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A series of benzothiazolopyrimidine-thiazole conjugates 7, 8, and 9 were produced through the reactions of 8-acetylbenzothiazolopyrimidine-thiosemicarbazone compound 6 with chloroacetone, (un)substituted phenacyl chlorides, and ethyl chloroacetate, respectively. Based on DFT study, the synthesized conjugates had a twisted shape, except for the parent benzothiazolopyrimidine 5 and its thiosemicarbazone compound 6, which were flat. The study of FMO's also showed that the substituted thiazole derivatives 7 and 8a-c have equivalent configurations of HOMO and LUMO, as well as exhibiting the least FMO's gap (ΔEH-L). The antimicrobic activeness of the constructed derivatives has been assessed against the two Gram's types of bacteria and fungi using the broth microdilution method. The benzothiazolopyrimidine-thiazole conjugate 8c exhibited the strongest inhibition towards Gram-negative E. coli (MIC

Letrozole (LTZ) is used as first-line treatment for hormone-positive breast cancer (BC) in postmenopausal women. However, its poor aqueous solubility and permeability have reduced its clinical efficacy. Herein, we developed LTZ-nanotransferosomes (LTZ-NT) to address above mentioned issues. The LTZ-NT were optimized statistically using Design Expert® followed by their characterization via dynamic light scattering (DLS), Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and Differential scanning calorimetry (DSC). The optimized LTZ-NT was incorporated into 1% chitosan-gel to develop LTZ-NTG. Moreover, in vitro drug release and ex vivo permeation of LTZ-NTG were performed and compared with LTZ-dispersion and LTZ-NT. Additionally, skin irritability and histopathology of LTZ-NTG were investigated. Furthermore, in vitro antitumor study of LTZ-NTG was investigated in BC cell lines. The optimized LTZ-NT showed suitable zeta potential (30.4 mV), spherical size (162.5 nm), and excellent entrapment efficiency (88.04%). Moreover, LTZ-NT exhibited suitable thermal behavior and no interactions among its excipients. In addition, LTZ-NTG had an optimal pH (5.6) and a suitable viscosity. A meaningfully sustained release and improved permeation of LTZ was observed from LTZ-NTG. Additionally, LTZ-NTG showed significantly enhanced cell death of MCF-7 and MCC-7 cells. It can be concluded that LTZ-NTG has the potential to deliver chemotherapeutic agents for possible treatment of BC. [ABSTRACT FROM AUTHOR]

Abstract: The degradation of title dyes with ferrioxalate and H2O2 couple has been investigated spectrophotometrically. In the absence of either one of the oxidizing agents no degradation occurred. The reaction rate was proportional to moderate concentrations of the dye and H2O2. At high concentration of the dye and H2O2 the reaction rate decreased. With regard to the concentration of the ferrioxalate complex the rate of reaction increased even over a wide range of complex concentration. Degradation of dyes does not occur in acidic medium. It is slow in neutral but thoroughly fast in alkaline medium. The reaction rate reaches a maximum value at pH 11.5. This behavior was again observed if HCl or NaOH were added. With HCl the reaction rate decreases with increasing acid concentration but greatly increases with NaOH concentration. Isopropanol showed inhibiting effect due to scavenging the in situ generated hydroxyl radical ( OH). Oxalate ion enhanced the rate, confirming an outer sphere mechanism. The activation parameters of the reaction are estimated and a possible mechanism is proposed. The mechanism is well confirmed with data simulation procedure. [Copyright &y& Elsevier]

