Primary osteosarcoma of the bone with rhabdoid features is a rare malignant tumor of bone, not previously described in the literature. Here we report a 69-year-old female who originally presented with a right femur pathologic fracture. Radiographs of the injury showed an aggressive-appearing lesion of the distal femur. Initial biopsy was done, which was not diagnostic; additional advanced imaging studies were performed, which failed to show any other site within the body with detectable disease process. Accordingly, the patient underwent radical resection of the distal femur and reconstruction with endoprosthesis. Histopathology obtained from the operative specimen showed osteosarcoma with rhabdoid features. Two months after surgery, the patient is symptom-free and doing well; she is currently pending adjuvant chemotherapy. Although rhabdoid features have been described in extraskeletal osteosarcoma, this appears to be the first mention of osteosarcoma of bone with rhabdoid features in the literature. Primary osteosarcoma with rhabdoid features is a rare, previously undescribed malignant neoplasm of bone with histologic features of both primary osteosarcoma and those of rhabdoid cells. Osteosarcoma is mesenchymal neoplasm which accounts for 15% of all primary tumors of bone . PrimaryRhabdoid tumors have been divided into three classes, based upon anatomic location: malignant rhabdoid tumor of the kidney, extrarenal extracranial rhabdoid tumor, and atypical teratoid rhabdoid tumor involving the central nervous system . RhabdoiExtraskeletal osteosarcoma with rhabdoid features has been previously described twice in the literature, first in the scalp by Pillay et al.  and lateAn otherwise healthy 69-year-old female presented to our emergency department with five days of acute right thigh pain and inability to ambulate after a low-energy fall from standing height. Prior to her acute presentation, the patient suffered from approximately 1 month of progressive knee and thigh pain; however she did not seek any medical care during that time period for her insidious lower extremity pain. The patient denied any constitutional symptoms, weight loss, or presence of other alarming symptoms during the time period leading up to her fracture. Initial radiographs of the right femur showed a pathologic fracture associated with an aggressive-appearing lesion in the distal femur. The associated lesion was a markedly expansile, poorly geographically defined lytic lesion measuring approximately 9 × 6.7 cm in the metaphysis of the distal femur. The films also revealed associated periosteal reaction with disorganized bone formation and cortical destruction laterally; the pathological fracture could be observed at the proximal extent of the lesion . Due to Given the lack of osteoid-producing cells seen on original histopathology, the differential diagnosis at that time did not feature osteosarcoma. Taking into account the presence of rhabdoid cells, the working diagnosis at that time was established as metastatic carcinoma of unknown origin with rhabdoid features, versus rhabdoid sarcoma of the thigh with local spread to the femur. Therefore, the patient was referred for chemotherapy; however, she experienced issues with payment due to the expiration of her insurance, and she was unable to initiate chemotherapeutic treatment. The patient's leg remained in a long leg cast, and she was lost to follow-up for a brief period of time. One month later, she again presented to the emergency department, now with severe pain, inability to ambulate, balance problems, and high fall risk. Due to the patient's unclear diagnosis, her inability to obtain chemotherapy, and the few reasonable treatment options in this setting, the decision was made to treat patient with right distal femur radical resection and reconstruction with an endoprosthesis . The proGross pathology of the surgical specimen showed the presence of new, disorganized bone formation ; and hisThe most common malignancy of bone is metastatic, particularly in the elderly population, which would have made a metastatic lesion a likely probability in our patient. However a thorough workup via CT and PET imaging showed no other lesions in the patient's body. Furthermore the imaging revealed multiple characteristics of osteosarcoma, such as a sunburst pattern of periosteal reaction, new disorganized bone formation extending into adjacent tissue, cortical destruction, and the location of the lesion. Nonetheless, malignancy of unknown primary source was still felt to be the most likely diagnosis after the patient's needle biopsy, given the findings of rhabdoid cells and lack of any finding of osteoid matrix .The working diagnosis was revised however, after histopathology obtained from the surgical specimen showed the presence of osteoid matrix and matrix-producing cells. As in the original needle biopsy sample, eosinophilic rhabdoid cells with their characteristic nuclei and nucleoli and cytoplasmic inclusions were prominently featured and clearly identified under the microscope Figures  and 5. HThe question remains however: is this a primary osteosarcoma of bone? The incidence of osteosarcoma is bimodal; the second, smaller peak appears in adults greater than 65 years of age . Our patThis patient's diagnosis, primary osteosarcoma of bone with rhabdoid features, is an apparently novel diagnosis, not yet described in the literature. Unlike the bimodal distribution observed in osteosarcoma, rhabdoid tumors are almost exclusively pediatric tumors. Typically, rhabdoid tumors are found in the central nervous system or in the kidneys . There h


Better understanding of gender differences in the adoption of agricultural intensification strategies is crucial for designing effective policies to close the gender gap while sustainably enhancing farm productivity. We examine gender differences in adoption rates, likelihood and determinants of adopting strategy sets that enhance yields, protect crops, and restore soils in the West African Sahel, based on analysis of cereal production in Burkina Faso. Applying a multivariate probit model to a nationally representative household panel, we exploit the individual plot as unit of analysis and control for plot manager characteristics along with other covariates. Reflecting the socio-cultural context of farming combined with the economic attributes of inputs, we find that female managers of individual cereal fields are less likely than their male counterparts to adopt yield-enhancing and soil-restoring strategies, although no differential is apparent for yield-protecting strategies. More broadly, gender-disaggregated regressions demonstrate that adoption determinants differ by gender. Plot manager characteristics, including age, marital status, and access to credit or extension services do influence adoption decisions. Furthermore, household resources influence the probability of adopting intensification strategy sets differently by gender of the plot manager. Variables expressing the availability of household labor strongly influence the adoption of soil-restoring strategies by female plot managers. By contrast, household resources such as extent of livestock owned, value of non-farm income, and area planted to cotton affect the adoption choices of male plot managers. Rectifying the male bias in extension services along with improving access to credit, income, and equipment to female plot managers could contribute to sustainable agricultural intensification. Donors Developing agricultural technologies to improve women’s well-being poses a “much more difficult challenge” than merely “taking women into account” . Indeed,In conducting gender research, the selection of the appropriate unit of analysis matters. A large body of case studies conducted in Africa controls for the sex of the household head when estimating the determinants of technology adoption and productivity. In their seminal work, Similarly, Several recent studies have examined the determinants of adoption of multiple yield-enhancing, protective, and/or conserving strategies, especially in Eastern and Southern Africa , and to In this analysis, we examine three fundamental questions regarding gender and technology adoption in cereal production. We apply multivariate probit models to test for gender differentials in (1) adoption rates; (2) the likelihood of adoption; and (3) determinants of adoption in the farming context of the West African Sahel, using Burkina Faso as an example. We consider the adoption of yield-enhancing, yield-protecting, and soil restorative strategy sets on individually managed plots of maize, sorghum, and millet.Our analysis contributes to the literature on gender roles and technology adoption in several ways. First, we add to the ongoing discussion on the gender gap in technology adoption by exploring jointly the determinants of a wide range of intensification strategy sets in a different farming context- the West African Sahel. Second, reflecting the cultural specificity of gender roles and farm decision-making in this region, we control not only for the sex of the plot manager but whether or not the manager is the household head. Third, we use a nationally representative household panel to exploit the individual plot as a unit of analysis and control for additional plot manager characteristics along with other covariates.2Historical, ethnographic research e.g.,  and moreThe allocation of individual plots is associated with the status of household members in relation to the patriarch . For exaAnother important feature of the Burkinabe farming structure is the interplay between customary norms and formal tenure rights. In recent years, socio-cultural norms and incentives guiding resource use have evolved in response to food insecurity, spurred in part by the land fragmentation that accompanies high rates of population growth . Guirkin3Enquête Permanente Agricole (EPA)) collected by the General Research and Sectoral Statistics Department ) of the Ministry of Agriculture and Food Security (Ministère de l’Agriculture et de la Sécurité Alimentaire (MASA)) in Burkina Faso. The sampling frame for the EPA is based on the 2006 Population Census. The nationally representative sample includes 4,130 household farms in 826 villages across all 45 provinces. The EPA generates production, area and yield data for rainfed crops, serves as an early warning system for food insecurity, and also furnishes general information about livestock holdings, income and expenditures of rural households, and farm input use. In this article, we utilize data covering the 3-year period from 2009–10 through 2011–12, which are the last years for which fully cleaned data are available. The format of the EPA data reflects the socio-demographic structure of farm family decision-making in Burkina Faso, as described in Section The data for this analysis are drawn from the Continuous Farm Household Survey   .4We utilize a straightforward latent variable framework to model the decision of individuals  to adopt as a binary outcome. Consistent with the overall perspective of decision-making within a complex household in the face of imperfect or missing markets, we consider that individual choices are conditioned on household and market-related characteristics. Recognizing that even if markets were perfect and complete, differentiation in input use could result from plot-specific variable features of land and micro-climate, we also model choices as conditional