Sex Differences in Intestinal Carbohydrate Metabolism Promote Food Intake and Sperm Maturation.

Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized.

The sex of organ geometry.

Organs have a distinctive yet often overlooked spatial arrangement in the body1-5. We propose that there is a logic to the shape of an organ and its proximity to its neighbours. Here, by using volumetric scans of many Drosophila melanogaster flies, we develop methods to quantify three-dimensional features of organ shape, position and interindividual variability. We find that both the shapes of organs and their relative arrangement are consistent yet differ between the sexes, and identify unexpected interorgan adjacencies and left-right organ asymmetries. Focusing on the intestine, which traverses the entire body, we investigate how sex differences in three-dimensional organ geometry arise. The configuration of the adult intestine is only partially determined by physical constraints imposed by adjacent organs; its sex-specific shape is actively maintained by mechanochemical crosstalk between gut muscles and vascular-like trachea. Indeed, sex-biased expression of a muscle-derived fibroblast growth factor-like ligand renders trachea sexually dimorphic. In turn, tracheal branches hold gut loops together into a male or female shape, with physiological consequences. Interorgan geometry represents a previously unrecognized level of biological complexity which might enable or confine communication across organs and could help explain sex or species differences in organ function.

Enteric neurons increase maternal food intake during reproduction.

Reproduction induces increased food intake across females of many animal species1-4, providing a physiologically relevant paradigm for the exploration of appetite regulation. Here, by examining the diversity of enteric neurons in Drosophila melanogaster, we identify a key role for gut-innervating neurons with sex- and reproductive state-specific activity in sustaining the increased food intake of mothers during reproduction. Steroid and enteroendocrine hormones functionally remodel these neurons, which leads to the release of their neuropeptide onto the muscles of the crop-a stomach-like organ-after mating. Neuropeptide release changes the dynamics of crop enlargement, resulting in increased food intake, and preventing the post-mating remodelling of enteric neurons reduces both reproductive hyperphagia and reproductive fitness. The plasticity of enteric neurons is therefore key to reproductive success. Our findings provide a mechanism to attain the positive energy balance that sustains gestation, dysregulation of which could contribute to infertility or weight gain.

An intestinal zinc sensor regulates food intake and developmental growth.

In cells, organs and whole organisms, nutrient sensing is key to maintaining homeostasis and adapting to a fluctuating environment1. In many animals, nutrient sensors are found within the enteroendocrine cells of the digestive system; however, less is known about nutrient sensing in their cellular siblings, the absorptive enterocytes1. Here we use a genetic screen in Drosophila melanogaster to identify Hodor, an ionotropic receptor in enterocytes that sustains larval development, particularly in nutrient-scarce conditions. Experiments in Xenopus oocytes and flies indicate that Hodor is a pH-sensitive, zinc-gated chloride channel that mediates a previously unrecognized dietary preference for zinc. Hodor controls systemic growth from a subset of enterocytes-interstitial cells-by promoting food intake and insulin/IGF signalling. Although Hodor sustains gut luminal acidity and restrains microbial loads, its effect on systemic growth results from the modulation of Tor signalling and lysosomal homeostasis within interstitial cells. Hodor-like genes are insect-specific, and may represent targets for the control of disease vectors. Indeed, CRISPR-Cas9 genome editing revealed that the single hodor orthologue in Anopheles gambiae is an essential gene. Our findings highlight the need to consider the instructive contributions of metals-and, more generally, micronutrients-to energy homeostasis.

Epidemiology of antiphospholipid syndrome: macro- and microvascular manifestations.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic and non-thrombotic macro- and microvascular manifestations and pregnancy complications in the setting of persistent antiphospholipid antibodies (aPL), namely anticardiolipin antibodies, anti-ß2 glycoprotein-I antibodies and lupus anticoagulant. Four decades after its first description, APS prevalence and incidence are still not completely understood due to the limited number of well-designed, population-based multi-ethnic studies. Furthermore, despite decades of efforts to standardise aPL immunoassays, considerable intraassay and interlaboratory variances in aPL measures still exist. Large multicentre APS cohorts have shown a 10-year survival of ∼91% and the presence of catastrophic APS occurs in about 1% of the entire population, associated with a 50% mortality rate. Clinically, any organ can be affected in the context of large, medium or small vessel (artery and/or vein) thrombosis. Macrovascular thrombosis is the hallmark of the disease and veins are more frequently affected than arteries. Deep vein thrombosis/pulmonary embolism thromboembolic disease is the most common APS manifestation, while stroke and transient ischaemic attack are the most frequent arterial thrombosis events. Myocardial infarction can also occur and contributes to increased mortality in APS. A minority of patients present with thrombosis affecting the intraabdominal organs, including the liver, spleen, small and large bowel, and the kidneys. Microvascular thrombosis, including APS nephropathy, chronic skin ulcers and livedoid vasculopathy represent a diagnostic challenge requiring histologic confirmation. In this narrative review we summarize the available evidence on APS epidemiology, focusing on the description of the prevalence of macro- and microvascular manifestations of the disease.

