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Abstract Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based “2 × 2” symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10–9 M for human PD1 and 2.557 × 10–8 M for human CD47, respectively, where the CD47 binding is significantly weaker as compared to the binding affinity of HX008 to PD1 as well as the binding affinity of SIRPα-Fc to CD47, leading to little binding to RBCs and platelets and is contrasting to many CD47-agents in development. However, HX009 effectively and simultaneously binds to the PD1 and CD47 on PD1+CD47+ T-cells via cis-binding and elicits enhanced T cell activation compared to the parental HX008. HX009 caused little cytokine-release in human peripheral blood mononuclear cells. HX009 cross-species binds to cynomolgus monkey PD1/CD47 but not to rodents, making cynomolgus monkeys the choice of species to investigate the pharmacokinetics (PK) and toxicology of HX009. HX009’s anti-tumor activities were confirmed in several humanized preclinical mouse models by determining either its anti-PD1 (humanized hu-CD47-MC38 models) or anti-CD47 (HuT-102 lymphoma CDX and three PDX-AML models) functions, although limited available humanized models have hindered broadly demonstration of enhanced anti-tumor activities contributed from the dual targeting of the BsAb. The expanded DLBCL-PDX trial data suggested that both EBV-status and OX40 expression could potentially be two positive predictors for response to HX009. An intravenous (IV) infusion PK study in cynomolgus monkey revealed its largely vasculature distribution, terminal half-life (T1/2) of ~ 50 h, and dose-proportional exposure without accumulation. The anti-drug antibody (ADA) was observed in all monkeys as expected, affecting the PK parameters of repeated administration. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150 mg/kg, while the repeated-dose (once weekly for 4 weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15 mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009’s candidacy for its clinical development.

Societal Impact Statement Unraveling the genetic intricacies and evolutionary history of Asian Hickories through advanced genome sequencing gives valuable insights into their ecological adaptations. Understanding the impact of historical dynamics, climate fluctuations, and geographical barriers on Asian hickories not only contributes to scientific knowledge but also empowers policymakers with evidence‐based decisions and guides conservationists in their efforts to protect vulnerable species. The identification of potential habitats, especially for the endangered Carya kweichowensis, offers a promising avenue for targeted conservation efforts, aligning with global initiatives to preserve Earth's precious biodiversity, but also ensures the conservation of a vital genetic reservoir for nut‐bearing economic tree species. Summary Biogeographic characteristics of disjunct distribution play a vital role in plant geography and the endangered mechanism. The whole genome resequencing provides an opportunity to study the genetic relationship, population diffusion, and floristic evolution of disjunctive‐distribution flora. Based on the SNPs (single nucleotide polymorphisms) data generated by the whole genome deep resequencing of five EA (Eastern Asian) Carya species, we constructed the phylogenetic tree, genetic structure, and species distribution modeling to clarify the phylogenetic relationships and to predict the potential distribution area of EA Carya. Phylogenetic analysis of Carya revealed two distinct clades, separating EA Carya from NA (North America) Carya. C. kweichowensis, an endangered species, showed the lowest nucleotide diversity and the earliest divergence among studied EA Carya species. Species distribution modeling predicted suitable habitats for five EA Carya species, revealing the potential distribution of endangered C. kweichowensis. Importantly, minimal spatial overlap was observed among distribution regions of EA Carya species during different time periods. The uneven regional distribution of EA Carya is believed to be a consequence of Quaternary climate fluctuations, mountain barriers hindering species dispersal, and the limited cold tolerance of these trees. EA Carya highlights the significant role of climate and geological changes in their regional distribution and migration routes in Asia. Furthermore, the discovery of potential habitats offers a promising avenue for the conservation of C. kweichowensis.

Abstract Retinol is widely used to treat skin ageing because of its effect on cell differentiation, proliferation and apoptosis. However, its potential benefits appear to be limited by its skin permeability. Herein, we investigated the transcutaneous behavior of retinol in semisolid cosmetics, in both in vitro and in vivo experiments. In vitro experiments used the modified Franz diffusion cell combined with Raman spectroscopy. In in vivo experiments, the content of retinol in rat skin and plasma was detected with HPLC. Retinol in semisolid cosmetics was mainly concentrated in the stratum corneum in the skin of the three animal models tested, and in any case did not cross the skin barrier after a 24 h dermatologic topical treatment in Franz diffusion cells tests. Similar results were obtained in live mice and rats, where retinol did not cross the skin barrier and did not enter the blood circulation. Raman spectroscopy was used to test the penetration depth of retinol in skin, which reached 16 μm out of 34 μm in pig skin, whereas the skin of mouse and rat showed too strong bakground interference. To explore epidermal transport mechanism and intradermal residence, skin transcriptomics was performed in rats, which identified 126 genes upregulated related to retinol transport and metabolism, relevant to the search terms “retinoid metabolic process” and “transporter activity”. The identity of these upregulated genes suggests that the mechanism of retinol action is linked to epidermis, skin, tissue and epithelium development.

The natural gas pipeline system (NGPS) is complex with a diverse network topology. This study elucidates the network characteristics of the NGPS, revealing that it shares commonalities with small-world networks, but with differences caused by its structural and operational characteristics. The combination of the low aggregation effect caused by branching structure and the offsetting effect caused by economic and geographical constraints results in a network with small world characteristics. NGPS has longer mean path than common small world network, but the aggregation factor is close to that of a standard small world network. With respect to its small-world characteristics and correlation with self-organized criticality (SOC), an in-depth study of the SOC characteristics of the NGPS was conducted utilizing a combination of traditional logarithm analysis and R/S analysis. The findings establish that there are atypical SOC characteristics, characterized by a weakened power law within a specific functional range, thereby encouraging the advancement of SCADA and other safety technologies. Because of the line-pack, which induces time lags in the NGPS, NGPS can prevent the cascade failures. The reasons for the periodicity and centrality of NGPS data are analyzed by the affecting components, with the R/S analysis verifying a weak positive correlation of the function data across different time series. The interlinking of the SOC and R/S analysis illustrates the connection between critical status, accident type, and operation index. The results prove the reasonability and importance of insurance measures, such as regular internal detection, higher grade steel pipes change and staff training et al., in a novel view of SOC. The future works in building accidents database and human factors study are proposed.

Abstract CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301’s high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50

Flexible pressure sensors are lightweight and highly sensitive, making them suitable for use in small portable devices to achieve precise measurements of tiny forces. This article introduces a low-cost and easy-fabrication strategy for piezoresistive flexible pressure sensors. By embedding silver nanowires into a polydimethylsiloxane layer with micro-pyramids on its surface, a flexible pressure sensor is created that can detect low pressure (17.3 Pa) with fast response (

Abstract Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo‐ and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene‐based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.