on plot and agro-climatic characteristics. As explained in the introduction, consistent with current analyses of gender-differentiated adoption and productivity, we include plot manager characteristics other than gender as key covariates for hypothesis testing.i at time t, be:itX is a set of observable covariates, β is a vector of parameter estimates, itu is the normally distributed error term independent of itX, and ic are the time-invariant unobserved effects (ity) and is expressed as:It is expected that individual family members will adopt intensification strategy sets that maximize their perceived benefits. Let the perceived benefits derived from adopting an intensification strategy set by farmer  effects . Althougity is a limited dependent variable, which takes a value of 1 if the farmer i makes the observable decision of adopting any intensification strategy within a set at time t and zero otherwise. As specified, both ic and β are unknown parameters to be estimated by the probability model Prob(Given the binary nature of the dependent variable (to adopt or not), the possible interdependence across a set of intensification strategies, a multivariate probit model is used to examine the gender differentials in the determinants of adoption.The multivariate probit model can be seen as an extension of the probit model, since it allows estimating several probit models simultaneously, while allowing the error terms in those models to be correlated . Ignorinic) to be correlated with observed covariates in nonlinear models, through the projection of those effects on the time average . According to per se. Though a linear model is a useful starting point for estimating average partial effects, the model imposes the restriction that 0 ⩽ itβX + ic ⩽ 1 for all itX. The linear functional form for equation 5 cannot hold over a wide range of values of itX and ic, and may thus may provide a poor approximation , and organic fertilizer, which is recommended in combination with these to restore soil fertility, in terms of its physical, chemical, and biological properties . In contThe choice of explanatory variables draws from the concepts we outline above and a vast theoretical and empirical literature on the adoption of agricultural innovations in developing country agriculture, including reviews by In addition to gender, plot manager characteristics include age, education, marital status, and headship, as well as plot manager access to credit and extension services. The number of years since plot managers received any extension services is expected to be negatively correlated with technology adoption. Credit access is defined as whether or not the plot manager reported access to credit in the preceding year, regardless of whether credit was used in the survey season. Plot physical characteristics include size, location, and topography .We then include the covariates known to explain differences in input adoption among households, including wealth, tenure security, and availability of labor, which is a complementary input for all intensification strategy sets. Total landholding, livestock, non-farm income, and number of cotton hectares are used as proxies for wealth. The number of livestock owned also provides information regarding the availability of manure. Households growing cotton benefit not only from the cash it generates, but from better access to inputs on credit and extension services provided through the cotton ginneries . We expeMarket-related factors affect adoption incentives via transaction costs and endogenous prices. The share of households in the village who are members of a cereal association is included to express access to socio-political capital as exogenous to the decisions of individual plot managers. Variables measuring the number of agro-dealers and population density at the province level are included as proxies for market access.To account for potential interannual fluctuation in moisture availability for cereal crops, the coefficients of variation in total annual rainfall at the commune level over the last three years are included. Cereal dummy variables are also included to control for crop differences.6(a)(b)p-value 0.0000). Multivariate probit is preferred statistically to univariate probit regressions, indicating that the probability of adopting one set is interdependent on the decision of whether to adopt another set. The estimates of the correlation between the regression error terms are positive and significant, suggesting complementarities across the yield-enhancing, yield-protecting, and soil-restoring sets.The regression coefficients in Female plot managers are significantly less likely to adopt either the yield-enhancing or the soil-restoring strategy sets, after controlling for other covariates. This finding is consistent with the notion that within households, women have less access to these inputs. Fertilizer, which is lumpy and costly per unit, is often extended via formal programs and projects to the household head. To utilize soil restorative practices, plot managers need access to larger livestock, additional labor and equipment, which are typically managed by the head on behalf of the household since they are deployed across numerous plots and crops. By contrast, no gender differential is evident in the probability of adopting yield-protecting (damage control) inputs, which are divisible, scale-neutral, and widely available through agro-dealers .per se but rather reflects how the socio-cultural farming context combined with the economic attributes of technology affect adoption. We examine this in greater detail below, when testing for underlying differences in the determinants of adoption by men and women.Our findings are consistent with some previous studies regarding gender differences in fertilizer use . Ndiritu(c)vs. Chi-squared critical value of 112 with 75 d.o.f at 1% significance). In other words, the underlying process that explains adoption differs between male and female plot managers. The statistical results are supported by observable differences in statistically significant determinants between the two sets of regressions  regression for all plot managers to separate (unrestricted) regressions for males and females only using a modified Chow test that is appropriate for nonlinear regressions . Compariressions , Table 5Among the socio-demographic characteristics, age of the plot manager positively influences the probability of adopting the soil-restoring strategy set for both males and females. In this society, where elderly people are highly regarded , the staExtension services, which mostly target male farmers, statistically influence their decision to adopt modern inputs. The longer it has been since male plot managers received any extension services, the less likely they are to adopt the yield-enhancing and yield-protecting sets. This finding adds to the evidence that receiving advice from extension agents positively influences adoption of yield-enhancing inputs  and damaPlot characteristics, such as topography, size, and location from residence influence the adoption of intensification strategy sets. The probability of adopting the soil-restoring strategy set, for both female and male farmers, is lower on plots that are considered far from the residence, since distant plots require more time, labor, and energy in transport. The larger is the plot size, the higher is the probability of adopting modern inputs (yield-enhancing and yield-protecting sets) for both male and female plot managers. In contrast, the plot’s topography affects adoption of intensification strategy sets differently for male and female plot managers. Although men are as likely as women to manage plots on land with slopes, the probability of adopting yield-enhancing and soil-restoring sets on these plots is statistically significant for women only. On lowland farm plots, the yield-enhancing set is more likely to be adopted by women but less likely to be adopted by men.The probability of adopting intensification strategy sets on individual cereal plots is influenced by household characteristics, but the influence of these factors depends on the gender of the plot manager. In a patrilineal society, such as in Burkina Faso, women have less bargaining power than men, which limits their access to and control over household resources , which iIn contrast, factors related to labor availability more significantly affect the decision to adopt intensification strategy sets for female compared to male plot managers. These results reinforce the idea that women’s access to labor plays a crucial role in technology adoption . FurtherGender differences are apparent in the ways market factors affect the probability of adopting intensification strategy sets. Villages that have a large share of households belonging to a cereal association are more powerful in attracting resources and public support. By serving as platforms to share general knowledge and tips regarding agricultural practices, cereal associations positively influence technology adoption, especially for female plot managers. The number of agro-dealers in each province negatively influences adoption of the yield-enhancing and soil-restoring sets, but positively influences adoption of the yield-protecting set. This reflects the weaknesses of the Burkinabe private input supply sector, especially in regards to yield-enhancing inputs. The public sector has been highly involved in the marketing of fertilizer and improved seeds, notably in the cotton-cereal farming system, which has led to the displacement of private agro-dealers . These yThe coefficient of variation of annual rainfall at the commune level is positive and significant for two out of three intensification sets, regardless of whether the plot manager is male or female. This suggests that all farmers respond to increased variability in water supply in their commune by adopting yield-enhancing and soil-restoring sets. Our results are consistent with The choice of crops also influences adoption decisions, in similar ways for both male and female plot managers. Compared to sorghum, maize plots are more likely to benefit from the adoption of yield-enhancement and soil-restoring strategy sets by both male and female managers. This finding reflects the economic importance of maize as a cash crop in this region. In contrast, the adoption of yield-protection strategies is less likely on millet than on sorghum plots for either male or female managers. Millet, a subsistence crop, is more widely grown in drier regions, where pest and disease pressures may be lower.7In this article, we have tested gender differences in the rates, likelihood, and determinants of adoption of sustainable intensification strategies between male and female plot managers growing cereals in the West African Sahel. We contribute to the literature on the gender gap in technology adoption by controlling for the sex of the plot manager along with other plot manager characteristics . We also contribute to the literature on adoption of sustainable farming practices by exploring the use of numerous inputs grouped in terms of strategies , and their interrelationships, while controlling for major cereal crops .Overall, the soil-restoring strategy set is the most frequently adopted, followed by the yield-protecting and the yield-enhancing, regardless of whether the plot manager is male or female. Findings from the descriptive statistics also suggest that female plot managers