Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study.

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.

Final-year medical student mental wellness during preparation for the examination for specialty in Turkey: a cross-sectional survey study.

BACKGROUND: In Turkey, most final-year medical students prepare for the Examination for Specialty in Medicine in a high-stress environment. To the best of our knowledge, this is the first study on final-year medical student general psychological distress during preparation for the Examination for Specialty in Turkey. We aim to evaluate psychological distress and understand the variables associated with depression, anxiety, and stress levels among final-year medical students preparing for the Examination for Specialty. METHODS: A self-reporting, anonymous, cross-sectional survey with 21 items consisting of demographic variables, custom variables directed for this study, and the DASS-21 was utilized. Survey results were expounded based on univariate analysis and multivariate linear regression analysis. RESULTS: Our study revealed four variables associated with impaired mental wellness among final-year medical students during preparation for the examination for Specialty: attendance to preparatory courses, duration of preparation, consideration of quitting studying, and psychiatric drug usage/ongoing psychotherapy. DISCUSSION: Considering that physician mental wellness is one of the most crucial determinants of healthcare quality, impaired mental wellness among future physicians is an obstacle to a well-functioning healthcare system. Our study targets researchers and authorities, who should focus on medical student mental wellness, and medical students themselves.

RhoA activation and nuclearization marks loss of chondrocyte phenotype in crosstalk with Wnt pathway.

De-differentiation comprises a major drawback for the use of autologous chondrocytes in cartilage repair. Here, we investigate the role of RhoA and canonical Wnt signaling in chondrocyte phenotype. Chondrocyte de-differentiation is accompanied by an upregulation and nuclear localization of RhoA. Effectors of canonical Wnt signaling including ß-catenin and YAP/TAZ are upregulated in de-differentiating chondrocytes in a Rho-dependent manner. Inhibition of Rho activation with C3 transferase inhibits nuclear localization of RhoA, induces expression of chondrogenic markers on 2D and enhances the chondrogenic effect of 3D culturing. Upregulation of chondrogenic markers by Rho inhibition is accompanied by loss of canonical Wnt signaling markers in 3D or on 2D whereas treatment of chondrocytes with Wnt-3a abrogates this effect. However, induction of canonical Wnt signaling inhibits chondrogenic markers on 2D but enhances chondrogenic re-differentiation on 2D with C3 transferase or in 3D. These data provide insights on the context-dependent role of RhoA and Wnt signaling in de-differentiation and on mechanisms to induce chondrogenic markers for therapeutic approaches.

Sulfated hydrogel matrices direct mitogenicity and maintenance of chondrocyte phenotype through activation of FGF signaling.

Deciphering the roles of chemical and physical features of the extracellular matrix (ECM) is vital for developing biomimetic materials with desired cellular responses in regenerative medicine. Here, we demonstrate that sulfation of biopolymers, mimicking the proteoglycans in native tissues, induces mitogenicity, chondrogenic phenotype, and suppresses catabolic activity of chondrocytes, a cell type that resides in a highly sulfated tissue. We show through tunable modification of alginate that increased sulfation of the microenvironment promotes FGF signaling-mediated proliferation of chondrocytes in a three-dimensional (3D) matrix independent of stiffness, swelling, and porosity. Furthermore, we show for the first time that a biomimetic hydrogel acts as a 3D signaling matrix to mediate a heparan sulfate/heparin-like interaction between FGF and its receptor leading to signaling cascades inducing cell proliferation, cartilage matrix production, and suppression of de-differentiation markers. Collectively, this study reveals important insights on mimicking the ECM to guide self-renewal of cells via manipulation of distinct signaling mechanisms.

Adaptation into Turkish and Psychometric Properties of Athens Insomnia Scale.

