Ni-electrocatalytic Csp3-Csp3 doubly decarboxylative coupling.

Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling1,2. The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond3-12. As one of the oldest known Csp3-Csp3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates13. In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century5, thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.

Cobalt-electrocatalytic HAT for functionalization of unsaturated C-C bonds.

The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s1, for energy storage, through the reduction of protons to generate hydrogen2,3, and for organic synthesis, for the functionalization of unsaturated C-C, C-O and C-N bonds4,5. In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s6 but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT)7. Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co-H generation that takes place through a low-valent intermediate.

Laser Additive Manufacturing of Three-Dimensional Ti/TiN Nanotube Arrays with Hierarchical Pore Structures and Promoted Supercapacitor Performances.

Titanium-based composites hold great promise in versatile functional application fields, including supercapacitors. However, conventional subtractive methods for preparing complex-shaped titanium-based composites generally suffer from several significant shortcomings, including low efficiency, strictly simple geometry, low specific surface area, and poor electrochemical performance of the products. Herein, three-dimensional composites of Ti/TiN nanotube arrays with hierarchically porous structures were prepared using the additive manufacturing method of selective laser melting combined with anodic oxidation and nitridation. The resultant Ti/TiN nanotube array composites exhibit good electrical conductivity, ultrahigh specific surface areas, and outstanding supercapacitor performances featuring the unique combination of a large specific capacitance of 134.4 mF/cm2 and a high power density of 4.1 mW/cm2, which was remarkably superior to that of their counterparts. This work is anticipated to provide new insights into the facile and efficient preparation of high-performance structural and functional devices with arbitrarily complex geometries and good overall performances.

Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres.

Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class of bioisosteres for benzoyl groups (highly prevalent structures in approved drugs), have been rarely utilized in agrochemicals and pharmaceuticals due to significant synthetic challenges. Here, we present a modular synthetic strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access to a library of functionalized oxetanes. This operationally simple protocol leverages the vast existing libraries of aryl halides and various nucleophiles. The power and generality of this approach is demonstrated by late-stage functionalization of complex molecules, as well as the rapid synthesis of oxetane analogues of bioactive molecules and marketed drugs. Preliminary mechanistic study suggests that the oxygen atom in the oxetane ring plays a crucial role in stabilizing the carbocation intermediates.

GAS6 as a potential target to alleviate neuroinflammation during Japanese encephalitis in mouse models.

Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB.

The role of hormones in ILC2-driven allergic airway inflammation.

Group 2 innate lymphoid cells (ILC2s) are a type of innate immune cells that produce a large amount of IL-5 and IL-13 and two cytokines that are crucial for various processes such as allergic airway inflammation, tissue repair and tissue homeostasis. It is known that damaged epithelial-derived alarmins, such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP), are the predominant ILC2 activators that mediate the production of type 2 cytokines. In recent years, abundant studies have found that many factors can regulate ILC2 development and function. Hormones synthesized by the body's endocrine glands or cells play an important role in immune response. Notably, ILC2s express hormone receptors and their proliferation and function can be modulated by multiple hormones during allergic airway inflammation. Here, we summarize the effects of multiple hormones on ILC2-driven allergic airway inflammation and discuss the underlying mechanisms and potential therapeutic significance.

Global vaccine coverage and childhood survival estimates: 1990-2019.

Objective: To quantify the association between reduction in child mortality and routine immunization across 204 countries and territories from 1990 to 2019. Methods: We used child mortality and vaccine coverage data from the Global Burden of Disease Study. We used a modified child survival framework and applied a mixed-effects regression model to estimate the reduction in deaths in children younger than 5 years associated with eight vaccines. Findings: Between 1990 and 2019, the diphtheria-tetanus-pertussis (DTP), measles, rotavirus and Haemophilus influenzae type b vaccines were significantly associated with an estimated 86.9 (95% confidence interval, CI: 57.2 to 132.4) million fewer deaths in children younger than 5 years worldwide. This decrease represented a 24.2% (95% CI: 19.8 to 28.9) reduction in deaths relative to a scenario without vaccines. The DTP and measles vaccines averted 46.7 (95% CI: 30.0 to 72.7) million and 37.9 (95% CI: 25.4 to 56.8) million deaths, respectively. Of the total reduction in child mortality associated with vaccines, 84.2% (95% CI: 83.0 to 85.1) occurred in 73 countries supported by Gavi, the Vaccine Alliance, with an estimated 45.4 (95% CI: 29.8 to 69.2) million fewer deaths from 2000 to 2019. The largest reductions in deaths associated with these four vaccines were in India, China, Ethiopia, Pakistan and Bangladesh (in order of the size of reduction). Conclusion: Vaccines continue to reduce childhood mortality significantly, especially in Gavi-supported countries, emphasizing the need for increased investment in routine immunization programmes.