are adopting any of the three intensification strategy sets at lower rates.More nuanced results emerge from the econometric analysis. The likelihood ratio test confirms the interrelatedness of intensification strategy sets and the appropriateness of the multivariate probit model as compared to independent probit models for predicting adoption. Results from the regression that includes a dummy for the sex of the plot manager show statistically significant differences in the probability of adopting the yield-enhancing and soil-restoring sets, after controlling for other plot manager characteristics and covariates. In contrast, sex of the plot manager does not statistically influence the probability of adopting the yield-protecting strategy set. This finding reflects how both the gendered, socio-cultural farming context and economic attributes of the technology affect incentives to adopt.Disaggregated regressions demonstrate that the determinants of adoption differ between male and female plot managers. Plot manager characteristics, including age, marital status, and access to credit or extension services do influence adoption decisions, but in different ways according to the sex of the plot manager. Access to extension is significant for male managers, who have been targeted by programs in the past—but not for female managers. Furthermore, household resources influence the probability of adopting intensification strategy sets differently by sex of the plot manager. Variables expressing the availability of household labor strongly influence the adoption of soil-restoring strategies by female plot managers. By contrast, household resources such as extent of livestock owned, value of non-farm income, and area planted to cotton more often affect the adoption choices of male plot managers.Our results provide insights on the influence of gender roles and economic attributes of technology on adoption decision that are relevant to the design and implementation of effective policies to sustainably increase production by farmers in Burkina Faso and similar areas of the West African Sahel. The interrelatedness of adoption strategies  confirms the policy importance of designing extension mechanisms and messages that encourage farmers to consider flexible combinations of techniques and practices so that they can benefit from agronomic and economic complementarities. The promotion of any single intensification strategy should take incentives for use of other sets, and current patterns of input use, into consideration.At the same time, the variation in input use confirms that farmers in these environments are not best approached with a fixed package in mind, but instead, with a recognition that due to constraints related to microclimate, labor, and cash, they will need the option of selecting from “menus” of practices and to suit their own conditions. Although plant breeders and agronomist must work to achieve complementarity by designing optimal packages of inputs, farmers’ optimal combinations will be as heterogeneous as the farm population and agro-ecology. The significance of plot characteristics in our models also supports this notion. Future research might explore the relative costs and benefits of research-and-extension designs that support this heterogeneity rather than blanket, uniform recommendations.Gender differentials in adoption rates for yield-enhancing and soil-restoring sets and among determinants of adoption confirm the need to collect data disaggregated at the plot level and design and promote policies that, while respecting socio-cultural norms, also respect opportunities and incentives for individuals within multigenerational, multi-family farms.The role of public extension services, for which funding support has declined in recent decades in favor of other types of information provision, nonetheless appears to be important in adoption decisions, especially in regards to modern inputs. Some changes are needed to redress the male bias in extension services, by including women as beneficiaries and covering topics on sustainable intensification, which takes into account women’s constraints to technology adoption. Credit access also remains crucial for inputs purchased with cash (yield-enhancing and yield-protecting sets), especially for women who have limited economic control within the household. Improving access to education, income, and equipment to women could contribute to increase their bargaining power and thereby, adoption of sustainable intensification strategies.Customary norms also appear to play key roles in adoption of strategies for sustainable intensification of agriculture. Marriage, in particular, appears as significant for young men, as compared to women plot managers, most of whom obtained usufruct rights upon marriage. Among men, major differences in social status are related to headship and marriage. Only a tiny minority of women in the sample are heads. Looking toward the next generation of farmers, and the transfer of rights and responsibilities, inter-generational differences among men within households may be as important to take into consideration as differences between men and women.


Preeclampsia has been linked to high morbidity and mortality during pregnancy. However, no efficient pharmacological options for the prevention of this condition are currently available. Preeclampsia is thought to share several pathophysiologic mechanisms with cardiovascular disease, which has led to investigations for the potential role of statins (HMG CoA reductase inhibitors) in its prevention and early management. Pravastatin seems to have a safer pharmacokinetic profile compared to other statins, however, the existing preclinical evidence for its effectiveness in preeclampsia treatment has been mostly restricted to animal models. This review aims to summarize the current data and delineate the potential future role of statins in the prevention and management of preeclampsia. Preeclampsia is a pregnancy-related disorder with multi-organ involvement, mainly including the emergence of high blood pressure (BP) in the second trimester of pregnancy. Affecting about 1 in 12 pregnant women in the USA, preeclampsia is the most common hypertensive condition complicating pregnancy, as well as one of the major causes of maternal and fetal complications and death . AlthougPreeclampsia is characterized by the development of new onset hypertension (HTN) and the establishment of proteinuria. Other signs and symptoms that accompany the disease include: headache, visual disturbances, epigastric or abdominal pain, weakness, altered mental status, HELLP syndrome  dyspnea Preeclampsia can result in a great number of severe and, in some cases, fatal short- and long-term consequences affecting both the mother and the fetus. Maternal complications include cardiometabolic disorders , cerebrovascular disease , neurologic abnormalities (eclamptic seizures) and renal impairment . Fetal oDelivery of the fetus is the only efficient therapy . If the Even though the precise etiology of preeclampsia remains obscure, the main pathophysiological mechanisms include maternal endothelial dysfunction  and placThe integrity of endothelial cells is crucial for the maintenance of angiogenic balance. Any endothelial damage such as deficient spiral artery remodeling mentioned above, can lead to placental oxidative stress and imbalance in the production of vasoconstrictive and vasodilative factors. Anti-angiogenic factors, such as soluble Fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng), have been shown to increase in preeclamptic gestations . Specifiin vitro and in vivo, resulting into the overexpression of vasodilating factor NO .Statins inhibit HMG-CoA reductase leading to increase of LDL receptors (LDLr) and thus, to the reduction of plasma cholesterol levels. The most serious adverse effects include rhabdomyolysis and transaminase elevation but their incidence is about 1%. Statin administration has been shown to be safe in pregnancy  presentiactor NO . Moreoveactor NO   is currently recruiting and investigators focus on the impact of pravastatin in the reduction of anti-angiogenic markers in women with early preeclampsia . AdditioPreeclampsia remains a pregnancy-related health issue with severe and life-threatening complications and clinicians should be alerted for early recognition, prompt diagnosis, prevention and effective treatment. Preliminary data suggest that statins can be a promising therapeutic alternative for the prevention and treatment of preeclampsia, however, larger clinical studies are still required.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families.We conducted a register-based nested case-control study during 1990–2013 in Sweden to assess whether patients with ALS had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 patients with ALS and 36,480 age-, sex-, and county of birth–matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of patients with ALS and their controls.Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS  compared to individuals without these diseases. After diagnosis, patients with ALS had increased risks of other neurodegenerative or psychiatric diseases  compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson disease, other dementia, Alzheimer disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of patients with ALS had higher risk of neurodegenerative diseases, whereas only children of patients with ALS had higher risk of psychiatric disorders, compared to relatives of the controls.Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to nonmotor symptoms of ALS and severe stress response toward the diagnosis. Using the unique personal identification numbers assigned to all Swedish residents,14 we followed the study population from January 1, 1990, or date of birth, whichever came later, until date of ALS diagnosis, death, emigration out of Sweden, or December 31, 2013, whichever came first, through cross-linkages to the Swedish Patient Register, Causes of Death Register, and Migration Register. The Patient Register collects data on hospital discharge records in Sweden since 1964 and has a nationwide coverage since 1987.14 Since 2001, it also collects data on hospital-based outpatient specialist care. Diagnoses from each hospital visit are classified according to the Swedish revisions of the International Classification of Disease (ICD) codes . We identified all newly diagnosed ALS cases during follow-up through the Patient Register, indicated by a hospital visit concerning ALS, and defined the first hospital visit as ALS diagnosis date. We ascertained date of death from the Causes of Death Register and date of first emigration out of Sweden from the Migration Register. We excluded individuals who had been diagnosed with ALS (n = 662), died , or emigrated out of Sweden  before the beginning of follow-up, leaving 8,269,319 (96%) participants in the study base.The Swedish Multi-Generation Register includes information on familial links for all individuals born in Sweden since 1932.We conducted a nested case-control study within the above study base to assess the association of previous neurodegenerative and psychiatric diseases with the subsequent ALS risk. We defined cases as individuals diagnosed with ALS during follow-up . For each index case, we randomly selected 10 controls from the study base, by incidence density sampling, and individually matched the controls to the cases by year and month