Predictors of damage accrual and its impact on health-related quality of life of thrombotic antiphospholipid syndrome: Independent validation of the damage index for antiphospholipid syndrome (DIAPS).

OBJECTIVES: We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL). METHODS: Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression. RESULTS: Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6 years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis. CONCLUSION: This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.

The pupillary dilation reflex to a nociceptive stimulus as a tool for analgesia management: A diagnostic study.

BACKGROUND: More than 70% of patients demonstrate pain after endotracheal aspiration. Tools are needed to objectify the need for analgesia in non-communicative critically ill patients. OBJECTIVE: The objective of this study was to identify the lowest intensity electrical stimulus for detecting pain before daily care interventions. METHODS: Study of diagnostic tests to assess pupillometry to detect pain through the pupillary dilation response to noxious stimuli versus the Behavioural Pain Scale. Patients older than 18 years, under analgosedation, subjected to invasive ventilation, baseline Behavioural Pain Scale of 3, and Richmond Agitation-Sedation Scale between -1 and -4 were studied. We assessed the Behavioural Pain Scale and the pupillary dilation response to 10, 20, 30, and 40 mA stimuli. We studied the diagnostic performance based on sensitivity and specificity, negative predictive value, positive predictive value, and accuracy of the selected points after the different stimulations. AlgiScan® Pupillometer measured the pupillary dilation response. The presence of pain was considered as a Behavioural Pain Scale score of ≥4. Significance was defined as p <0.05. RESULTS: Measurements were performed on 31 patients. In the 20 mA stimulus, we found an area under the curve of 0.85 (0.69-1.0). The cut-off point of pupillary dilation was 11.5%, with a sensitivity of 100% (34.2-100) and a specificity of 75.9% (57.9-87.8). This point had an accuracy of 77.4 (60.2-88.6) and a Youden's Index of 0.8. CONCLUSIONS: Pupillary variation measurement during a 20 mA stimulus could help assess the need for analgesia before potentially painful interventions. Further studies are needed to confirm this. REGISTRATION: Phase 1 of the project PUPIPAIN ClinicalTrials.gov Identifier: NCT04078113.

A one-point increase in the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality in thrombotic antiphospholipid syndrome.

OBJECTIVES: To determine whether early damage and its kinetics measured by the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality. METHODS: We carried out a single-centre retrospective analysis of thrombotic APS patients (2006 Sydney criteria), using the DIAPS for damage assessment. Early damage was considered to be at six months after disease onset; early damage increase (delta-DIAPS) was deemed to be at least a one-point rise in DIAPS within the first five years of illness. Groups were compared using appropriate statistical tests. Survival was analysed by the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of mortality. RESULTS: A total of 197 patients (71.1% female; 65.9% primary APS; 72.4% Caucasian) were followed for up to 43 years (median 10). Damage developed in 143 (73.6%) patients. Twenty-three patients (12%) died. Secondary APS (HR 3.07, 95%CI 1.32-7.12, p=0.009), male sex (HR 3.14, 95%CI 1.35-7.33, p=0.008) and age at APS onset ≥40 years (HR 5.34, 95%CI 1.96-14.53, p=0.001) were risk factors for death. Early damage (n=69, 35.0%) was not associated with death (p=0.231). Having a first arterial event was associated with early damage (p<0.001), but not with delta-DIAPS (p=0.539) nor with the risk of death (p=0.151). Delta-DIAPS (n=53/181, 29.3%) predicted mortality (HR 5.40, 95%CI 2.33-12.52, p<0.001), even after adjusting individually for APS category (secondary), sex (male), early damage and age at APS onset (≥40 years) (all p<0.005). CONCLUSIONS: Evolving damage in the first five years of illness, but not early damage, predicted mortality regardless of the nature of the first thrombotic event, sex, APS category and age.

Optimized Placement of Frost-Measuring Sensors in Heat Exchangers via Image Processing of Frost Formation Pattern.