Abstract Background Proneural genes encode basic helix–loop–helix transcription factors that specify distinct neuronal identities in different regions of the nervous system. In the embryonic telencephalon, the proneural genes Neurog1 and Neurog2 specify a dorsal regional identity and glutamatergic projection neuron phenotype in the presumptive neocortex, but their roles in cell fate specification in the olfactory bulb, which is also partly derived from dorsal telencephalic progenitors, have yet to be assessed. Given that olfactory bulb development is guided by interactions with the olfactory epithelium in the periphery, where proneural genes are also expressed, we investigated the roles of Neurog1 and Neurog2 in the coordinated development of these two olfactory structures. Results Neurog1/2 are co-expressed in olfactory bulb progenitors, while only Neurog1 is widely expressed in progenitors for olfactory sensory neurons in the olfactory epithelium. Strikingly, only a remnant of an olfactory bulb forms in Neurog1−/−;Neurog2−/− double mutants, while this structure is smaller but distinguishable in Neurog1−/− single mutants and morphologically normal in Neurog2−/− single mutants. At the cellular level, fewer glutamatergic mitral and juxtaglomerular cells differentiate in Neurog1−/−;Neurog2−/− double-mutant olfactory bulbs. Instead, ectopic olfactory bulb interneurons are derived from dorsal telencephalic lineages in Neurog1−/−;Neurog2−/− double mutants and to a lesser extent in Neurog2−/− single mutants. Conversely, cell fate specification is normal in Neurog1−/− olfactory bulbs, but aberrant patterns of cell proliferation and neuronal migration are observed in Neurog1−/− single and Neurog1−/−;Neurog2−/− double mutants, probably contributing to their altered morphologies. Finally, in Neurog1−/− and Neurog1−/−;Neurog2−/− embryos, olfactory sensory neurons in the epithelium, which normally project to the olfactory bulb to guide its morphogenesis, fail to innervate the olfactory bulb. Conclusions We have identified a cell autonomous role for Neurog1/2 in specifying the glutamatergic identity of olfactory bulb neurons. Furthermore, Neurog1 (and not Neurog2) is required to guide olfactory sensory neuron innervation of the olfactory bulb, the loss of which results in defects in olfactory bulb proliferation and tissue morphogenesis. We thus conclude that Neurog1/2 together coordinate development of the olfactory system, which depends on tissue interactions between the olfactory bulb and epithelium.

The aim of this study was to develop paroxetine (PXT) loaded nanotransferosomal gel (PXT-NTFG) for intranasal brain delivery. The process involved fabricating PXT-NTFs (paroxetine-loaded nanotransferosomes) through a thin film hydration method and optimizing them based on parameters such as particle size (PS), zeta potential (ZP), polydispersity index (PDI), and entrapment efficiency (EE). The optimized PXT-NTFs exhibited uniform morphology with a PS of 158.30 ± 2.73 nm, low PDI (0.142 ± 0.072), high ZP (21.00 ± 0.75 mV), and excellent EE (88.09 ± 3.40 %). Characterization through various techniques confirmed the incorporation of PXT into the nanotransferosomes and its conversion to amorphous state. Moreover, PXT-NTFG was formulated with suitable viscosity and mucoadhesive properties. In vitro release studies demonstrated sustained drug release from PXT-NTFG at different pH levels as compared to PXT-NTFs and NTF dispersion. Similarly, ex vivo experiments showed 4 folds enhanced drug permeation from PXT-NTFG when compared with PXT conventional gel. Stability studies indicated that the optimized PXT-NTFs remained stable for four months at 4°C and 25°C. Additionally, improved behavioral outcomes, increased neuronal survival rates, and upregulated brain-derived neurotrophic factor (BDNF) expression was observed in lipopolysaccharide (LPS) induced depressed Sprague-Dawley rats after treatment with PXT-NTFG as compared to PXT-dispersion treated and untreated LPS-control groups. Notably, the formulation led to a significant reduction in brain and plasma TNF-α levels. In conclusion, intranasal PXT-NTFG is a promising formulation with sustained drug release, improved brain targeting and enhanced antidepressant activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The gap between organ supply and demand in liver transplantation remains large in most parts of the world. One strategy to increase the donor pool is to use grafts infected with HCV, HBV, and/or HIV viruses. We aimed to explore the current use of HBsAg-positive liver grafts worldwide. A prospective cross-sectional web-based survey was designed, with a total of 28 queries, assessing national and local regulations, center experience, and center-specific experience related to the topic, and sent to all members of International Liver Transplantation Society, European Association for the Study of the Liver, and American Association for the Study of the Liver, and promoted on social media. A total of 135 liver transplant centers answered the survey: 38% from WHO European Regions, 39% from American regions, and 9.7% from South-East Asian regions. Most of the participating centers (67.3%) had been performing liver transplantation for over 15 years, with a mean of 66.5 liver transplants per year, and 54% also performed living-donor liver transplants. HBV-related disease was the indication for liver transplantation in an average of 15% of all liver transplantation cases. Regarding national and/or regional regulations, 40% of the centers reported that the use of HBsAg-positive donors was permitted, and an additional 20% could use them under special circumstances. Thirty-two centers (31%) had previously used HBsAg-positive donors. Among these centers, 62.5% conducted living-donor liver transplants and showed an increased inclination toward the use of HBsAg-positive grafts in centers with elevated waitlist mortality. HBsAg-positive donors are underutilized worldwide. The use of HBsAg-positive liver grafts could help to increase the donor pool, particularly in highly endemic areas., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Research has been conducted investigating the neuronal pathways responsible for the generation of chronic neuropathic pain, including the components of it in conditions such as chronic post-surgical pain, phantom limb pain, and cluster headaches. Forming part of the management of such conditions, capsaicin as a molecule has proven effective. This review has investigated the central nervous system modifications exhibited in such conditions and the pharmacological mechanisms of capsaicin relevant to this. The current paradigm for explaining topical capsaicin-induced analgesia is that TRPV1-mediated calcium ion influx induces calpain, in turn causing axonal ablation and functional defunctionalisation in the PNS (Peripheral Nervous System). Demonstrated through the analysis of existing data, this review demonstrates the changes seen in the CNS (Central Nervous System) in chronic neuropathic pain, as well as some of the evidence for capsaicin modulation on the CNS. Further supporting this, the specific molecular mechanisms of capsaicin-induced analgesia will also be explored, including the action of TRPV1, as well as discussing the further need for clinical research into this area of uncertainty due to the limited specific data with suitable parameters. Further research this review identified as potentially useful in this field included fMRI (functional Magnetic Resonance Imaging) studies, though more specific observational studies of patients who have already been administered capsaicin as a current treatment may prove helpful in studying the modification of the CNS in the long term.