of birth, sex, and county of birth . Eligible controls had to be alive, living in Sweden, and ALS-free, at the time of the diagnosis of the index case.To investigate whether relatives of patients with ALS had increased risk of neurodegenerative and psychiatric diseases before the diagnosis of the proband ALS patient, we conducted a second nested case-control study, including relatives of the index patients with ALS and their matched controls. We identified parents, full siblings, half-siblings, and children of the index cases and controls from the Multi-Generation Register and used them as cases and controls for the nested case-control study II. We used the index dates of the index cases and controls as the index dates for the respective relatives. We excluded from the analyses relatives who had died or emigrated out of Sweden before the index date.To examine the relative risks of neurodegenerative and psychiatric diseases after ALS diagnosis, we prospectively followed the above nested case-control studies from the index date. In these analyses, we included only individuals without any neurodegenerative or psychiatric diseases diagnosed prior to the index dates, leading to 3,169 ALS cases and 33,110 controls in the follow-up study of nested case-control study I, and 13,313 relatives of patients with ALS and 130,321 relatives of the index controls in the follow-up study of the nested case-control study II. We followed all individuals from the index date to the date of first diagnosis of neurodegenerative or psychiatric diseases, death, emigration out of Sweden, or December 31, 2013, whichever came first.15 Psychiatric disorders examined in this study included schizophrenia, bipolar disorder, depression, neurotic disorders, stress-related disorders, alcohol abuse/dependence, and drug abuse/dependence. We defined a diagnosis of these diseases through a hospital visit concerning the specific disease as recorded in the Patient Register and used the date of first hospital visit as the diagnosis date. Because the Patient Register achieved good coverage on psychiatric diagnoses in 1973,16 we ascertained the diagnoses of neurodegenerative and psychiatric diseases from 1973 until the index date for the nested case-control studies and from the index date until the end of follow-up for the follow-up studies. A list of the corresponding ICD codes is provided in table e-1 at Neurology.org.Neurodegenerative diseases examined in this study included frontotemporal dementia (FTD), Alzheimer disease (AD), other or unspecific dementia, and PD, because we had previously reported risk of ALS among relatives of patients with ALS.In the nested-case control studies, we estimated odds ratios (ORs) of ALS (or becoming a relative of an ALS patient) and corresponding 95% confidence intervals (CIs) using conditional logistic regression as measures of the associations between previous neurodegenerative or psychiatric diseases and the subsequent ALS risk. Because cases and controls were individually matched by year and month of birth, sex, and county of birth in the nested case-control study I, these variables were automatically adjusted for in the analyses. In the nested case-control study II, we adjusted all models for year and month of birth, sex, and county of birth of the relatives as well as of the proband individuals.In the follow-up studies, we fitted Cox proportional hazard regression to derive hazard ratios (HRs) for the future risk of neurodegenerative and psychiatric diseases, comparing patients with ALS to their controls and the relatives of patients with ALS to the relatives of the index controls. We used attained age as the underlying time scale and further adjusted all models for sex and county of birth. We tested the assumption of proportional hazards using Schoenfeld residuals.In addition to the overall analyses, we separately analyzed specific time windows in the nested case-control studies and the follow-up studies . The period ≤1 year before ALS diagnosis might be representative of a time period of symptoms onset and clinical diagnostic workup.To assess the potential influence of age and sex on the studied associations, we separately analyzed men and women and individuals at age ≤55 and at age ≥56. Because familial ALS cases might have different association with other neurodegenerative diseases, compared to sporadic ALS cases, we separately analyzed ALS cases with a family history. By crosslinking the nested case-control study I to the Multi-Generation Register, we identified grandparents, parents, uncles/aunts, full and half siblings, children, nephews/nieces, and grandchildren of patients with ALS and their corresponding controls. We then linked these relatives to the Patient Register to obtain ALS diagnosis among them and defined a family history of ALS as having at least one of these relatives diagnosed with ALS until the end of 2013.17 we additionally assessed the risk of other neurodegenerative diseases among patients with ALS after excluding FTD from the definition of neurodegenerative diseases. Finally, as depression, neurotic disorders, and stress-related disorders might represent collectively the psychological burden of ALS symptoms and diagnosis on patients with ALS and their families, we analyzed the risk of having depression, neurotic disorders, or stress-related disorders before and after ALS diagnosis.To investigate if misdiagnosis of neurodegenerative diseases might explain some of the associations between other neurodegenerative diseases and ALS, we conducted an additional analysis by restricting the definition of ALS and other neurodegenerative diseases to patients with at least 2 hospital visits concerning respective diseases. Given the established ALS/FTD overlap,p value ≤0.05. We performed analyses using Stata software, version 14 .We considered statistically significant associations with a 2-sided The Regional Ethical Review Board in Stockholm, Sweden, approved this study.Both before and after the index date, we found higher risks for all neurodegenerative diseases studied and for depression, neurotic disorders, and drug abuse/dependence among patients with ALS, compared to controls . The assOverall, parents, siblings, and children of patients with ALS had higher risk of neurodegenerative diseases, both before and after the index date, compared to relatives of ALS-free individuals, although the associations were only statistically significant for siblings . ChildreThe associations of FTD, AD, other or unspecific dementia, PD, depression, neurotic disorders, and drug abuse/dependence with the subsequent ALS risk appeared to be strongest during the year before ALS diagnosis, although we also noted positive associations during 2–5 years before diagnosis . We obseAll results of the main analyses appeared comparable between males and females (tables e-4 and e-5) and between individuals younger or older than 55 years (tables e-6 and e-7). We identified a total of 173 patients with ALS with a family history of ALS (3.9%); separate analysis of these familial ALS cases generally provided similar results as in the main analyses (table e-8).Among the 3,648 patients with ALS in our study, 3,048 had at least 2 hospital records concerning ALS, and among the 600 cases with only one record, 246 had ALS as a cause of death in the Causes of Death Register. Restricting the definition of ALS and other neurodegenerative diseases to patients with at least 2 hospital visits concerning respective diseases slightly attenuated the associations between other neurodegenerative diseases and ALS both prior to  and after  ALS diagnosis. Excluding FTD from the definition of neurodegenerative diseases attenuated slightly the associations of ALS with other neurodegenerative diseases in the overall analyses  and the temporal pattern analyses (table e-9).The risk of having depression, neurotic disorders, or stress-related disorders was significantly higher among patients with ALS, compared to controls, both before  and after  ALS diagnosis. The risk increase peaked during the year before  and the year after  ALS diagnosis.Using a nationwide population-based study sample, we found that patients with ALS had higher risks of neurodegenerative and psychiatric diseases, both before and after diagnosis. Parents, siblings, and children of patients with ALS tended to have increased risk of neurodegenerative diseases, whereas only children of patients with ALS had increased risk of psychiatric disorders.4 our study is the first to demonstrate the temporal pattern of the increased risks from years before until years after ALS diagnosis. We further showed that parents, siblings, and children of patients with ALS tended also to have increased risks of other neurodegenerative diseases, corroborating findings of a recent study in Ireland.6 Our results lend further support to the hypothesis that shared etiologies or disease mechanisms might underlie different neurodegenerative diseases.9 Such mechanisms might include shared genetic risk factors,18 leading for example to accumulation of protein aggregates in the brain, a common pathologic finding from different neurodegenerative diseases.19 Nongenetic risk factors such as exposure to agrochemicals and previous head trauma have also been linked to different neurodegenerative diseases.20Although previous studies reported increased risks of dementia and PD after ALS diagnosis,21 Restricting the definition of ALS and other neurodegenerative diseases to patients with at least 2 hospital visits concerning respective diseases attenuated slightly, but did not diminish the results, arguing against misdiagnosis as the pure explanation for the observed associations. Furthermore, patients with ALS might have been more closely surveyed and more likely to receive a diagnosis of another neurodegenerative disease compared to ALS-free individuals, leading to a higher than expected risk of other neurodegenerative diseases. It is also possible that some symptoms of other neurodegenerative diseases become underdetected because of the predominant ALS symptoms.The stronger associations with neurodegenerative diseases noted during the 5 years before and after ALS diagnosis were not reported previously and might be due to different reasons. Misdiagnosis between ALS and other neurodegenerative diseases could contribute partially to the increased risk of other neurodegenerative diseases among patients with ALS. The diagnosis of ALS in the Patient Register appears to have high accuracy because a validation study of 280 patients in Stockholm showed a positive predictive value of 91% for medical records–based ALS diagnosis.12 The increased risks of neurotic disorders and stress-related disorders are not surprising, because depression, neurotic disorders, and stress-related disorders are highly correlated clinically.22We found an increased risk of psychiatric disorders among patients with ALS both before and after diagnosis. The increased risk of depression is in line with previous reports.23 and may mimic psychiatric symptoms.24 The increased risk of depression might partially represent increased prevalence of cognitive impairment among patients with ALS. The increased risks of depression, neurotic disorders, and stress-related disorders, peaking during the year before and after ALS diagnosis, might on the other hand collectively suggest a reactive nature of these psychiatric disorders, potentially due to the emotional burden of ALS symptoms and diagnosis.The