Quantifying Contributions of Different Repulsion to Film Drainage Time during the Bubble-Solid Surface Attachment and Implications for the Flotation of Fine Particles.

The flotation recovery of fine particles faces serious challenges due to the lack of kinetic energy required for supporting their radial displacement and attachment with bubbles. Generally, the hydrodynamic resistance and repulsive disjoining pressure successively inhibit the liquid outflow intervening between the bubble and solid surfaces. To quantitatively characterize the influence of the main repulsion on film thinning time, experiments have been designed in three different aqueous systems. Bubble surface mobility closely associated with hydrodynamic resistance was determined by the rising bubble technique, and the DLVO theory was employed to confirm the evolution of electrostatic repulsion. The film drainage process was then measured based on the high-speed microscopic interferometry. Furthermore, the influence of the main repulsion on bubble-solid surface interactions was examined by flotation recovery. Results show that the earlier buildup of hydrodynamic force ran through the whole film thinning process, and under immobile conditions, the central region gradually became dominant in film thinning due to the very limited fluid flow at the thinnest rim position. Therefore, to achieve the identical film thickness (∼100 nm), the large hydrodynamic resistance could prolong the film thinning time by about 1 order of magnitude, compared with that induced by electrostatic repulsion, which accounts for the increased flotation recovery by 10% using mobile bubbles. This study not only enhances the understanding of how typical repulsive forces work in film drainage dynamics but also opens up an avenue for enhancing flotation and avoiding wasting resources by modulating bubble surface mobility and thus micro/nanoscale fluid flow.

Medium-Chain Chlorinated Paraffins Trigger Thyroid Hormone Synthesis and Interfere with Mitochondrial Function in the Thyroid Gland.

Medium-chain chlorinated paraffins (MCCPs, C14-C17) are frequently detected in diverse environmental media. It has been proposed to be listed in Annex A of the Convention on Persistent Organic Pollutants in 2023. Although MCCPs are a crucial health concern, their toxicity remains unclear. This study investigated the toxic effects of MCCPs (0.1-50 mg/kg body weight/day) on the thyroid gland of female Sprague-Dawley rats and characterized the potential toxic pathways via transcriptomics and metabolomics approaches. MCCPs exposure caused histopathological changes to the endoplasmic reticula and mitochondria in thyroid follicular cells at a dose of 50 mg/kg bw/d and increased serum thyrotropin-releasing hormone, thyroid-stimulating hormones, and thyroxine when exposed to a higher dose of MCCPs. Transcriptomic analysis indicated the excessive expression of key genes related to thyroid hormone synthesis induced by MCCPs. Integrating the dual-omics analysis revealed mitochondrial dysfunction of the thyroid by mediating fatty acid oxidation, Kreb's cycle, and oxidative phosphorylation. Significant metabolic toxicity on the thyroid might be linked to the characteristics of the chlorine content of MCCPs. This study revealed the toxicity of MCCPs to the thyroid gland via triggering thyroid hormone synthesis and interfering with mitochondrial function, which can provide new insights into the modes of action and mechanism-based risk assessment of MCCPs.

A first-principles study of 2D single-layer SiP as anode materials for lithium-ion batteries and sodium-ion batteries.

