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Retinal ganglion cells (RGCs) relay visual information from the eye to the brain. RGCs are the first cell type generated during retinal neurogenesis. Loss of function of the transcription factor Atoh7, expressed in multipotent early neurogenic retinal progenitors leads to a selective and essentially complete loss of RGCs. Therefore, Atoh7 is considered essential for conferring competence on progenitors to generate RGCs. Despite the importance of Atoh7 in RGC specification, we find that inhibiting apoptosis in Atoh7-deficient mice by loss of function of Bax only modestly reduces RGC numbers. Single-cell RNA sequencing of Atoh7;Bax-deficient retinas shows that RGC differentiation is delayed but that the gene expression profile of RGC precursors is grossly normal. Atoh7;Bax-deficient RGCs eventually mature, fire action potentials, and incorporate into retinal circuitry but exhibit severe axonal guidance defects. This study reveals an essential role for Atoh7 in RGC survival and demonstrates Atoh7-dependent and Atoh7-independent mechanisms for RGC specification.

This study has made significant findings in A-share market data processing and portfolio management. Firstly, by adopting the Lasso method and CPCA framework, we effectively addressed the problem of multicollinearity among feature indicators, with the Lasso method demonstrating superior performance in handling this issue, thus providing a new method for financial data processing. Secondly, Deep Feedforward Neural Networks (DFN) exhibited exceptional performance in portfolio management, significantly outperforming other evaluated machine learning methods, and achieving high levels of out-of-sample performance and Sharpe ratios. Additionally, we consistently identified price changes, earnings per share, net assets per share, and excess returns as key factors influencing predictive signals. Finally, this study combined the Lasso method with DFN, providing a new perspective and methodological support for asset pricing measurement in the financial field. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) plays an important role in the function and health of neurons. In vertebrate cone photoreceptors, Ca2+ controls photoresponse sensitivity, kinetics, and light adaptation. Despite the critical role of Ca2+ in supporting the function and survival of cones, the mechanism for its extrusion from cone outer segments is not well understood. Here, we show that the Na+/Ca2+, K+ exchanger NCKX4 is expressed in zebrafish, mouse, and primate cones. Functional analysis of NCKX4-deficient mouse cones revealed that this exchanger is essential for the wide operating range and high temporal resolution of cone-mediated vision. We show that NCKX4 shapes the cone photoresponse together with the cone-specific NCKX2: NCKX4 acts early to limit response amplitude, while NCKX2 acts late to further accelerate response recovery. The regulation of Ca2+ by NCKX4 in cones is a novel mechanism that supports their ability to function as daytime photoreceptors and promotes their survival.

B-type lamins are major constituents of the nuclear lamina in all metazoan cells, yet have specific roles in the development of certain cell types. Although they are speculated to regulate gene expression in developmental contexts, a direct link between B-type lamins and developmental gene expression in an in vivo system is currently lacking. Here, we identify lamin B1 as a key regulator of gene expression required for the formation of functional olfactory sensory neurons. By using targeted knockout in olfactory epithelial stem cells in adult mice, we show that lamin B1 deficient neurons exhibit attenuated response to odour stimulation. This deficit can be explained by decreased expression of genes involved in mature neuron function, along with increased expression of genes atypical of the olfactory lineage. These results support that the broadly expressed lamin B1 regulates expression of a subset of genes involved in the differentiation of a specific cell type.

Background: This study aimed to evaluate whether inosine enhances the efficacy of immune‐checkpoint inhibitors in human malignant solid tumors. Methods: This single‐center, prospective, randomized, open‐label study was conducted, from January 2021 to December 2022, in Beijing Friendship Hospital, Capital Medical University, and participants were randomly assigned (1:1) to either the inosine (trial) or non‐inosine (control) group that received inosine (dosage: 0.2 g, three times/day) + PD‐1/PD‐L1 inhibitor or only PD‐1/PD‐L1 inhibitor ± targeted ± chemotherapy, respectively. Efficacy was assessed every 6 weeks (i.e., after every two–three treatment cycles). The primary endpoint was the objective response rate (ORR); the secondary endpoints were disease control rate, overall survival (OS), and progression‐free survival (PFS). The trial was registered at ClinicalTrials.gov (NCT05809336). Results: Among the 172 participants with advanced malignant solid tumors, 86 each were assigned to the inosine and non‐inosine groups, wherein the median PFS (95% CI) was 7.00 (5.31–8.69) and 4.40 (3.10–5.70) months, respectively (hazard ratio [HR] 0.63; 95% CI 0.44–0.90, p = 0.011), and the ORR was 26.7% and 15.1%, respectively (p = 0.061). In the inosine and non‐inosine groups, the median OS was not reached and was 29.67 (95% CI 17.40–41.94) months, respectively (HR 1.05 [95% CI 0.59–1.84], p = 0.874). Compared with the non‐inosine group, the median PFS and ORR of the inosine group were significantly prolonged and improved in the multiple exploratory subgroup analyses. The safety analysis showed that Grades 3 and 4 adverse reactions occurred in 25 (29%) and 31 (36%) patients in the inosine and non‐inosine groups, respectively, and tended to decrease in the inosine group compared with the non‐inosine group. Conclusion: Inosine had a tendency to enhance the efficacy of immune‐checkpoint inhibitors and reduced immunotherapy‐related adverse reactions. Compared with the control group, the median progression‐free survival was significantly prolonged and the objective response rate tended to increase in the inosine group. Inosine has a tendency to enhance the efficacy of immune‐checkpoint inhibitors and reduce immunotherapy‐related adverse reactions in clinical applications. [ABSTRACT FROM AUTHOR]

Author(s): Diego Carlos Fernandez [sup.1] , Ruchi Komal [sup.1] , Jennifer Langel [sup.1] , Jun Ma [sup.1] , Phan Q. Duy [sup.1] [sup.3] , Mario A. Penzo [sup.1] , Haiqing [...], Daily changes in light and food availability are major time cues that influence circadian timing.sup.1. However, little is known about the circuits that integrate these time cues to drive a coherent circadian output.sup.1-3. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)--the central circadian pacemaker--and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs).sup.4. We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGL.sup.NPY neurons), guiding the assembly of a functional IGL.sup.NPY-SCN circuit. Moreover, silencing IGL.sup.NPY neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGL.sup.NPY terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGL.sup.NPY-SCN circuit to allow entrainment to time-restricted feeding. Ablating retinal input at early postnatal stages--but not later time points--impaired entrainment to time-restricted feeding in adult mice, as did silencing intergeniculate-leaflet neurons that express neuropeptide Y and project to the central pacemaker

The preparation of a high-performance low-strength concrete with a MB value of 1.6 g/kg and a stone powder content of 8.8% with high silt-containing silt sand and high-performance low-strength concrete for highways in plateau and mountainous areas, and its influence on workability and mechanical properties were studied. The test results show that moderately increasing the cement, fly ash, sand ratio, and water reducing agent in the mountain sand concrete can effectively improve its working performance and enhance the strength of the concrete; among them, the amount of cement and fly ash content affects the strength of the mountain sand concrete obviously, the amount of water-reducing agent and the amount of cement have the most significant impact on the slump of mountain sand concrete. The best dosage of the mountain sand C30 low-strength high-performance concrete material is: cement, fly ash, mountain sand, crushed stone, water, water reducing agent =312,55,824,1049,156,3.67 kg/m³, the prepared concrete has good durability properties such as impermeability, frost resistance, shrinkage, and carbonization resistance. [ABSTRACT FROM AUTHOR]