stronger associations with psychiatric disorders noted during the 5 years before and after ALS diagnosis might be due to both nonmotor symptoms of ALS and severe stress response toward these symptoms and the final diagnosis. Nonmotor symptoms of ALS including cognitive impairment are increasingly recognized11 we noted an increased risk of schizophrenia during the 5 years before ALS diagnosis, although the association was only statistically significant during the year before diagnosis. A recent genome-wide association study also suggested a genetic overlap between ALS and schizophrenia.25In line with a previous study that identified an association of schizophrenia with subsequent ALS,26–29 we did not find an association between alcohol abuse/dependence and a lower ALS risk. Lack of adjustment for smoking and total energy intake in the present study might partially explain these conflicting results. In accord with the previously suggested association between use of opioids and ALS,30 our study reports a higher risk of drug abuse or dependence  among patients with ALS, both before and after ALS diagnosis. While drug abuse/dependence might be partially secondary to depression and stress-related disorders,31–33 these associations diminished but did not disappear after excluding individuals with concurrent drug abuse/dependence, depression, or stress-related disorders (data not shown).In contrast to previous studies,34We observed an increased risk of psychiatric disorders among children, but not siblings or parents, of patients with ALS. The vast majority of children of patients with ALS who received a psychiatric diagnosis  received a diagnosis of depression, neurotic disorders, or stress-related disorders, suggesting that psychological distress was likely the primary reason for such increased risk. This is possibly explained by the fact that children are more involved in caring for patients with ALS compared to other relatives.Main strengths of our study are the large sample size and the population-based design. The long-term study period and the complete follow-up, the prospectively collected information, as well as the ability to objectively identify family members and their disease history, represent other main strengths.35 Some of the patients with FTD might have been misclassified as other dementia, partially accounting for the increased risk of other dementia among patients with ALS. Because the vast majority of children of patients with ALS were younger than 60 years, risk of neurodegenerative diseases at older ages of children needs to be further assessed. Although the clear temporal pattern before and after ALS diagnosis argues against confounding as an important explanation for the noted associations, residual confounding remains a possibility. Finally, whether or not these findings are generalizable to other populations needs to be tested in further studies.We lacked information on the genetic and clinical characteristics of patients with ALS, and were therefore unable to separately analyze different subtypes of ALS. Although the completeness of ALS diagnosis is presumably high in the Swedish Patient Register because all patients with ALS are diagnosed by a specialist, we might have underestimated the prevalence of some neurodegenerative and psychiatric diseases because health care provided by general practitioners is not included in the register. The 1% prevalence of FTD among the patients with ALS might reflect a lack of FTD detection.We found that patients with ALS and their first-degree relatives had increased risks of neurodegenerative diseases before and after diagnosis, lending further support to a common etiopathogenesis for different neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to both the nonmotor symptoms of ALS and severe stress response to the progressive symptoms and diagnosis of a fatal disease.


Strong evidence points to the presence of a window of opportunity in early life, during which changes in gut microbial colonization can result in immune dysregulation that predisposes susceptible hosts to disease. Although the ecological patterns of microbial succession in the first year of life have been partly defined in specific human cohorts, the taxonomic and functional features, and diversity thresholds that characterize these microbial alterations are, for the most part, unknown. In this review, we summarize the most important links between the temporal mosaics of gut microbial colonization and the age-dependent immune functions that rely on them. We also highlight the importance of applying ecology theory to design studies that explore the interactions between this complex ecosystem and the host immune system. Focusing research efforts on understanding the importance of temporally structured patterns of diversity, keystone groups, and inter-kingdom microbial interactions for ecosystem functions has great potential to enable the development of biologically sound interventions aimed at maintaining and/or improving immune system development and preventing disease.Alterations in gut microbial colonization during early life have been reported in infants that later developed asthma, allergies, type 1 diabetes, as well as in inflammatory bowel disease patients, previous to disease flares. Mechanistic studies in animal models have established that microbial alterations influence disease pathogenesis  Recent advances in immune-mediated disease research have provided a considerable body of proof revealing the importance of the early gut microbiome for neonatal immune system development and disease pathogenesis . BridgmBacteroides spp., Clostridium spp., Ruminococcus spp., Faecalibacterium spp., Roseburia spp., and Anaerostipes spp., as well as the reduction in Bifidobacterium spp. and Enterobacteriaceae  was associated with an increase in lla spp. , 40.per se represents a robust indicator of infant gut microbiome disruption, especially since (1) there could a threshold to be crossed for the gut ecosystem to suffer a significant loss of function; and (2) diversity as a diagnostic tool provides no information on the gut microbial community composition or functional properties.The impact of early-life dysbiosis on the risk of developing several human diseases has led to the hypothesis that there is a critical window during which changes in the gut microbiome are most influential in immune development. During this “window of opportunity,” the infant gut harbors a highly variable and increasingly diverse microbial community of low resilience, which renders it easily disrupted by disturbances such as antibiotic treatments . During Many studies have argued that a loss of community diversity could indicate a disruption of the natural infant gut microbiome community. After birth, both the taxonomic and functional diversity of the infant bacterial microbiome have been shown to increase . Life-thFaecalibacterium, Lachnospira, Rothia, and Veillonella), fecal acetate and deconjugated bile acids were significantly altered in babies at risk of asthma. By contrast, Kostic et al.  will provide key information for the development of diagnostic tools.The increase in both taxonomic and functional diversity of the infant bacterial gut microbiome in the few months after birth appears to be associated with multiple aspects of the immune system development, providing further evidence that the immune system relies on a temporally structured succession of the gut microbiome. However, the infant gut microbial diversity Bifidobacterium and Bacteroides to be keystone taxa and their role on infant immune system training.In community ecology, the concept of a keystone species or group of species is described as an actor of a community that is so important to its organization and diversity that losing it provokes a massive cascade of extinctions and loss of ecosystem function , 24, 127B. longum is the predominant species in the human gut, but several B. longum subspecies have different levels of adaptability and functionality in the infant gut. B. longum subsp. infantis (Bifidobacterium infantis), B. longum subsp. longum (B. longum), and B. longum subsp. breve (B. breve) are commonly isolated from healthy breastfed infant feces, while formula-fed infants are also colonized with Bifidobacterium adolescentis -17 -induced production of multiple inflammatory cytokines and chemokines (Another species involved in immune system development is  (IL)-17 . Monocolesponses . In addiammation . B. fragemokines .Bacteroides and immune system training suggest that, although they are important members of the early gut microbiome, an overabundance of Bacteroides spp. and a corresponding increase of exposure to their LPS, result in improper stimulation of the innate immune system and in inhibition of LPS tolerance in non-obese diabetic mice. This mechanism was proposed to explain the disparity in type 1 diabetes incidence in Northern Europe, where Russian children have reduced Bacteroides spp. abundance and lower disease rates, compared to Finnish and Estonian children  and host biology, and depending heavily on auto-correlated local interactions between microbial groups. Further understanding of this complex adaptive system will also require (1) sampling a variety of geographically distinct human populations, (2) carrying out longitudinal cohorts that sample numerous times during the first 12 months, and (3) combining amplicon-based surveys with functional assays, such as metagenomics and metabolomics.In this review, we advocate that the infant gut microbiome should be considered as a complex adaptive system crucial to the maintenance of various emergent properties . These ecosystem properties are hardly attributable to a single group, instead they seem to rely on a temporally structured pattern of bacterial diversity increase after birth and the succession of particular keystone groups. The properties of complex adaptive systems highlight the great challenges faced by studies of the infant gut microbiome: a system far-from equilibrium dynamics, characterized by permanent novelty and incessant adaptation, dispersed multi-level interactions, and the absence of a global controller . The emeAnother important influence in gut microbiome composition that remains vastly unexplored is the role of non-bacterial microorganisms. The role of the virome, the collection of viruses colonizing the host, has been previously explored in adult animals. Similarly to the bacteriome, the virome strongly interacts with the host immune system, with both positive and negative consequences for host health [see Ref. –174 for Eventually, the identification of the critical events and factors that influence microbiome resilience and function will enable the development of effective interventions aimed at maintaining and/or improving immune system development and disease prevention. Although an astounding amount of work has been carried out to understand the reliance of the immune system on the infant gut microbiome, much remains to be elucidated on the particular mechanisms responsible for this training. Improvements in our understanding will arise from continuing multidisciplinary joint efforts between immunologists, microbiologists, clinicians, bioinformaticians, and ecologists.M-CA formulated the concept for this review, and IL-L wrote the first draft. Both authors co-wrote and revised the entire review article.The authors declare that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Resilin is an