The anatomical organization of the rodent claustrum remains obscure due to lack of clear borders that distinguish it from neighboring forebrain structures. Defining what constitutes the claustrum is imperative for elucidating its functions. Methods based on gene/protein expression or transgenic mice have been used to spatially outline the claustrum but often report incomplete labeling and/or lack of specificity during certain neurodevelopmental timepoints. To reliably identify claustrum projection cells in mice, we propose a simple immunolabelling method that juxtaposes the expression pattern of claustrum-enriched and cortical-enriched markers. We determined that claustrum cells immunoreactive for the claustrum-enriched markers Nurr1 and Nr2f2 are devoid of the cortical marker Tle4, which allowed us to differentiate the claustrum from adjoining cortical cells. Using retrograde tracing, we verified that nearly all claustrum projection neurons lack Tle4 but expressed Nurr1/Nr2f2 markers to different degrees. At neonatal stages between 7 and 21 days, claustrum projection neurons were identified by their Nurr1-postive/Tle4-negative expression profile, a time-period when other immunolabelling techniques used to localize the claustrum in adult mice are ineffective. Finally, exposure to environmental novelty enhanced the expression of the neuronal activation marker c-Fos in the claustrum region. Notably, c-Fos labeling was mainly restricted to Nurr1-positive cells and nearly absent from Tle4-positive cells, thus corroborating previous work reporting novelty-induced claustrum activation. Taken together, this method will aid in studying the claustrum during postnatal development and may improve histological and functional studies where other approaches are not amenable., (© 2024. The Author(s).)

