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Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3 or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

Abstract Photonics offers a transformative approach to artificial intelligence (AI) and neuromorphic computing by enabling low-latency, high-speed, and energy-efficient computations. However, conventional photonic tensor cores face significant challenges in constructing large-scale photonic neuromorphic networks. Here, we propose a fully integrated photonic tensor core, consisting of only two thin-film lithium niobate (TFLN) modulators, a III-V laser, and a charge-integration photoreceiver. Despite its simple architecture, it is capable of implementing an entire layer of a neural network with a computational speed of 120 GOPS, while also allowing flexible adjustment of the number of inputs (fan-in) and outputs (fan-out). Our tensor core supports rapid in-situ training with a weight update speed of 60 GHz. Furthermore, it successfully classifies (supervised learning) and clusters (unsupervised learning) 112 × 112-pixel images through in-situ training. To enable in-situ training for clustering AI tasks, we offer a solution for performing multiplications between two negative numbers.

Abstract Background Macrophages are involved in tissue homeostasis, angiogenesis and immunomodulation. Proangiogenic and anti-inflammatory macrophages (regulatory macrophages, Mreg) can be differentiated in-vitro from CD14+ monocytes by using a defined cell culture medium and a stimulus of IFNγ. Aim of the study To scrutinize the potential impact of temporal IFNγ exposure on macrophage differentiation as such exposure may lead to the emergence of a distinct and novel macrophage subtype. Methods Differentiation of human CD14+ monocytes to Mreg was performed using a GMP compliant protocol and administration of IFNγ on day 6. Monocytes from the same donor were in parallel differentiated to MregIFNγ0 using the identical protocol but with administration of IFNγ on day 0. Cell characterization was performed using brightfield microscopy, automated and metabolic cell analysis, transmission electron microscopy, flow cytometry, qPCR and secretome profiling. Results Mreg and MregIFNγ0 showed no differences in cell size and volume. However, phenotypically MregIFNγ0 exhibited fewer intracellular vesicles/vacuoles but larger pseudopodia-like extensions. MregIFNγ0 revealed reduced expression of IDO and PD-L1 (P

Abstract Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult.

Abstract The scientific community studies tight focusing of radially and azimuthally-polarized vector beams as it is a versatile solution for many applications. We offer a new method to produce tight focusing that ensures a more uniform intensity profile in multiple dimensions, providing a more versatile and stable solution. We manipulate the polarization of the radially and azimuthally polarized vector beams to find an optimal operating point. We examine in detail optical fields whose polarization states lie on the equator of the relevant Poincaré spheres namely, the fundamental Poincaré sphere, the hybrid order Poincaré sphere (HyOPS), and the higher order Poincaré sphere. We find via simulation that the fields falling on these equators have focal plane intensity distributions characterized by a single rotation parameter $$\alpha$$ α determining the individual state of polarization. The strengths of the component field distributions vary with $$\alpha$$ α and can be tuned to achieve equal strengths of longitudinal (z) and transverse (x and y) components at the focal plane. Without control of this parameter (e.g., using $$\alpha =0$$ α = 0 in radially and $$\alpha =\pi$$ α = π in azimuthally-polarized vector beams) intensity in x and y components are at 20% of the z component. In our solution with $$\alpha =\pi /2$$ α = π / 2 , all components are at 80% of the maximum possible intensity of z. In examining the impact of $$\alpha$$ α on a tightly focused beam, we also found that a helicity inversion of HyOPS beams causes a rotation of 180 degree in the axial intensity distribution.

The combination of the high wear resistance and mechanical strength of W with the high thermal conductivity of Cu makes the Cu/W system an attractive candidate material for heat sinks in plasma experiments and for radiation tolerance applications. However, the resulting mechanical properties of multilayers and coatings strongly depend on the microstructure of the layers. In this work, the mechanical properties of Cu/W nanomultilayers with different densities of internal interfaces are systematically investigated for two opposite in-plane stress states and critically discussed in comparison with the literature. Atomistic simulations with the state-of-the-art neural network potential are used to explain the experimental findings of Young’s modulus and hardness. The results suggest that the microstructure, specifically the excess free volume associated with porosity and interface disorder interconnected with the stress state, has a great impact on the mechanical properties, notably Young’s modulus of Cu/W nanomultilayers.

Paediatric cardiovascular diseases have been referred to as diseases of injustice as access to care is inequitable globally. For example, Africa only has 78 cardiac centres, with 22 located in Sub-Saharan Africa. Most of these centres rely on visiting surgical teams to provide clinical care. While visiting surgical teams provide essential care, building a sustainable and locally run cardiac workforce in Africa is critical to addressing these inequities in access to care. This paper considers the role of south-to-south partnerships in building sustainable surgical programmes using Rwanda’s paediatric cardiac surgery programme as an example.

Vibrio coralliilyticus is a pathogen of coral and shellfish, leading to devastating economic and ecological consequences worldwide. Although rising ocean temperatures correlate with increased V. coralliilyticus pathogenicity, the specific molecular mechanisms and determinants contributing to virulence remain poorly understood. Here, we systematically analyzed the type VI secretion system (T6SS), a contact-dependent toxin delivery apparatus, in V. coralliilyticus. We identified 2 omnipresent T6SSs that are activated at temperatures in which V. coralliilyticus becomes virulent; T6SS1 is an antibacterial system mediating interbacterial competition, whereas T6SS2 mediates anti-eukaryotic toxicity and contributes to mortality during infection of an aquatic model organism, Artemia salina. Using comparative proteomics, we identified the T6SS1 and T6SS2 toxin arsenals of 3 V. coralliilyticus strains with distinct disease etiologies. Remarkably, T6SS2 secretes at least 9 novel anti-eukaryotic toxins comprising core and accessory repertoires. We propose that T6SSs differently contribute to V. coralliilyticus's virulence: T6SS2 plays a direct role by targeting the host, while T6SS1 plays an indirect role by eliminating competitors.

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Abstract Objective Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. Methods This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. Results The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p

Abstract Myeloid cells including microglia and macrophages play crucial roles in retinal homeostasis by clearing cellular debris and regulating inflammation. These cells are activated in several blinding ischemic retinal diseases including diabetic retinopathy, where they may exert both beneficial and detrimental effects on neurovascular function and angiogenesis. Myeloid cells impact the progression of retinal pathologies and recent studies suggest that targeting myeloid cells is a promising therapeutic strategy to mitigate diabetic retinopathy and other ischemic retinal diseases. This review summarizes the recent advances in our understanding of the role of microglia and macrophages in retinal diseases and focuses on the effects of myeloid cells on neurovascular injury and angiogenesis in ischemic retinopathies. We highlight gaps in knowledge and advocate for a more detailed understanding of the role of myeloid cells in retinal ischemic injury to fully unlock the potential of targeting myeloid cells as a therapeutic strategy for retinal ischemia.

The microstructural evolution of Cu/Mo nanomultilayers upon annealing was investigated by X-ray diffraction and transmission electron microscopy. The isothermal annealing process in the temperature ranges of 300–850°C was conducted to understand the thermal behavior of the sample and follow the transformation into a nanocomposite. Annealing at 600°C led to the initiation of grain grooving in the investigated nanomultilayer, and it degraded into a spheroidized nanocomposite structure at 800°C. The sample kept the as-deposited Cu {111}//Mo{110} fiber texture up to 850°C. The residual stress was investigated to explain microstructure changes. The activation energy of degradation kinetics of Cu/Mo nanomultilayers was determined to understand the rate-determining mechanism for the degradation of nanolaminate structures.