elastomeric protein typically occurring in exoskeletons of arthropods. It is composed of randomly orientated coiled polypeptide chains that are covalently cross-linked together at regular intervals by the two unusual amino acids dityrosine and trityrosine forming a stable network with a high degree of flexibility and mobility. As a result of its molecular prerequisites, resilin features exceptional rubber-like properties including a relatively low stiffness, a rather pronounced long-range deformability and a nearly perfect elastic recovery. Within the exoskeleton structures, resilin commonly forms composites together with other proteins and/or chitin fibres. In the last decades, numerous exoskeleton structures with large proportions of resilin and various resilin functions have been described. Today, resilin is known to be responsible for the generation of deformability and flexibility in membrane and joint systems, the storage of elastic energy in jumping and catapulting systems, the enhancement of adaptability to uneven surfaces in attachment and prey catching systems, the reduction of fatigue and damage in reproductive, folding and feeding systems and the sealing of wounds in a traumatic reproductive system. In addition, resilin is present in many compound eye lenses and is suggested to be a very suitable material for optical elements because of its transparency and amorphousness. The evolution of this remarkable functional diversity can be assumed to have only been possible because resilin exhibits a unique combination of different outstanding properties. Schistocerca gregaria) , Aeshna [Elastomeric proteins occur in a large range of organisms and biological structures, and the spectrum of their biological functions is very broad . They fe, Aeshna . Additio, Aeshna –4 result, Aeshna . Resilin, Aeshna . Within , Aeshna –8. Such , Aeshna .The mechanical properties of resilin strongly depend on the degree of hydration because resilin is plasticised by water . When re44Until today, resilin has been found to exist mainly in insect exoskeleton structures where this protein has a number of different functions, which include (1) the storage of elastic energy in jumping systems –20, (2) The properties of resilin-containing exoskeletons can strongly differ between structures and organisms. The reason is that in biological structures resilin seems to be rarely present in pure or nearly pure form but is known to commonly exist together with other proteins and/or chitin fibres in resilin-containing composites, which exhibit a mixture of the properties of the single components. In such composites, the resilin properties can even be ‘overlain’ by the properties of the other components making an identification of the presence of resilin in the respective structures with the criteria of Andersen and Weis-Fogh  very difIn order to allow a classification of exoskeleton structures as resilin-containing exoskeleton according to the definition of Andersen and Weis-Fogh , these sDrosophila melanogaster pro-resilin (rec1-resilin) was developed and has been shown to be cross-reactive and to label resilin in different insects [13The described resilin identification and visualization methods are not absolutely specific. Therefore, it is strongly advisable to apply not only one single method but a combination of several different ones to increase the reliability of the identification and detection of resilin. In recent years, an antibody to a recombinant  insects –1341–42.The development and improvement of methods applying techniques such as micromechanical testing, atomic force microscopy and confocal laser scanning microscopy (CLSM) have facilitated detailed studies of the distribution, composition and mechanical properties of resilin-containing exoskeleton structures in diverse organisms and at different levels of their organisation. One of these methods utilises a combination of different autofluorescences. In addition to resilin, other arthropod exoskeleton materials also exhibit autofluorescences, which can be efficiently visualized with fluorescence microscopy. This allows the production of overlays consisting of different micrographs that show different autofluorescences. Such overlays nicely exhibit differences in the autofluorescence composition, which are good indications for differences in the material composition and clearly reveal structures with relatively large resilin proportions within the analysed specimens ,23,43. HIf the autofluorescences are visualized by means of CLSM, the results will be very detailed and precise . With a Very often, gradients of the material composition with a considerably changing proportion of resilin are present in arthropod exoskeleton structures. Such resilin proportion gradients must also be reflected by gradients of the mechanical properties of the respective resilin-containing composites. The material composition of adhesive tarsal setae of beetles  represenResilin is known from numerous arthropod exoskeletons where it is present in diverse structures and allows manifold functions, which in most cases are based on its very pronounced elasticity and its ability to completely recover after deformation. For example, resilin plays an important role in flight systems of insects, in particular in insects that use a wing beat with a low frequency 10–50 Hz) (see below). Resilin-containing exoskeleton structures have been described for various mechanical systems including leg joints ,50, vein Hz  , for example, membranous cuticle with large proportions of resilin forms a spring-like (or joint-like) element (Membranous cuticle often contains large proportions of resilin . Example element –C that m element .Libellula depressa) contains relatively large proportions of resilin, while the neighbouring sclerites are mainly composed of sclerotised chitinous material [The neck membrane of dragonflies is another example. This flexible cuticle connects the neck sclerites and enables an extensive mobility of the head . A recenmaterial   (Cercopidae), the complete extension of the hind leg takes less than one millisecond [In Auchenorrhyncha and Sternorrhyncha, the jumps are performed by metathoracic muscles that are directly connected to the trochanter of the hind leg and responsible for the movements of both trochanter and coxa ,74 Figu. In the lisecond  ) and a long fatigue time are of key importance for the functioning of this structure.One of these flight system elements is a sausage-like swollen thoracic dragonfly tendon, which consists of virtually pure resilin and connects the pleuro-subalar muscle  to the subalar sclerite, which in turn connects to the axillary sclerites of the wing base  Figure ,B. TogetCalliphora, Bombus, Apis and Oryctes [The wing hinge ligament of the forewing of locusts is located between the (meso-)pleural wing process and the second axillary wing sclerite . In Odon Oryctes ,84. So f Oryctes ,81,83,85The prealar arm is located at the front edge of the mesotergum and establishes a connection to the first basalar sclerite of the pleural thoracic wall via a tough, flexible ligament . The basCross veins in wings of dragonflies and damselflies were shown to form either stiff, inflexibly fused joints or flexible, resilin-bearing joints to the adjacent longitudinal veins –2678,86 26Apis mellifera) and assumed that they might play an analogous role in increasing the chordwise wing flexibility. Based on the distribution of resilin patches, wing veins, the occurrence of a flexible hook-mediated forewing–hindwing connection and observed wing deformations, they further suggested the existence of five flexion lines in one forewing–hindwing entity and assumed that these probably increase the cordwise flexibility and support camber formation. In addition, Mountcastle and Combes [By artificially stiffening single flexible, resilin-bearing vein joints in bumblebee wings through the application of micro-splints (extra-fine polyester glitter glued with cyanoacrylate), it was experimentally shown that even a single resilin-bearing joint plays an important role in overall wing flexibility and vertical aerodynamic force production . Ma et ad Combes  demonstrd Combes .Forficula auricularia) and the lesser earwig (Labia minor)) or by wing flapping  [The occurrence of resilin in several broadened vein patches as well as in membranous folding lines was described for fan-like dermapteran hind wings ,92. Thesmus sp.) ,93. Bothmus sp.) ,93. Thesmus sp.) .In beetle wings, resilin was found to occur at the marginal joint, between veins that separate during folding, and along flexion lines in membranous areas, leading to the hypothesis that elastic energy storage by resilin can support wing unfolding also in beetle wings . HoweverCalliphora vicina), resilin is mainly present in the proximal part of the wing, predominantly in the form of resilin-bearing patches between veins [In wings of the urban bluebottle blowfly (en veins . The occen veins .Coccinella septempunctata) [The contact formation of insect adhesive pads on substrates depends on the ability of the pads to adapt to the surface topography. In this context, specific micro- and nanostructures can enhance the quality of the contact –101. In unctata)   . Since tunctata)   .Tettigonia viridissima) (Ensifera) and the migratory locust (Locusta migratoria) (Caelifera), whose adhesive pads generally have a similar structural organisation [L. migratoria feature a clearly thicker superficial layer as well as a higher density of rods than those of T. viridissima  lose water much faster than those of L. migratoria . This prey-capture apparatus can be protruded towards a prey within a few milliseconds. When sticky pads (modified paraglossae), which are located at the distal end of the prementum, adhere to the prey, the labium is withdrawn immediately, and thereby the prey is transported to the mouth region of the beetle where it can be seized with the mandibles [A remarkable resilin-containing adhesive prey-capture device, which is formed by the elongated labium, exists in rove beetles of the genus andibles –118. TheCentropages hamatus feature two larger and relatively compact teeth , this organ is located on the right side of the ventral abdomen part where it is visible as a notch-like modification of the posterior edge of the fifth segment that exposes the subjacent intersegmental membrane and cuticle of the sixth segment , for example, hair plate sensilla with rather long and relatively thick hairs are present  in compound eye lenses has been described for different arthropods ,131–134 Exoskeleton structures with large proportions of resilin are common among arthropods. This review demonstrates the broad range of resilin functions in various exoskeleton structures. Resilin facilitates flexibility and compliance, elastic energy storage, elastic recovery, fatigue and damage reduction, sealing and transparency and thereby makes the respective exoskeleton systems rather effective. Due to its remarkable combination of different properties, resilin is a highly efficient multi-functional protein. In addition, together with other compounds and materials, it often forms complex and powerful composites that combine the properties and benefits of the single components and are capable of performing rather specific and challenging functions. These characteristics have very likely been the reason for the evolution of the large functional diversity of resilin-containing exoskeleton structures in arthropods.