Introduction: The study aimed to adapt the "Athens Insomnia Scale" developed by Soldatos et al. into Turkish and to conduct validity and reliability analysis. Methods: This research was conducted on 215 patients with insomnia complaints and applied to Family Medicine, Neurology (Sleep Polyclinic), and Psychiatry outpatient clinics. Introductory Information Form, 8-item Athens Insomnia Scale, and Pittsburg Sleep Quality Index were administered to the participants. After the language adaptation of the scale, Cronbach's alpha value was used as the consistency coefficient for reliability analysis. Exploratory factor analysis was examined for structural validity, and correlation coefficients between the Athens Insomnia Scale and its subscales and the Pittsburg Sleep Quality Index were examined for concurrent validity. Results: Cronbach's alpha coefficient was calculated as 0.87. "Kaiser-Meyer-Olkin value was calculated for factor analysis." In the Exploratory Factor Analysis, a two-factor structure with eigenvalues >1.0 and explaining 73.4% of the variance was obtained. According to the Exploratory Factor Analysis results for the Atina Insomnia Scale, the absolute value of the factor loadings of the eight items ranged between 0.650 and 0.865. The correlation coefficients between the total score and sub-dimensions of the Athens Insomnia Scale and the Pittsburg Sleep Quality Index-a scale assessing sleep quality were between 0.489-0.725 (p<0,01). For discriminant validity, Athens Insomnia Scale discriminated well between patients and healthy volunteers (Z=2.630, p=0,009). Conclusion: The Athens Insomnia Scale has been shown to have adequate reliability and validity in Turkish.

Association Between Dipeptidyl Peptidase-4 Inhibitor Use and Cognitive Functions, Brain-Derived Neurotrophic Factor, and Pentraxin-3 Levels in Patients With Type 2 Diabetes.

Background Diabetes mellitus is an important risk factor for dementia, Alzheimer's disease, and other neurodegenerative diseases. Recent findings have made the relationship between the inhibition of the dipeptidyl peptidase-4 (DPP-4) enzyme and cognitive functions an important research topic. Objective This study aimed to evaluate the association between DPP-4 inhibitor use and cognitive functions, serum brain-derived neurotrophic factor (BDNF), and pentraxin-3 (PTX-3) levels in patients with type 2 diabetes, compared with the patients who only use metformin treatment. Design, patients, and methods A total of 50 patients with type 2 diabetes (hemoglobin A1c levels at ≤%7.5) who were under treatment with metformin±DPP-4 inhibitor (n=25) or only metformin (n=25) were included in this cross-sectional study. Serum BDNF and PTX-3 levels were assessed using an enzyme-linked immunosorbent assay. A standardized mini-mental test (sMMSE) was used to evaluate cognitive functions. Results There were no significant differences in the characteristics of the study groups. The mean sMMSE score of the patients receiving DPP-4±metformin treatment was statistically higher when compared with patients receiving only metformin treatment (27.16±1.95 vs. 25.40±3.07; p=0.041). The BDNF levels of the patients receiving DPP-4±metformin treatment were considerably higher than the patients receiving only metformin treatment (394.51±205.66 ng/ml vs. 180.63±297.94 ng/ml; p=0.001). The difference in PTX-3 levels between study groups was not statistically significant (5.47±3.44 vs. 3.79±2.53; p=0.055). Conclusion When compared to metformin alone, the use of DPP-4 inhibitors in the treatment of patients with type 2 diabetes was associated with increased serum BDNF levels and improved cognitive functions.

Hypermagnesemia is associated with poor outcomes during hospitalization.

BACKGROUND: Hypermagnesemia is one of the vital electrolyte disturbances and is associated with such chronic conditions as cardiovascular, endocrinologic, renal diseases, and malignancy. AIM: This study evaluates the association between hypermagnesemia and clinical course in hospitalized patients. METHODS: This study was conducted at the University of Health Sciences Haseki Training and Research Hospital Internal Medicine Clinic. We evaluated a total of 3850 patients. 2130 patients have met the inclusion criteria were included in the study. Those who were discharged with healing were evaluated as having a good prognosis. Patients who died or were transferred to the intensive care unit (ICU) were defined as having a poor prognosis. We divided the patients' serum magnesium levels into four quartiles and examined the clinical course/conditions of the patients. RESULTS: Of 2130 patients, 1013 (51.9%) were female. The mean age of patients with poor prognoses (69.2 ± 14.9) was higher than those with good prognoses (59.7 ± 19.1). Hypermagnesemia (4th quartile) was detected in 61 (33.9%), and hypomagnesemia (1st quartile) was found in 42 (23.3%) patients out of 180 patients with poor clinical outcomes. It was statistically significant that hypermagnesemia was more common in patients with poor prognoses (p: 0.002). Chronic kidney disease (CKD) was diagnosed in 258 (53.3%) of 484 hypermagnesemia patients. Hypermagnesemia was found to be more common in patients with CKD, which was statistically significant (p: 0.003). CONCLUSIONS: Hypermagnesemia is associated with poor prognosis independent of comorbidities. Besides hypomagnesemia, hypermagnesemia should be considered a critical electrolyte imbalance.

Comparison of Controlling Nutritional Status Score with Bedside Index for Severity in Acute Pancreatitis Score and Atlanta Classification for Mortality in Patients with Acute Pancreatitis.

