Assessment of the chemical composition of buriti (Mauritia flexuosa Liliopsida) and cassava (Manihot esculenta Crantz) residues and their possible application in the bioproduction of coconut aroma (6 pentyl-α-pyrone).

This work aimed to define strategies to increase the bioproduction of 6 pentyl-α-pyrone (bioaroma). As first strategy, fermentations were carried out in the solid state, with agro-industrial residues: Mauritia flexuosa Liliopsida. and Manihot esculenta Crantz in isolation, conducting them with different nutrient solutions having Trichoderma harzianum as a fermenting fungus. Physicochemical characterizations, centesimal composition, lignocellulosic and mineral content and antimicrobial activity were required. Fermentations were conducted under different humidification conditions (water, nutrient solution without additives and nutrient solutions with glucose or sucrose) for 9 days. Bioaroma was quantified by gas chromatography, assisted by solid-phase microextraction. The results showed the low production of this compound in fermentations conducted with sweet cassava (around 6 ppm (w/w)). The low bioproduction with sweet cassava residues can probably be related to its starch-rich composition, homogeneous substrate, and low concentration of nutrients. Already using buriti, the absence of aroma production was detected. Probably the presence of silicon and high lignin content in buriti minimized the fungal activity, making it difficult to obtain the aroma of interest. Given the characteristics presented by the waste, a new strategy was chosen: mixing waste in a 1:1 ratio. This fermentation resulted in the production of 156.24 ppm (w/w) of aroma using the nutrient solution added with glucose. This combination, therefore, promoted more favorable environment for the process, possibly due to the presence of fermentable sugars from sweet cassava and fatty acids from the buriti peel, thus proving the possibility of an increase of around 2500% in the bioproduction of coconut aroma.

The effect of hydrostatic pressure on lipid membrane lateral structure.

High pressure is both an environmental challenge to which deep sea biology has to adapt, and a highly sensitive thermodynamic tool that can be used to trigger structural changes in biological molecules and assemblies. Lipid membranes are amongst the most pressure sensitive biological assemblies and pressure can have a large influence on their structure and properties. In this chapter, we will explore the use of high pressure small angle X-ray diffraction and high pressure microscopy to measure and quantify changes in the lateral structure of lipid membranes under both equilibrium high pressure conditions and in response to pressure jumps.

Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy.

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Advice after urgent suspected cancer referral when cancer is not found in England: Survey of patients' preferences and perceived acceptability.

Objective: No standardised approach exists to provide advice after urgent suspected cancer (USC) referral when cancer is not found. This study aimed to assess preferences and acceptability of receiving advice after USC referral related to: 1) managing ongoing symptoms, 2) responding to early symptoms of other cancers, 3) cancer screening, 4) reducing risks of future cancer. Methods: 2,541 patients from two English NHS Trusts were mailed a survey 1-3 months after having no cancer found following urgent suspected gastrointestinal or head and neck cancer referral. Participants were asked about: willingness to receive advice; prospective acceptability; preferences related to mode, timing and who should provide advice; and previous advice receipt. Results: 406 patients responded (16.0%) with 397 in the final analyses. Few participants had previously received advice, yet most were willing to. Willingness varied by type of advice: fewer were willing to receive advice about early symptoms of other cancers (88.9%) than advice related to ongoing symptoms (94.3%). Acceptability was relatively high for all advice types. Reducing the risk of future cancer advice was more acceptable. Acceptability was lower in those from ethnic minority groups, and with lower levels of education. Most participants preferred to receive advice from a doctor; with results or soon after; either face to face or via the telephone. Conclusions: There is a potential unmet need for advice after USC referral when no cancer is found. Equitable intervention design should focus on increasing acceptability for people from ethnic minority groups and those with lower levels of education.

Adenovirus infections after allogeneic hematopoietic cell transplantation in children and adults: a study from the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation.

The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children.

FDA, CDC, and NIH Co-sponsored Public Workshop Summary-Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.

There is an unmet need for developing drugs for the treatment of gonorrhea, due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets. On April 23, 2021, the U.S. Food and Drug Administration; Centers for Disease Control and Prevention; and National Institute of Allergy and Infectious Diseases, National Institutes of Health co-sponsored a workshop with stakeholders from academia, industry, and regulatory agencies to discuss the challenges and strategies, including potential collaborations and incentives, to facilitate the development of drugs for the treatment of gonorrhea. This article provides a summary of the workshop.

Gobionellus stomatus Starks 1913 (Oxudercidae: Gobionellinae): range extension for the coastal zone of the Brazilian Amazon region.

Gobionellus stomatus, a fish species endemic to Brazil, was previously known to occur from the State of Piauí to the State of Rio Grande do Sul. Here we present the first record of this species for the State of Maranhão, specifically for the Upaon-Açu island, extending its distribution further west, to the coastal zone of the Amazon region. This species inhabits estuarine ecosystems susceptible to environmental pressures, such as pollution and the introduction of non-native species. Despite G. stomatus being classified as of least concern for conservation, it is crucial to highlight potential risks associated with human activities in these environments, emphasizing the importance of preservation measures to mitigate future impacts on the populations of this species, as well as of other estuarine gobies.