Heat exchangers (HXs) play a critical role in maintaining human thermal comfort and ensuring product safety and quality in various industries. However, the formation of frost on HX surfaces during cooling operations can significantly impact their performance and energy efficiency. Traditional defrosting methods primarily rely on time-based control of heaters or HX operation, overlooking the actual frost formation pattern across the surface. This pattern is influenced by ambient air conditions (humidity and temperature) and surface temperature variations. To address this issue, frost formation sensors can be strategically placed within the HX. However, the non-uniform frost pattern poses challenges in sensor placement. This study proposes an optimized sensor placement approach using computer vision and image processing techniques to analyze the frost formation pattern. Through creating a frost formation map and evaluating various sensor locations, frost detection can be optimized to control defrosting operations with higher accuracy, thereby enhancing the thermal performance and energy efficiency of HXs. The results demonstrate the effectiveness of the proposed method in accurately detecting and monitoring frost formation, providing valuable insights for sensor placement optimization. This approach presents significant potential in enhancing the overall performance and sustainability of the operation of HXs.

What is the role of active packaging in the future of food sustainability? A systematic review.

Nowadays, the strong increase in products consumption, the purchase of products on online platforms as well as the requirements for greater safety and food protection are a concern for food and packaging industries. Active packaging brings huge advances in the extension of product shelf-life and food degradation and losses reduction. This systematic work aims to collect and evaluate all existing strategies and technologies of active packaging that can be applied in food products, with a global view of new possibilities for food preservation. Oxygen scavengers, carbon dioxide emitters/absorbers, ethylene scavengers, antimicrobial and antioxidant active packaging, and other active systems and technologies are summarized including the products commercially available and the respective mechanisms of action. © 2022 Society of Chemical Industry.

Innovative processes in smart packaging. A systematic review.

Smart packaging provides one possible solution that could reduce greenhouse gas emissions. In comparison with traditional packaging, which aims to extend the product's useful life and to facilitate transport and marketing, smart packaging allows increased efficiency, for example by ensuring authenticity and traceability from the product's origin, preventing fraud and theft, and improving security. Consequently, it may help to reduce pollution, food losses, and waste associated with the food supply chain. However, some questions must be answered to fully understand the advantages and limitations of its use. What are the most suitable smart packaging technologies for use in agro-industrial subsectors such as meat, dairy, fruits, and vegetables, bakery, and pastry? What are the opportunities from a perspective of life extension, process optimization, traceability, product quality, and safety? What are the future challenges? An up-to-date, systematic review was conducted of literature relevant to the application of indicator technologies, sensors, and data carriers in smart packaging, to answer these questions. © 2022 Society of Chemical Industry.

tartan underlies the evolution of Drosophila male genital morphology.

Male genital structures are among the most rapidly evolving morphological traits and are often the only features that can distinguish closely related species. This process is thought to be driven by sexual selection and may reinforce species separation. However, while the genetic bases of many phenotypic differences have been identified, we still lack knowledge about the genes underlying evolutionary differences in male genital organs and organ size more generally. The claspers (surstyli) are periphallic structures that play an important role in copulation in insects. Here, we show that divergence in clasper size and bristle number between Drosophila mauritiana and Drosophila simulans is caused by evolutionary changes in tartan (trn), which encodes a transmembrane leucine-rich repeat domain protein that mediates cell-cell interactions and affinity. There are no fixed amino acid differences in trn between D. mauritiana and D. simulans, but differences in the expression of this gene in developing genitalia suggest that cis-regulatory changes in trn underlie the evolution of clasper morphology in these species. Finally, analyses of reciprocal hemizygotes that are genetically identical, except for the species from which the functional allele of trn originates, determined that the trn allele of D. mauritiana specifies larger claspers with more bristles than the allele of D. simulans Therefore, we have identified a gene underlying evolutionary change in the size of a male genital organ, which will help to better understand not only the rapid diversification of these structures, but also the regulation and evolution of organ size more broadly.