The salience network (SN) plays a central role in cognitive control by integrating sensory input to guide attention, attend to motivationally salient stimuli and recruit appropriate functional brain-behavior networks to modulate behavior. Mounting evidence suggests that disturbances in SN function underlie abnormalities in cognitive control and may be a common etiology underlying many psychiatric disorders. Such functional and anatomical abnormalities have been recently apparent in studies and meta-analyses of psychiatric illness using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM). Of particular importance, abnormal structure and function in major cortical nodes of the SN, the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), have been observed as a common neurobiological substrate across a broad spectrum of psychiatric disorders. In addition to cortical nodes of the SN, the network’s associated subcortical structures, including the dorsal striatum, mediodorsal thalamus and dopaminergic brainstem nuclei, comprise a discrete regulatory loop circuit. The SN’s cortico-striato-thalamo-cortical loop increasingly appears to be central to mechanisms of cognitive control, as well as to a broad spectrum of psychiatric illnesses and their available treatments. Functional imbalances within the SN loop appear to impair cognitive control, and specifically may impair self-regulation of cognition, behavior and emotion, thereby leading to symptoms of psychiatric illness. Furthermore, treating such psychiatric illnesses using invasive or non-invasive brain stimulation techniques appears to modulate SN cortical-subcortical loop integrity, and these effects may be central to the therapeutic mechanisms of brain stimulation treatments in many psychiatric illnesses. Here, we review clinical and experimental evidence for abnormalities in SN cortico-striatal-thalamic loop circuits in major depression, substance use disorders (SUD), anxiety disorders, schizophrenia and eating disorders (ED). We also review emergent therapeutic evidence that novel invasive and non-invasive brain stimulation treatments may exert therapeutic effects by normalizing abnormalities in the SN loop, thereby restoring the capacity for cognitive control. Finally, we consider a series of promising directions for future investigations on the role of SN cortico-striatal-thalamic loop circuits in the pathophysiology and treatment of psychiatric disorders. Psychiatric illnesses are among the leading causes of disability and disease burden worldwide in the 21st century. For example, the 2010 Global Burden of Disease study identified major depressive disorder (MDD) as the second leading cause of years of life lost to disability  and diffusion tensor imaging (DTI), as well as functional imaging techniques including functional magnetic resonance imaging (fMRI), and positron emission tomography (PET).Over the last 25 years, one of the major advances in the field has been the development of increasingly detailed maps of the neural pathways that are affected in psychiatric illnesses. Steady progress is being made in localizing abnormalities of both brain structure and brain function. The neurologist’s traditional question, “Where is the lesion?”, formerly had few well-defined answers for most psychiatric disorders. However, today there is at least a first approximation of an answer to this question for many of the most prevalent types of mental illness. Progress in localizing psychiatric neuropathology has come from advances in non-invasive neuroimaging techniques suitable for In healthy control subjects, application of these brain-imaging techniques has been especially fruitful for delineating the overall functional architecture of the human brain. One major discovery has been that brain activity, during tasks or at rest, is organized into functional networks of regions showing correlated activity over time. The networks themselves appear to be fairly consistent across individuals, with one influential report identifying a set of seven reliably reproducible major networks, subdivisible into a finer set of 17 smaller subnetworks  and anxiety disorders  the MDN, the dorsal striatum and dopaminergic nuclei within the midbrain and brainstem. The striatum, along with the entire basal ganglia, is important in coordinating and sequencing the diverse functions of the frontal lobes, from goal formation to executive function to cognition and the selection of specific actions and movements  that assists in flexible action selection by integrating information from cortical, limbic and basal ganglia regions  that are distressing and disruptive to normal function, followed by repetitive actions (compulsions) aimed at reducing the associated distress  has the highest mortality of any psychiatric disorder  may have modulatory downstream effects on the dACC by propagating stimulation effects through the rostral cingulate cortex  has been successful in some cases of treatment-resistant depression, with responders showing improvements in hedonic capacity  correlate to the behavioral and clinical effects of rTMS?Regarding the first question, the neurophysiological mechanisms of rTMS are complex and still under investigation; accounts have been proposed at various levels of explanation from genetic and cell-molecular processes, to neurotransmitters and their receptors to synapses, to micro- and macro-level network connectivity changes  delivered to the left dlPFC impaired performance on the Montreal Card Sorting Task, a set-shifting task requiring the cognitive control functions of the SN. This impairment was associated with reduced dopamine release in a circumscribed region of the head of the caudate nucleus  electrical currents to target brain regions, thereby modulating ongoing brain activity . Alternative possibilities are that the therapeutic effects of tDCS ensue purely through modulation of cortico-cortical network connectivity, or conceivably through local modulation of synaptic connections under the cortical stimulation site alone. Future studies of therapeutic tDCS in psychiatric illness will need to incorporate not only larger sample sizes, but also more detailed measures of cognitive control capacity, as well as neuroimaging observations before and after treatment, in order to identify the behavioral and neural correlates of clinical improvement. Such studies may help to determine whether tDCS of SN nodes enhances cognitive control, and if so, whether this enhancement ensues via modulation of the SN-CSTC loop circuits.The emerging picture from the evidence reviewed in the previous three sections is that: (i) the SN-CSTC loop may play a critical role in the voluntary engagement of cognitive control; (ii) abnormalities of cognitive control are a common, pervasive and transdiagnostic feature of many psychiatric illnesses; (iii) these transdiagnostic deficits of cognitive control may arise from abnormalities of functioning within a specific member of the brain’s many CSTC loops—namely, the CSTC loop serving the SN; and (iv) emerging brain stimulation therapies such as DBS, rTMS and tDCS exert neurophysiological effects on targeted CSTC loop circuits, and these effects may be central to the mechanisms by which they alleviate psychiatric illness.At the moment, this account of the CSTC loop through the SN must be considered preliminary, with many findings requiring further replication and study, and many questions still outstanding. In this final section, we review some potentially fruitful directions for further study.At present, it would be helpful to have a clearer understanding of the SN’s role in cognitive control. Specifically, more information should be generated about the contributions of the SN to self-regulation of cognition, emotion and behavior in healthy brain function. The particular contributions of the SN should be distinguished from contributions of other functional networks involved in executive function, such as the neighboring frontoparietal networks known as dorsal attention or central executive networks. It would also be helpful to have a clearer understanding of the distinct roles of the SN vs. its immediately posterior counterpart comprising the posterior insula and mid-cingulate cortex. Finally, it is necessary to better understand how engagement of the subcortical projection sites of the SN  relates to the voluntary vs. passive engagement of cognitive control functions.within each disease category, or whether instead only a certain sub-population of patients within MDD, PTSD, OCD or SUD show abnormalities of SN-CSTC functioning. The latter case, if true, may help to explain the problematic heterogeneity of outcomes currently seen with brain stimulation therapies, and may lead to methods for predicting which individuals are the best candidates for treatments targeting the SN-CSTC loop circuits. Better characterization of individual patients’ pathology using the Research Domain Criteria  may be useful in this regard  where such pathology is relatively absent. Finally, as relatively few studies to date have explored the neural heterogeneity of illness among individuals with MDD, PTSD, OCD, SUD or other Axis I disorders (as defined by the DSM-IV), it will be helpful to understand whether SN-CSTC pathology is a pervasive feature across most individuals only, or even the most important, pathological feature in many individuals. For example, pathology of the “reward” or “incentive” CSTC loop from the NAcc to the vmPFC and frontal pole increasingly appears to be important across a variety of disorders. Aside from the well-established example of SUD, pathology of this loop may be important in OCD, MDD (particularly for the symptom of anhedonia), schizophrenia, and other psychiatric disorders (as noted throughout the previous three sections of this review). In addition, interactions  between the activity of the dorsal striatal-SN loop and the ventral