After a virtual congress in 2021 and a previous absence in 2020 because of the coronavirus disease 2019 pandemic, the 27th Annual Congress of the International Liver Transplantation Society was held from May 4 to 7, 2022, in a hybrid format in Istanbul, with 1123 (58% on-site) liver transplant professionals from 61 countries attending the meeting. The hybrid format successfully achieved a balance of much yearned-for "in-person interaction" and global online participation. Almost 500 scientific abstracts were presented. In this report, the Vanguard Committee aims to present a summary of key invited lectures and selected abstracts for the liver transplant community., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Steroid avoidance in kidney transplantation has been proven noninferior. Long-term outcome data on steroid avoidance in simultaneous pancreas-kidney (SPK) remains scant., Methods: Utilizing the Scientific Registry of Transplant Recipients between 2000 and 2020, we studied all primary crossmatch negative SPK recipients (N = 5683) who received antithymocyte globulin induction and were discharged alive with functioning grafts on tacrolimus and mycophenolate ± steroid maintenance. Recipients were grouped according to steroid use into 2 groups: steroid maintenance (n = 4191) and steroid avoidance (n = 1492). Kaplan-Meier curves censored at 10 y were generated for recipient and allograft survival by steroid maintenance. Predictors for recipient and graft survival were examined using Cox Proportional Hazards. Models were adjusted for age, body mass index, ethnicity, diabetes type, human leukocyte-antigen mismatches, cold ischemia time, transplant era, preemptive transplantation, and pancreas donor risk index with the transplant center included as a random effect., Results: Steroid avoidance gained popularity over time, accounting for over one-fourth of the studied cohort. One-year acute rejection rates by steroid avoidance were comparable for kidney (8.6% versus 9%, P  = 0.783); however, the pancreas rejection rate was lower in the steroid avoidance group (7.9% versus 10%; P  = 0.035). After adjustment, steroid avoidance did not influence recipient survival (lower level of confidence interval, adjusted hazard ratio, upper level of confidence interval: 0.94, 1.15, 1.39), pancreas (0.75, 0.93, 1.16), or kidney (0.95, 1.18, 1.45) death-censored survival, compared with steroid maintenance., Conclusions: Accounting for the recipient and graft characteristics, steroid avoidance is associated with similar recipient, pancreas, and kidney graft outcomes compared with steroid maintenance in SPK recipients after antithymocyte globulin induction with tacrolimus and mycophenolate maintenance., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Long-term outcome data by induction type in simultaneous pancreas-kidney (SPK) is limited., Methods: Utilizing the Scientific Registry of Transplant Recipients, we examined all primary SPK transplants between 2000 and 2020, excluding crossmatch-positive recipients. We grouped recipients according to induction regimen into 3 groups: rabbit anti-thymocyte globulin (r-ATG) (n = 5678), alemtuzumab (n = 1199), and interleukin-2 receptor antagonist (IL-2RA; n = 1593). We analyzed the 10-y recipient and composite (kidney and pancreas) graft survival using the Kaplan-Meier survival function. Cox-proportion hazard models were generated to examine the association between induction type, the 10-y recipient, and graft survival. Models were adjusted for recipient age, sex, ethnicity, HLA-mismatch, diabetes type, dialysis dependency, cold-ischemia time, local versus imported organs, panel reactive antibody, steroid maintenance, and Pancreas Donor Risk Index., Results: r-ATG was associated with the lowest 1-y kidney and pancreas rejection rates compared with other agents ( P < 0.001). In the univariable analysis, induction type was not associated with recipient (log-rank P = 0.11) or graft survival (log-rank P = 0.36). In the multivariable model for the composite graft survival, alemtuzumab use was associated with 22% increased kidney or pancreas graft loss compared with r-ATG (adjusted hazard ratio, 1.22; 95% confidence interval, 1.05-1.42), whereas IL-2RA use was not a predictor of graft survival. Induction type did not influence recipient survival in the adjusted model., Conclusions: r-ATG use was associated with the lowest SPK rejection rates. Compared with r-ATG, alemtuzumab but not IL-2RA was associated with worse long-term death-censored SPK graft outcome. Our analysis supports the common use of r-ATG for induction in US primary SPK recipients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

After a 1-y absence due to the coronavirus disease 2019 pandemic, the 26th Annual Congress of the International Liver Transplantation Society was held from May 15 to 18, 2021, in a virtual format. Clinicians and researchers from all over the world came together to share their knowledge on all the aspects of liver transplantation (LT). Apart from a focus on LT in times of coronavirus disease 2019, featured topics of this year's conference included infectious diseases in LT, living donation, machine perfusion, oncology, predictive scoring systems and updates in anesthesia/critical care, immunology, radiology, pathology, and pediatrics. This report presents highlights from invited lectures and a review of the select abstracts. The aim of this report, generated by the Vanguard Committee of International Liver Transplantation Society, is to provide a summary of the most recent developments in clinical practice and research in LT., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Sexual differentiation of the brain is influenced by testosterone and its metabolites during the perinatal period, when many aspects of brain development, including the maturation of GABAergic transmission, occur. Whether and how testosterone signaling during the perinatal period affects GABAergic transmission is unclear. Here, we analyzed GABAergic circuit functional markers in male, female, testosterone-treated female, and testosterone-insensitive male rats after the first postnatal week and in young adults. In the hippocampus, mRNA levels of proteins associated with GABA signaling were not significantly affected at postnatal day (P) 7 or P40. Conversely, membrane protein levels of KCC2, which are critical for determining inhibition strength, were significantly higher in females compared to males and testosterone-treated females at P7. Further, female and testosterone-insensitive male rats at P7 showed higher levels of the neurotrophin BDNF, which is a powerful regulator of neuronal function, including GABAergic transmission. Finally, spontaneous GABAergic currents in hippocampal CA1 pyramidal cells were more frequent in females and testosterone-insensitive males at P40. Overall, these results show that perinatal testosterone levels modulate GABAergic circuit function, suggesting a critical role of perinatal sex hormones in regulating network excitability in the adult hippocampus., (© 2022. The Author(s).)