Humoral Immune Response of SARS-CoV-2-Infected Patients with Cancer: Influencing Factors and Mechanisms.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with cancer show worse outcomes compared with patients without cancer. The humoral immune response (HIR) of patients with cancer against SARS-CoV-2 is not well characterized. To better understand it, we conducted a serological study of hospitalized patients with cancer infected with SARS-CoV-2. MATERIALS AND METHODS: This was a unicentric, retrospective study enrolling adult patients with SARS-CoV-2 admitted to a central hospital from March 15 to June 17, 2020, whose serum samples were quantified for anti-SARS-CoV-2 receptor-binding domain or spike protein IgM, IgG, and IgA antibodies. The aims of the study were to assess the HIR to SARS-CoV-2; correlate it with different cancer types, stages, and treatments; clarify the interplay between the HIR and clinical outcomes of patients with cancer; and compare the HIR of SARS-CoV-2-infected patients with and without cancer. RESULTS: We included 72 SARS-CoV-2-positive subjects (19 with cancer, 53 controls). About 90% of controls revealed a robust serological response. Among patients with cancer, a strong response was verified in 57.9%, with 42.1% showing a persistently weak response. Treatment with chemotherapy within 14 days before positivity was the only factor statistically shown to be associated with persistently weak serological responses among patients with cancer. No significant differences in outcomes were observed between patients with strong and weak responses. All IgG, IgM, IgA, and total Ig antibody titers were significantly lower in patients with cancer compared with those without. CONCLUSION: A significant portion of patients with cancer develop a proper HIR. Recent chemotherapy treatment may be associated with weak serological responses among patients with cancer. Patients with cancer have a weaker SARS-CoV-2 antibody response compared with those without cancer. IMPLICATIONS FOR PRACTICE: These results place the spotlight on patients with cancer, particularly those actively treated with chemotherapy. These patients may potentially be more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, so it is important to provide oncologists further theoretical support (with concrete examples and respective mechanistic correlations) for the decision of starting, maintaining, or stopping antineoplastic treatments (particularly chemotherapy) not only on noninfected but also on infected patients with cancer in accordance with cancer type, stage and prognosis, treatment agents, treatment setting, and SARS-CoV-2 infection risks.

Seroprevalence of anti-SARS-CoV-2 antibodies in COVID-19 patients and healthy volunteers up to 6 months post disease onset.

SARS-CoV-2 has emerged as a human pathogen, causing clinical signs, from fever to pneumonia-COVID-19-but may remain mild or asymptomatic. To understand the continuing spread of the virus, to detect those who are and were infected, and to follow the immune response longitudinally, reliable and robust assays for SARS-CoV-2 detection and immunological monitoring are needed. We quantified IgM, IgG, and IgA antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) or the Spike (S) protein over a period of 6 months following COVID-19 onset. We report the detailed setup to monitor the humoral immune response from over 300 COVID-19 hospital patients and healthcare workers, 2500 University staff, and 198 post-COVID-19 volunteers. Anti-SARS-CoV-2 antibody responses follow a classic pattern with a rapid increase within the first three weeks after symptoms. Although titres reduce subsequently, the ability to detect anti-SARS-CoV-2 IgG antibodies remained robust with confirmed neutralization activity for up to 6 months in a large proportion of previously virus-positive screened subjects. Our work provides detailed information for the assays used, facilitating further and longitudinal analysis of protective immunity to SARS-CoV-2. Importantly, it highlights a continued level of circulating neutralising antibodies in most people with confirmed SARS-CoV-2.

Prevalence and outcome of thrombocytopenia in systemic lupus erythematous: single-centre cohort analysis.

OBJECTIVES: We aimed to characterise the frequency of thrombocytopenia in systemic lupus erythematosus (SLE) and determine its time of onset during the course of the disease, and its severity and impact on mortality. METHODS: This was a single-centre cohort analysis of 707 patients with SLE followed for up to 40 years. We reviewed the patients' clinical notes identifying the presence of thrombocytopenia, its time of onset and ascertained other clinical and serological features of the disease. Thrombocytopenia was classified as mild (100-149x109/L), moderate (31-99x109/L) or severe (≤30x109/L platelets). It was also classified as asymptomatic, with minor bleeding or with major bleeding. RESULTS: 22.9% of patients (n=162) had thrombocytopenia prior to or during the course of SLE. Twenty-three patients (14.2%) had isolated immune thrombocytopenia (ITP) before the diagnosis of SLE. Median follow-up time was 19 years (IQR=13). Most patients (n=67, 41.4%) had mild thrombocytopenia. More than half the patients (n=98, 60.5%) developed asymptomatic thrombocytopenia and only 6 patients (3.7%) had major bleeding events in the context of thrombocytopenia. The development of severe thrombocytopenia any time during the course of SLE was associated with an increased risk of death (HR=3.57, p=0.025). Anti-phospholipid syndrome was over twice as common in patients with thrombocytopenia in the cohort. There is an increased risk of death for male patients (HR=3.41, p=0.036) who develop thrombocytopenia and for those who present with concomitant haemolytic anaemia (HR=3.07, p=0.027). CONCLUSIONS: The presence of severe thrombocytopenia (platelets ≤30x109) in patients with SLE is associated with an increased risk of death, regardless of bleeding events. Male patients with SLE and thrombocytopenia have an increased mortality risk, as have those who develop concomitant thrombocytopenia and haemolytic anaemia.