Background/Objectives: Acute pancreatitis (AP) is characterized by pancreatic gland inflammation, and its clinical course ranges from mild to severe. Predicting the severity of AP early and reliably is important. In this study, we investigate the potential use of the Controlling Nutritional Status (CONUT) score as a prognostic marker in acute pancreatitis. Methods: We examined 336 patients who had been hospitalized with an AP diagnosis in the internal medicine clinic. The patients included in the study were followed up for 5 years. The study analyzed the specific variables of age, gender, and AP etiology as recorded biochemical parameters for all study participants and calculated the effects of age, sex, Bedside Index of Severity in AP (BISAP), the revised Atlanta classification, and the CONUT score on mortality. Results: When compared with surviving patients, non-surviving patients had higher scores for BISAP, CONUT, and the Atlanta Classification (p ˂ 0.001). In the non-surviving group, hemoglobin, lymphocyte, and albumin levels were significantly lower and creatinine, uric acid, and procalcitonin levels were significantly higher compared to the surviving group (p ˂ 0.001, 0.003, ˂0.001, ˂0.001, 0.005, ˂0.001, respectively). The multivariate analysis showed a significant association of mortality with age, CONUT, and BISAP scores (p ˂ 0.003, 0.001, 0.012 respectively). The CONUT score was separated into two groups based on the median value. The predicted survival time in the group with a CONUT score > 2 (53.8 months) was significantly lower than in the group with a CONUT score ≤ 2 (63.8 months). The cumulative incidence of all-cause mortality was significantly higher in the patients with higher CONUT scores. Conclusions: This study has assigned the CONUT score as an independent risk factor for mortality in AP.

Organotypic lung tissue culture as a preclinical model to study host- influenza A viral infection: A case for repurposing of nafamostat mesylate.

Reliable and effective models for recapitulation of host-pathogen interactions are imperative for the discovery of potential therapeutics. Ex vivo models can fulfill these requirements as the multicellular native environment in the tissue is preserved and be utilized for toxicology, vaccine, infection and drug efficacy studies due to the presence of immune cells. Drug repurposing involves the identification of new applications for already approved drugs that are not related to the prime medical indication and emerged as a strategy to cope with slow pace of drug discovery due to high costs and necessary phases to reach the patients. Within the scope of the study, broad-spectrum serine protease inhibitor nafamostat mesylate was repurposed to inhibit influenza A infection and evaluated by a translational ex vivo organotypic model, in which human organ-level responses can be achieved in preclinical safety studies of potential antiviral agents, along with in in vitro lung airway culture. The safe doses were determined as 10 µM for in vitro, whereas 22 µM for ex vivo to be applied for evaluation of host-pathogen interactions, which reduced virus infectivity, increased cell/tissue viability, and protected total protein content by reducing cell death with the inflammatory response. When the gene expression levels of specific pro-inflammatory, anti-inflammatory and cell surface markers involved in antiviral responses were examined, the significant inflammatory response represented by highly elevated mRNA gene expression levels of cytokines and chemokines combined with CDH5 downregulated by 5.1-fold supported the antiviral efficacy of NM and usability of ex vivo model as a preclinical infection model.

Developing Bovine Brain-Derived Extracellular Matrix Hydrogels: a Screen of Decellularization Methods for Their Impact on Biochemical and Mechanical Properties.

Tissue models that recapitulate the key biochemical and physical aspects of the brain have been highly pursued in neural tissue engineering. Decellularization of native organs offers the advantage of preserving the composition of native extracellular matrix (ECM). Brain ECM has distinct features which play a major role in neural cell behavior. Cell instructive ligands and mechanical properties take part in the regulation of cellular processes in homeostasis and diseases. One of the main challenges in decellularization is maintaining mechanical integrity in reconstituted hydrogels and achieving physiologically relevant stiffness. The effect of the decellularization process on different mechanical aspects, particularly the viscoelasticity of brain-derived hydrogels, has not been addressed. In this study, we developed bovine brain-derived hydrogels for the first time. We pursued seven protocols for decellularization and screened their effect on biochemical content, hydrogel formation, and mechanical characteristics. We show that bovine brain offers an easily accessible alternative for in vitro brain tissue modeling. Our data demonstrate that the choice of decellularization method strongly alters gelation as well as the stiffness and viscoelasticity of the resulting hydrogels. Lastly, we investigated the cytocompatibility of brain ECM hydrogels and the effect of modulated mechanical properties on the growth and morphological features of neuroblastoma cells.