striatal reward loop may be important for understanding psychiatric pathology and its heterogeneity; such interactions between dorsal and ventral CSTC loops are an increasingly prevalent theme of study in recent work combining neuroimaging and neurostimulation in psychiatric illness  will be essential in assessing the direct effects of stimulation on neural activity. Much of the available literature to date has focused on motor CSTC loops rather than other prefrontal loops. However, in light of the increasing popularity of brain stimulation in treating psychiatric illness, more attention is due to the SN-CSTC loop in future study.which types of patients respond best to treatment, or whether responders are characterized specifically by deficiencies of cognitive control rather than conventional mood symptoms per se, as proposed in this review. A more nuanced outcome measure  may be helpful in providing a benchmark for optimizing the parameters of stimulation. For example, if the mechanism of effect for dlPFC- or dmPFC-rTMS does indeed depend upon enhancements in deficient cognitive control and SN-CSTC loop circuit integrity, then obtaining markers of cognitive control and SN integrity will be essential to any parameter-optimization study. Candidate markers might include behavioral measures such as performance on flanker or delayed discounting tasks, electrophysiological measures such as coupling between theta and gamma oscillations, or neuroimaging markers such as D2 receptor occupancy on PET or SN-striatal-thalamic functional connectivity on fMRI. Future studies of therapeutic brain stimulation may need to make use of such markers in order to make progress in exploring the many dimensions of stimulation parameters that are still awaiting optimization. Future studies involving fMRI should also consider the false-positive rate of fMRI in the application of past research, and study design and processing  for therapeutic brain stimulation as a primary aim. The assessment of relative efficacy in most cases has been empirical, based on clinical measures  that may not be well suited to capturing the nuanced effects of therapeutic brain stimulation. For example, after 20 years of clinical trials of rTMS in MDD, there is a wealth of evidence about crude response and remission rates for this heterogeneous population, but very little evidence about Converging evidence suggests that, of the brain’s many CSTC loop circuits, the specific circuit serving the SN may be of particular relevance to cognitive control, and of transdiagnostic relevance to psychiatric pathology. This proposal, if supported by future work, is of more than purely academic interest. With the emergence of anatomically selective brain stimulation technologies as therapeutic tools, it is becoming possible to target specific CSTC loop circuits of the brain in an increasingly precise manner, and to modulate their activity in a variety of ways. Therapeutic brain stimulation of the SN-CSTC loop circuit may constitute a method for directly targeting the underlying pathophysiology of several types of psychiatric illness, or at least a subpopulation of individuals within these categories of illness. Stimulation targeting other CSTC loops, such as those through the ventral striatum, may further expand the range of disorders and individuals whose illness is amenable to brain stimulation treatments. With a better understanding of CSTC function in health and psychiatric disease, it may become possible to tailor the target and parameters of stimulation to the individual, depending on the underlying pathology. This individualized, brain-based approach to psychiatric treatment would constitute an important step forward in addressing the daunting prevalence and burden of mental illness around the world.SKP, KD and JD wrote and edited the manuscript and figures.SKP has received funding from the University of Toronto Ontario Graduate Fund. KD has received funding from the Canadian Institute for Health Research (CIHR) Vanier Scholarship. JD has received research support from CIHR, NIH, the Klarman Family Foundation, the Buchan Family Foundation and the Toronto General and Western Hospital Foundation. He has also received a travel stipend from Lundbeck and from ANT Neuro, and in-kind equipment support for an investigator-initiated study from Tonika/Magventure.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.


C) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.The prion glycoprotein (PrP Thus, FTgpi bound the endoplasmic reticulum (ER) chaperone Immunoglobulin heavy chain-Binding Protein/Glucose-Regulated Protein 78 (Bip/GRP78), and such binding was followed by sustained ER stress, reduced FTgpi protein/mRNA ratio due to rapid proteolysis, as well as activation of the Protein Kinase R-like ERKinase (PERK), and cell death  motility and extension of neurites, through in trans interactions that depend on cell surface PrPC as well as NCAM, both of which are recruited to common sites at the GC plasma membrane, and involve the activation of several downstream signaling pathways , showed that the relative content of the unglycosylated and glycosylated forms differed between the two samples , thus preventing proper cAMP-dependent regulation of the latter, and leading to delayed repolarization of the ventricular action potential  aC as a scaffold protein appears to be the closest to philosophical concepts of biological function, which imply an unambiguous, unconditional, generalized property of a biological unit (Cummins, C, such a concept recommends a wider, systemic approach to the variety of signaling modules scaffolded by the prion protein in either physiological or pathophysiological contexts. In view of the failure of several clinical trials directed at either the TSEs or AD (Stewart et al., The recognition of PrPCummins, . Rather RL is the sole author and fully responsible for this article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objective: Several longitudinal studies had shown that early deprivation and institutionalization during the first six months of life affects the emotional, cognitive, social and neurophysiologic development. Nevertheless, our understanding of possible similar effects of delayed institutionalization, in preschool-age remains unclear to this day. The goal of this study is to evaluate the cognitive performance of institutionalized children with history of preschool-age physical abandonment.Method: 18 male institutionalized children with history of abandonment during the preschool-age (2–5 years old) and comparison group matched by age, handedness, gender, educational and socioeconomic level were tested on multiple tasks of attention, memory and executive functions.Results: We found a cognitive impairment in the institutionalized children in several measures of attention, memory and executive functions. This is the first report of cognitive impairment related to late abandonment and institutionalization effects (after 2 years old), extending the already known effects on early institutionalization.Conclusions: This preliminary study suggests that environmental factors including abandonment and institutional care, can affect not only the infancy period, but also the preschool period providing new insights into our understanding of neurocognitive development.


The advances in the suspensor.During early embryogenesis, the proembryo consists of two domains, the embryo proper and the suspensor. Unlike the embryo proper, which has been investigated extensively, research on the suspensor has been limited in past decades. Recent studies have revealed that the suspensor plays an important role in early embryogenesis and the process of suspensor formation and degeneration may provide a unique model for studies on cell division pattern, cell fate determination, and cell death. In this review, we briefly summarize the advances in research on the suspensor, which provide new insight in our understanding of the mechanism of early embryogenesis and show great potential for a unique model for future investigations. Nicotiana tabacum, the larger basal cell divides twice vertically to produce a four-cell suspensor , encoding a mitogen-activated protein kinase kinase (MAPKK) kinase, and its downstream MAPKs MPK3/6 are required for zygote elongation and asymmetric division , a member of the receptor-like kinases (RLK)/Pelle family in Arabidopsis, has been useful to determine the contribution of zygote asymmetric division and its elongation to its daughter cell fate determination , the suspensor cells failed to generate a second embryo , has been shown to positively regulate PCD  underlying suspensor generation, development, and degeneration.Our understanding of suspensor development has increased greatly over the past 10 years; however, many key issues still remain to be determined. Although research has confirmed transcript differences between apical and basal cells, the mechanisms controlling the polar distributions of specific transcripts in the zygote and the proportions of these specific transcripts into the apical or basal cell are unknown. Some genes have been found to contribute to the asymmetric division of the zygote and show specific localization in apical or basal cells, while the molecules controlling the fate of the daughter cells of the zygote need further investigation. Cell division is always horizontal in the suspensor, unlike in the embryo proper (Zhao et al. Further transcriptome analysis based on new sequencing techniques will identify additional genes specifically expressed in apical and basal cells, the hypophysis, and the suspensor, which will help in elucidating the cell fate determinants of these cells. Additionally, investigating the signal cascades of the known genes involved in suspensor development will deepen our understanding of the mechanisms of this process.Mengxiang Sun and Xiongbo Peng wrote and reviewed the manuscript.