Background: Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking infiltration of activated PBMCs into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS., Methods: To establish our model, we first extracted PBMCs from rat spleen, then, immunologically primed PBMCs with lipopolysaccharide (LPS), followed by further activation with nigericin. Thereafter, we co-cultured these activated PBMCs with organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. We further targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 h, we analyzed inflammation markers in the cortex and the hippocampus using semiquantitative immunofluorescence. In addition, we analyzed neuronal activity by whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons., Results: In the cortex, co-culturing immunoreactive PBMCs treated with LPS + nigericin on top of OCHSCs upregulated inflammatory markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs (i.e. treated with LPS only), to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, prevented neuroinflammation and hippocampal hyperexcitability in OCHSCs., Conclusions: Our study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Surgical residency training has an extended tradition of long hours. Residency programs use a variety of call schedules to combat resident fatigue and sleep deprivation while maintaining adherence to duty hour restrictions. Nonetheless, there is a paucity of data regarding objective measurements of sleep during the different call schedules included in general surgery training., Objective: The primary objective of this study was to compare the quantity of sleep in 24-hour time frames across all types of shifts worked by general surgery residents at our institution. The secondary objective was to measure activity level in total steps during various time frames., Methods: This prospective observational study was performed between April 4 and August 26, 2018, with general surgery residents. Each resident was assigned a Fitbit Charge 2 to wear during all rotations, including general surgery and subspecialty services., Results: Twenty-six out of 31 residents voluntarily participated in the study (84%). In-house call (IHC) had significantly less sleep in a 24-hour time frame than home call and night float (144 vs 283 vs 246 minutes, P < .001 and P < .028). IHC had significantly more steps than home call (11 245 vs 8756 steps, P = .039). The smallest number of steps was obtained when residents were not working (7904 steps)., Conclusions: Our data demonstrate that surgical residents on IHC have significantly less sleep compared to all other types of on-call time frames. Residents on IHC have the most steps across all time frames., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Focal cortical dysplasia is a common cause of medication resistant epilepsy. A better understanding of its presentation, pathophysiology and consequences have helped us improved its treatment and outcome. This paper reviews the most recent classification, pathophysiology and imaging findings in clinical research as well as the knowledge gained from studying genetic and lesional animal models of focal cortical dysplasia. This review of this recently gained knowledge will most likely help develop new research models and new therapeutic targets for patients with epilepsy associated with focal cortical dysplasia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture., Methodology/principal Findings: In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam., Conclusions/significance: We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and identify Pten as an integral component of a novel cell positioning pathway in the retina.

Cajal-Retzius cells are essential pioneer neurons that guide neuronal migration in the developing neocortex. During development, Cajal-Retzius cells arise from distinct progenitor domains that line the margins of the dorsal telencephalon, or pallium. Here, we show that the proneural gene Ascl1 is expressed in Cajal-Retzius cell progenitors in the pallial septum, ventral pallium, and cortical hem. Using a short-term lineage trace, we demonstrate that it is primarily the Ascl1-expressing progenitors in the pallial septum and ventral pallium that differentiate into Cajal-Retzius cells. Accordingly, we found a small, albeit significant reduction in the number of Reelin(+) and Trp73(+) Cajal-Retzius cells in the Ascl1(-/-) neocortex. Conversely, using a gain-of-function approach, we found that Ascl1 induces the expression of both Reelin, a Cajal-Retzius marker, and Tbr1, a marker of pallial-derived neurons, in a subset of early-stage pallial progenitors, an activity that declines over developmental time. Taken together, our data indicate that the proneural gene Ascl1 is required and sufficient to promote the differentiation of a subset of Cajal-Retzius neurons during early neocortical development. Notably, this is the first study that reports a function for Ascl1 in the pallium, as this gene is best known for its role in specifying subpallial neuronal identities.