Development and Characterization of Decellularized Lung Extracellular Matrix Hydrogels.

The use of extracellular matrix (ECM)-derived hydrogels in tissue engineering has become increasingly popular, as they can mimic cells' natural environment in vitro. However, maintaining the native biochemical content of the ECM, achieving mechanical stability, and comprehending the impact of the decellularization process on the mechanical properties of the ECM hydrogels are challenging. Here, a pipeline for decellularization of bovine lung tissue using two different protocols, downstream characterization of the effectiveness of decellularization, fabrication of reconstituted decellularized lung ECM hydrogels and assessment of their mechanical and cytocompatibility properties were described. Decellularization of the bovine lung was pursued using a physical (freeze-thaw cycles) or chemical (detergent-based) method. Hematoxylin and Eosin staining was performed to validate the decellularization and retention of major ECM components. For the evaluation of residual collagen and sulfated glycosaminoglycan (sGAG) content within the decellularized samples, Sirius red and Alcian blue staining techniques were employed, respectively. Mechanical properties of the decellularized lung ECM hydrogels were characterized by oscillatory rheology. The results suggest that decellularized bovine lung hydrogels can provide a reliable organotypic alternative to commercial ECM products by retaining most native ECM components. Furthermore, these findings reveal that the decellularization method of choice significantly affects gelation kinetics as well as the stiffness and viscoelastic properties of resulting hydrogels.

Different Decellularization Methods in Bovine Lung Tissue Reveals Distinct Biochemical Composition, Stiffness, and Viscoelasticity in Reconstituted Hydrogels.

Extracellular matrix (ECM)-derived hydrogels are in demand for use in lung tissue engineering to mimic the native microenvironment of cells in vitro. Decellularization of native tissues has been pursued for preserving organotypic ECM while eliminating cellular content and reconstitution into scaffolds which allows re-cellularization for modeling homeostasis, regeneration, or diseases. Achieving mechanical stability and understanding the effects of the decellularization process on mechanical parameters of the reconstituted ECM hydrogels present a challenge in the field. Stiffness and viscoelasticity are important characteristics of tissue mechanics that regulate crucial cellular processes and their in vitro representation in engineered models is a current aspiration. The effect of decellularization on viscoelastic properties of resulting ECM hydrogels has not yet been addressed. The aim of this study was to establish bovine lung tissue decellularization for the first time via pursuing four different protocols and characterization of reconstituted decellularized lung ECM hydrogels for biochemical and mechanical properties. Our data reveal that bovine lungs provide a reproducible alternative to human lungs for disease modeling with optimal retention of ECM components upon decellularization. We demonstrate that the decellularization method significantly affects ECM content, stiffness, and viscoelastic properties of resulting hydrogels. Lastly, we examined the impact of these aspects on viability, morphology, and growth of lung cancer cells, healthy bronchial epithelial cells, and patient-derived lung organoids.

Systemic Immune-Inflammation and Systemic Inflammation Response Indices are Predictive Markers of Mortality in Inpatients Internal Medicine Services.

Purpose: Internal medicine services serve the patient population with many chronic diseases. Therefore, it is high mortality rates compared to other departments of the hospital. Estimating the prognostic risk of hospitalized patients may be useful in mortality for patients. In this study, we evaluated the level of Systemic Immune Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI) and its association with mortality in inpatients. Patients and methods: This study was performed in 2218 patients who were hospitalized between January 1st-December 31th of 2019. Patients were followed up for three years about primary endpoint as all-cause (except for unnatural deaths) mortality. Participants were divided into 4 equal groups according to their increasing levels of SII and SIRI. (Quartile 1-4) Age, gender, diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, malignancies (solid), white blood cell, neutrophil, lymphocyte, monocytes, hemoglobin, hematocrit, platelet, CRP, albumin, Systemic Inflammation Response Index (Quartile 1-4), Systemic Immune Inflammation Index (Quartile 1-4) were compared between survival and non-survival groups. Results: There were 1153 female and 1065 male participants enrolled. Compared with surviving patients, patients who died were older and had a higher prevalence of diabetes mellitus, hypertension, malignancy, chronic kidney disease and coronary artery disease (p < 0.001). There was a lower proportion of female patients among the patients who died. Compared to the survivor group, group who died exhibited a significant increase in CRP level, neutrophil, white blood cell and monocyte counts, but had a lower lymphocyte count, albumin level and hemoglobin count (P < 0.001). Results of Cox regression analysis showed that age, chronic kidney disease, malignancy, SIRI quartile 3, 4 and SII quartile 3, 4 pointed out a close relationship with mortality risk. (P < 0.001). Conclusion: The SIRI and SII have indicated the clinical importance of as novel markers for predicting mortality in inpatients.