An In Vitro Study of Retention and Marginal Adaptation of Endocrowns With Different Intracoronal Depths.

BACKGROUND: Marginal adaptation and retention of endocrowns are crucial for the success and survival of endocrowns. This study aimed to investigate the effect of different materials and intracoronal depth on the retention and marginal adaptation of CAD/CAM fabricated all-ceramic endocrowns. METHODS: Thirty-six mandibular premolar teeth with an average surface area of 64.49 mm2 were prepared to receive CAM/CAM fabricated endocrowns. Samples were divided randomly and equally into groups of lithium disilicate with 2 mm intracoronal depth (LD2), lithium disilicate with 4 mm intracoronal depth (LD4), polymer infiltrated ceramic network with 2 mm intracoronal depth (PICN2) and polymer infiltrated ceramic network with 4 mm intracoronal depth (PICN4). All endocrowns were cemented using ParaCore resin cement with 14N pressure and cured for 20 seconds. Fifty measurements of absolute marginal discrepancy (AMD) were done using a stereomicroscope after cementation. After 24 hours, all samples were subjected to thermocycling before the retention test. This involved using a universal testing machine with a crosshead speed of 0.5 mm/min and applying a load of 500N. The maximum force to detach the crown was recorded in newtons and the mode of failure was identified. RESULTS: Two-way ANOVA revealed that the AMD for PICN was statistically significantly better than lithium disilicate (p=0.01). No statistically significant difference was detected in the AMD between the two intracoronal depths (p=0.72). PICN and endocrowns with 4 mm intracoronal depth had statistically significant better retention (p<0.05). 72.22% of the sample suffered from cohesive failures and 10 LD endocrowns suffered adhesive failures. CONCLUSIONS: Within the limitations of this study, we found that different materials and intracoronal depths can indeed influence the retention of CAD/CAM fabricated endocrowns. Based on the controlled setting findings, PICN was found to have better retention and better marginal adaptation than similar lithium disilicate premolar endocrowns.

Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression.

Electroconvulsive shocks (ECS) and ketamine are antidepressant treatments with a relatively fast onset of therapeutic effects compared to conventional medication and psychotherapy. While the exact neurobiological mechanisms underlying the antidepressant response of ECS and ketamine are unknown, both interventions are associated with neuroplasticity. Restoration of neuroplasticity may be a shared mechanism underlying the antidepressant efficacy of these interventions. In this systematic review, literature of animal models of depression is summarized to examine the possible role of neuroplasticity in ECS and ketamine on a molecular, neuronal, synaptic and functional level, and specifically to what extent these mechanisms are shared between both interventions. The results highlight that hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) levels are consistently increased after ECS and ketamine. Moreover, both interventions positively affect glutamatergic neurotransmission, astrocyte and neuronal morphology, synaptic density, vasculature and functional plasticity. However, a small number of studies investigated these processes after ECS. Understanding the shared fundamental mechanisms of fast-acting antidepressants can contribute to the development of novel therapeutic approaches for patients with severe depression.

Hematopoietic stem cell transplantation for DLBCL: a report from the European Society for Blood and Marrow Transplantation on more than 40,000 patients over 32 years.

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990-1999) to 46% (2015-2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies.

Neuroimaging and fluid biomarkers in Parkinson's disease in an era of targeted interventions.

A major challenge in Parkinson's disease is the variability in symptoms and rates of progression, underpinned by heterogeneity of pathological processes. Biomarkers are urgently needed for accurate diagnosis, patient stratification, monitoring disease progression and precise treatment. These were previously lacking, but recently, novel imaging and fluid biomarkers have been developed. Here, we consider new imaging approaches showing sensitivity to brain tissue composition, and examine novel fluid biomarkers showing specificity for pathological processes, including seed amplification assays and extracellular vesicles. We reflect on these biomarkers in the context of new biological staging systems, and on emerging techniques currently in development.

Immune Dysfunction in Schizophrenia Spectrum Disorders.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

Dietary fiber source and direct-fed microbial supplementation effects on lactation performance and feeding behavior of high-producing dairy cows.

The objective of this study was to evaluate the effects of dietary fiber source and direct-fed microbial supplementation on lactation performance and feeding behavior of high-producing dairy cows. Sixty-four multiparous Holstein cows (3.5 ± 1.6 lactations; 76 ± 22 DIM and 735 ± 67 kg of BW at covariate period initiation) and 32 gate feeders were enrolled in a study with a completely randomized design and a 2 × 2 factorial arrangement. Cows and gate feeders were randomly assigned to treatments (16 cows and 8 gate feeds per treatment). Cows were allowed 1 week to acclimate to feeding gates followed by a 2-week covariate period. During the acclimation and covariate periods, all cows were fed the same diet to meet or exceed the nutrient requirements. Following the covariate period, cows were enrolled in a 8-week treatment period during which cows were randomly assigned to 1 of 4 treatments consisting of forage inclusion in the diet, either 45.8% (LF) or 56.7% (HF) of DM, and the supplementation of 75 mL/hd/d of a direct-fed microbial (DFM) containing herbal extracts (mallow, mint, and sage), L. plantarum, L. buchneri, Saccharomyces cerevisiae, and sugar cane molasses (Valibiom Mix, Valibiotics, Traiskirchen, Austria) or without supplementation (CON). The average covariate period value of each variable was used as a covariate. Three-way interactions were observed for DMI and feed efficiency. Dry matter intake was 2 to 3 kg greater for LF-DFM than HF-CON and HF-DFM during wk 2, 3, 5, and 8 of the treatment period. Milk production was 2.1 kg/d greater for LF than HF diets. Both milk fat and MUN concentrations were greater for HF than LF diets. Conversely, milk protein concentration was lower for HF than LF diets. The respiration rate measured in the morning was lower with DFM supplementation than CON. Rectal temperature measured in the morning and averaged for the day were greater for LF than HF diets. Under the conditions of the present study, feeding high-forage diets may be an alternative for producers to reduce feeding costs depending on the price of purchased feeds. However, non-forage fiber sources (i.e., soy hulls) must be considered when producers are challenged by either forage shortages or forage with a lower nutritive value. Additionally, DFM supplementation reduced respiration rate in the morning and affected meal behavior of lactating cows.

Shock wave formation in radiative plasmas.

The temporal evolution of weak shocks in radiative media is theoretically investigated in this work. The structure of radiative shocks has traditionally been studied in a stationary framework. Their systematic classification is complex because layers of optically thick and thin regions alternate to form a radiatively driven precursor and a temperature-relaxation layer, between which the hydrodynamic shock is embedded. In this work we analyze the formation of weak shocks when two radiative plasmas with different pressures are put in contact. Applying a reductive perturbative method yields a Burgers-type equation that governs the temporal evolution of the perturbed variables including the radiation field. The conditions upon which optically thick and thin solutions exist have been derived and expressed as a function of the shock strength and Boltzmann number. Below a certain Boltzmann number threshold, weak shocks always become optically thick asymptotically in time, while thin solutions appear as transitory structures. The existence of an optically thin regime is related to the presence of an overdense layer in the compressed material. Scaling laws for the characteristic formation time and shock width are provided for each regime. The theoretical analysis is supported by FLASH simulations, and a comprehensive test case has been designed to benchmark radiative hydrodynamic codes.

Ubiquitin: Not just a one-way ticket to the proteasome, but a therapeutic dial to fine-tune the molecular landscape of disease.

Recently, there is a rise in studies that recognize the importance of targeting ubiquitin and related molecular machinery in various therapeutic contexts. Here we briefly discuss the history of ubiquitin, its biological roles in protein degradation and beyond, as well as the current state of ubiquitin-targeting therapeutics across diseases. We conclude that targeting ubiquitin machinery is approaching a renaissance, and tapping its full potential will require embracing a wholistic perspective of ubiquitin's multifaceted roles.

Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice.

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

Association between depression and ultra-processed food consumption: a population-based study (Vigitel, 2023).

OBJECTIVES: To evaluate the association of ultra-processed food (UPF) consumption with depression among Brazilian adults (≥18 years). STUDY DESIGN: Cross-sectional study. METHODS: Data were obtained from a population-based survey conducted in 2023 (n = 21,690). UPF consumption was investigated using a questionnaire regarding the consumption on the previous day of 13 subgroups of UPF selected from those most consumed in Brazil according to a previous national survey (cutoff score ≥5 subgroups). The medical diagnosis of depression was self-reported. Logistic regression models were used to estimate the adjusted (by sex, age, education, presence of partner/spouse, and overweight) Odds Ratio (aOR) of UPF consumption according to the presence of depression. Analyses were conducted for the total population and stratified by sex. RESULTS: Medical diagnosis of depression was reported by 12.3%. The prevalence of high UPF consumption (≥5 subgroups) was 17.7%, being higher in men (22.0%) and those with depression (19.3%). Depression increased the chance of presenting a high UPF consumption among the total population (aOR 1.35; CI 95% 1.08-1.68) and women (aOR 1.35; CI 95% 1.03-1.77), with no association among men. CONCLUSION: The presence of depression was associated with greater consumption of UPF among Brazilian adults, especially among the female population. Public health actions to reduce UPF consumption could benefit from targeting this population group.

Lack of Acute Agomelatine Effect in a Model of Social Anxiety in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST). METHODS: Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs. RESULTS: The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo. CONCLUSIONS: Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models.

Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes.

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings add additional evidence for LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.