The assessment of patients with the antiphospholipid antibody syndrome: where are we now?

The antiphospholipid antibody syndrome (APS), a chronic autoimmune thrombophilia with an increased mortality and morbidity, has been recognized for more than three decades. Unlike other autoimmune rheumatic conditions such as systemic lupus erythematosus, myositis and Sjögren's syndrome, relatively few attempts have been made to develop activity, damage or disease-specific quality of life indices for APS. In this review of the literature, we consider those attempts that have been made to develop assessment tools for patients with APS, but also reflect upon the nature of the condition, to discuss, in particular, whether an activity index is appropriate for this disease.

Controlled trial of an mHealth intervention to promote healthy behaviours in adolescence (TeenPower): Effectiveness analysis.

AIM: To evaluate the effectiveness on lifestyle change of an mHealth intervention to promote healthy behaviours in adolescence (TeenPower) and to analyse the predictors of the mHealth intervention effectiveness. DESIGN: This study is designed as a non-randomized controlled trial with a two-arm structure. METHODS: Adolescents of 12-16-year old were recruited from three school districts, with access to the Internet and smartphone/tablet devices. The intervention group was invited to engage in the mHealth intervention (TeenPower) for 6 months in addition to a school-based intervention. The control group only followed the school-based intervention. A repeated measures factorial ANOVA was used and the main effectiveness outcome was the lifestyle change measured by the adolescent lifestyle profile. RESULTS: The outcomes of the mHealth intervention (TeenPower) show a significant effect on nutrition (ƞ2 p  = 0.03, p = .03), positive life perspective (ƞ2 p  = 0.04, p = .01), and global lifestyle (ƞ2 p  = 0.02, p = .05), with a dropout rate of 62.1%. The analysis of the effectiveness predictors of the mHealth intervention suggested that older adolescents tended to show a significant increase in the rates of stress management (r = .40; p < .05). CONCLUSIONS: Although the considerable dropout rate, the mHealth intervention presented significant impact on multiple lifestyle domains, providing support for the effectiveness of mHealth interventions for health promotion as an add-on to standard interdisciplinary interventions. IMPACT: Adolescents must have the necessary and appropriate knowledge for the correct and responsible decision-making regarding their health and lifestyle. Innovative strategies (mHealth intervention) were used to promote healthy behaviours. This study evaluates the effectiveness of an mHealth intervention (TeenPower) specifically designed for adolescents. We found a significant impact in several lifestyle domains such as health responsibility, nutrition, positive life perspective, and global lifestyle.

Prevalence of acute and chronic wounds - with emphasis on pressure ulcers - in integrated continuing care units in Alentejo, Portugal.

The aim of the study was to describe the prevalence and general characteristics of acute and chronic wounds in 2018 in Alentejo (Portugal) continuing care units. In order to look at associations, wound characteristics studied were location, type, place of acquisition, number, and duration, and patient characteristics were sex, age, and presence of risk factors. During the first 2 weeks of February 2018, a total of 770 patients were assessed at continuing care units of Alentejo. Of these, 135 exhibited wounds, a prevalence of 17.5%. Almost two out of three patients (63%) had arterial hypertension, slightly more than one in three (37%) had a stroke and/or immobility and 30% had diabetes. Of the total wounds identified, 18% were acute wounds and 82% were chronic wounds. Of the 24 acute wounds, traumatic wounds (76%), and surgical wounds (22%) were the most prevalent. The four types of pressure ulcers represented 80% of the chronic wounds. The median duration of the pressure ulcers was 5.5 months and 25% had duration over 10 months.

Human eye conditions: insights from the fly eye.

The fruit fly Drosophila melanogaster has served as an excellent model to study and understand the genetics of many human diseases from cancer to neurodegeneration. Studying the regulation of growth, determination and differentiation of the compound eyes of this fly, in particular, have provided key insights into a wide range of diseases. Here we review the regulation of the development of fly eyes in light of shared aspects with human eye development. We also show how understanding conserved regulatory pathways in eye development together with the application of tools for genetic screening and functional analyses makes Drosophila a powerful model to diagnose and characterize the genetics underlying many human eye conditions, such as aniridia and retinitis pigmentosa. This further emphasizes the importance and vast potential of basic research to underpin applied research including identifying and treating the genetic basis of human diseases.