Molecular and biophysical mechanisms regulating hypertrophic differentiation in chondrocytes and mesenchymal stem cells.

Chondrocyte hypertrophy is one of the key physiological processes involved in the longitudinal growth of long bones, yet the regulation of hypertrophy is also becoming increasingly relevant for clinical application of mesenchymal stem cells (MSCs) and screening for drugs to treat hypertrophic osteoarthritis. The extraordinary cell volume increase during hypertrophy is accompanied by an up-regulation of collagen X, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF), all which are targets of the runt-related transcription factor 2 (Runx2). Many pathways, including parathyroid hormone-related protein (PTHrP)/Indian Hedgehog, Wingless/Int (Wnt)/ß-catenin, and transforming growth factor beta (TGF-ß)/Sma and Mad Related Family (Smad) pathways, can regulate hypertrophy, but factors as diverse as hypoxia, co-culture, epigenetics and biomaterial composition can also potently affect Runx2 expression. Control of hypertrophic differentiation can be exploited both for cartilage repair, where a stable phenotype is desired, but also in bone regeneration, where hypertrophic cartilage could act as a template for endochondral bone formation. We hope this review will motivate the design of novel engineered microenvironments for skeletal regeneration applications.

Biomedical optical fibers.

Optical fibers with the ability to propagate and transfer data via optical signals have been used for decades in medicine. Biomaterials featuring the properties of softness, biocompatibility, and biodegradability enable the introduction of optical fibers' uses in biomedical engineering applications such as medical implants and health monitoring systems. Here, we review the emerging medical and health-field applications of optical fibers, illustrating the new wave for the fabrication of implantable devices, wearable sensors, and photodetection and therapy setups. A glimpse of fabrication methods is also provided, with the introduction of 3D printing as an emerging fabrication technology. The use of artificial intelligence for solving issues such as data analysis and outcome prediction is also discussed, paving the way for the new optical treatments for human health.

Lung carcinoma spheroids embedded in a microfluidic platform.

Three-dimensional (3D) spheroid cell cultures are excellent models used in cancer biology research and drug screening. The objective of this study was to develop a lung carcinoma spheroid based microfluidic platform with perfusion function to mimic lung cancer pathology and investigate the effect of a potential drug molecule, panaxatriol. Spheroids were successfully formed on agar microtissue molds at the end of 10 days, reaching an average diameter of about 317.18 ± 4.05 µm and subsequently transferred to 3D dynamic microfluidic system with perfusion function. While the size of the 3D spheroids embedded in the Matrigel matrix in the platform had gradually increased both in the static and dynamic control groups, the size of the spheroids were reduced and fragmented in the drug treated groups. Cell viability results showed that panaxatriol exhibited higher cytotoxic effect on cancer cells than healthy cells and the IC50 value was determined as 61.55 µM. Furthermore, panaxatriol has been more effective on single cells around the spheroid structure, whereas less in 3D spheroid tissues with a compact structure in static conditions compared to dynamic systems, where a flow rate of 2 µL/min leading to a shear stress of 0.002 dyne/cm2 was applied. Application of such dynamic systems will contribute to advancing basic research and increasing the predictive accuracy of potential drug molecules, which may accelerate the translation of novel therapeutics to the clinic, possibly decreasing the use of animal models. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-021-00470-7.

Erratum: "Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response" [Biomicrofluidics 15, 021501 (2021)].

[This corrects the article DOI: 10.1063/5.0038924.].

Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response.

Respiratory viral infections are leading causes of death worldwide. A number of human respiratory viruses circulate in all age groups and adapt to person-to-person transmission. It is vital to understand how these viruses infect the host and how the host responds to prevent infection and onset of disease. Although animal models have been widely used to study disease states, incisive arguments related to poor prediction of patient responses have led to the development of microfluidic organ-on-chip models, which aim to recapitulate organ-level physiology. Over the past decade, human lung chips have been shown to mimic many aspects of the lung function and its complex microenvironment. In this review, we address immunological responses to viral infections and elaborate on human lung airway and alveolus chips reported to model respiratory viral infections and therapeutic interventions. Advances in the field will expedite the development of therapeutics and vaccines for human welfare.

The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons.

Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology.