively communicate the participant's goals and needs with friends/family, and strategies for coping with resistance from others. Lastly, the skill of “Medication Guide” would be discussed, which would include general education on the purpose and function of the various approved medications for smoking cessation  and a discussion with the participant as to who to contact for more information and how to obtain medications .The SMK+A condition was tailored to address alcohol use in several ways. First, the SMK+A condition included information on the participant's drinking patterns  during the personalized feedback component. Second, during the pros and cons discussion, participants in SMK+A additionally reviewed the pros and cons of reducing alcohol use while quitting smoking. Third, the therapist chose the “Reduce Alcohol Use” skill as one of the three skills to discuss during the skill selection component of the tailored intervention. This skill included education on the co-reinforcing properties of smoking and alcohol, discussion on identifying individualized high-risk situations that could lead to heavy drinking, and helped the participant plan feasible ways to reduce heavy drinking and smoking, such as staggering drinks at longer intervals, limiting cash to create a spending limit, and reducing availability of cigarettes during social drinking. Other than the addition of the Reduce Alcohol Use Skill, all skill items on the menu were identical to the SMK condition.T-tests and chi-square tests assessed potential demographic, skill use/acceptability, and substance use baseline differences between participants in each condition. Frequency of skill use and ratings of skill helpfulness are reported as indices of intervention acceptability, and participant retention and percentage of eligible participants among interested individuals were assessed for feasibility. Cessation based on 7-day point-prevalence at 30-day follow-up was operationalized as having a CO reading ≤ 4 parts per million (PPM) and cotinine levels ≤ 3 ng/mL, consistent with smoking cessation studies in the United States .Demographic, behavioral, and substance use characteristics are presented in Table In total, ~25% of interested individuals were eligible for this study after initial phone screening. Of the 61 eligible individuals after the phone screening, 22 participants came to the laboratory for the in-person assessment and were randomized. This ratio of eligible to enrolled participants is consistent with recruitment rates in previous studies of treatment-seeking smokers . All 22 Participants chose a quit date that ranged from 1 to 26 days post-intervention , with no differences between intervention groups. Participants demonstrated variability in how frequently they used the skills discussed during the counseling session over the 30 days post-quit  after randomization, these results demonstrate that recruitment and longitudinal retention of this subgroup of smokers for this brief intervention is feasible.Acceptability was also demonstrated in this study through participant endorsement of skill utility. Addressing alcohol use in the SMK+A condition demonstrated the highest self-reported helpfulness score in achieving cessation and reduction goals. Although participants endorsed a range for how frequently they utilized each of the skills, the skills relating to utilization of quitlines and medications were reported to be the least helpful resources, and demonstrated the lowest frequency of utilizing these resources. Previous studies have documented the underutilization of these effective treatments among smokers , 44. PotRegarding RTC, a significant proportion of participants in both conditions reported sustaining or developing an interest in reducing cigarette smoking at 1 month follow-up. Participants in both conditions also expressed an elevated interest in reducing alcohol use, with over half of the participants in the SMK+A condition reporting that they have already taken steps to reduce alcohol use at 1 month follow-up. Previous studies have found that brief motivational interventions produce immediate changes in motivation for reducing cigarette use, but that these effects dissipate after 1 month . Though While the primary aim of the study was feasibility and treatment development, preliminary data were obtained and revealed that a meaningful number of participants successfully quit smoking following the brief intervention, with 6 out of 22 participants (27.3%) reporting successful biochemically verified quit at 1-month follow-up across both conditions. It is also promising that no participants in either condition reported an increase in cigarette smoking or alcohol use at follow-up. Previous work has suggested that level of alcohol consumption moderates the effects of smoking interventions with integrated alcohol components, such that moderate drinkers appear to benefit more from these interventions than heavy drinkers . FurtherThe most unique strengths of this intervention include its brief duration, practicality, feasibility, low cost, and the ease with which it can be incorporated within various types of settings  and administered by myriad health service professionals . Limitations of the current study include its small sample size that preclude reliable effect size estimates and reinforce the need for replication, the absence of a control condition to control for quit rates attributable to study enrollment, and lack of quantitative assessment regarding participant's chosen smoking cessation skills. Future studies that examine and further develop these treatments in multiple settings, particularly in the context of combined treatments, may be important to understand whether this intervention provides compounded benefits in sustaining motivation for smoking and alcohol reduction. For instance, though there are mixed results regarding the efficacy of naltrexone in increasing smoking abstinence and decreasing alcohol use , 51, theThis initial study provides preliminary feasibility and acceptability data on a brief counseling intervention for smoking cessation targeted for heavy-drinking smokers. Discussing the use of alcohol reduction in the context of motivational-interview based smoking cessation counseling was overall deemed acceptable and feasible. Larger studies will help to elucidate this intervention's effects on readiness to change, smoking cessation, and alcohol reduction. Such work that builds upon current practice guidelines for heavy-drinking smokers may be crucial for this difficult to treat population.This study was carried out in accordance with the recommendations of University of California Los Angeles Office of the Human Research Protection Program with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University of California Los Angeles Institutional Review Board.CL conducted data analyses and wrote the first draft of the manuscript. NM, KC, and VA acquired study data, developed hypotheses, and conducted preliminary analyses. AML and LR provided critical revisions on all manuscript sections. LR also conceived of the study and its design. All authors contributed extensively to the manuscript.LR has served as a paid consultant for GlaxoSmithKline and received study medication from Pfizer. The remaining 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.