The promotion of lithium-ion batteries and sodium-ion batteries is limited by the deficiency of suitable anode materials with desired electrochemical properties. In this work, the models of 2D single-layer SiP are constructed to explore its potential as an anode material for LIBs and SIBs using density functional theory (DFT). The diffusion of Li in bulk SiP is anisotropic. There is a low diffusion energy barrier of 0.28 eV along the X-axis. The low surface exfoliation energy suggests that there is a high probability of preparing 2D single-layer SiP experimentally. Its structure stability is verified by ab initio molecular dynamics (AIMD) simulations at 300 K and 400 K. The intercalation and diffusion behaviors of Li/Na on 2D single-layer SiP indicate that Li/Na tends to diffuse along the X-axis direction of 2D single-layer SiP. The diffusion energy barrier of Li/Na on 2D single-layer SiP is lower compared to that of bulk SiP. The conductivity of 2D single-layer SiP is improved after lithiation due to the upshift of Fermi levels. 2D single-layer SiP has a lower average open circuit voltage (1.50 V for LIBs and 1.08 V for SIBs) and a high theoretical capacity (520 mA h g-1). Hence, 2D single-layer SiP can be an ideal anode material for LIBs and SIBs.

Large Exchange Bias Effect and Coverage-Dependent Interfacial Coupling in CrI3/MnBi2Te4 van der Waals Heterostructures.

Igniting interface magnetic ordering of magnetic topological insulators by building a van der Waals heterostructure can help to reveal novel quantum states and design functional devices. Here, we observe an interesting exchange bias effect, indicating successful interfacial magnetic coupling, in CrI3/MnBi2Te4 ferromagnetic insulator/antiferromagnetic topological insulator (FMI/AFM-TI) heterostructure devices. The devices originally exhibit a negative exchange bias field, which decays with increasing temperature and is unaffected by the back-gate voltage. When we change the device configuration to be half-covered by CrI3, the exchange bias becomes positive with a very large exchange bias field exceeding 300 mT. Such sensitive manipulation is explained by the competition between the FM and AFM coupling at the interface of CrI3 and MnBi2Te4, pointing to coverage-dependent interfacial magnetic interactions. Our work will facilitate the development of topological and antiferromagnetic devices.

N-Carbamylglutamate in ovo feeding improves carcass yield, muscle fiber development, and meat quality in broiler chickens.

BACKGROUND: Insufficient endogenous nutrients in the broiler embryo can lead to muscle gluconeogenesis, which ultimately affects the post-hatching performance of chicks. This study investigated the effects of in ovo feeding (IOF) of N-carbamylglutamate (NCG) on the growth hormones, carcass yield, and meat quality in broilers. Fertile eggs from a 30-week-old Ross 308 breeder flock were divided into three treatment groups: NC (non-injection), SC (100 µL saline-injection), and NCG (2 mg NCG injection). Each group had six replicates, with 70 eggs per replicate during incubation. Injections were administered on the 17.5th day of embryonic development. After hatching, 270 chicks were selected for 42-day rearing for further sampling. RESULTS: Chicks in the NCG group had significantly higher body weight (BW) and average daily gain (ADG) at the growing phase, increased growth and testosterone hormone in both feeding phases (21 and 42 days), and improved average daily gain (ADG) and food conversion ratio (FCR) in both grower and entire feeding phases (P < 0.05). Triiodothyronine (T3) and tetraiodothyronine (T4) levels, carcass yield, dressing, drum weight, breast muscle weight, drumstick weights, thighs, pectoralis major, and their part percentage of carcass were improved in the NCG group (P < 0.05), these effects were varied along feeding phases. Moreover, IOF of the NCG also improved pectoralis breast muscle color values at 24 h post mortem (P < 0.05). CONCLUSION: These results suggest that NCG injection at the late embryonic age of broiler enhances growth performance and meat quality throughout the lifespan and this can probably be attributed to an increase in thyroid and testosterone hormones, indicating potential involvement in metabolic and nutrient partitioning pathway regulation. © 2024 Society of Chemical Industry.

Residual levels and health risk assessment of trace metals in Chinese resident diet.

Large-scale metal contamination across the food web is an intractable problem due to increasing pollutant emissions, atmospheric transport, and dry and wet deposition of elements. The present study focus on several trace metals that are rarely studied but have special toxicity, including tin (Sn), antimony (Sb), gold (Au), hafnium (Hf), palladium (Pd), platinum (Pt), ruthenium (Ru), tellurium (Te) and iridium (Ir). We investigated trace metals residues and distribution characteristics, and further evaluated the potential health risks from major daily food intakes in 33 cities in China. Sn, Sb, Ir, Hf, and Au were frequently detected in food samples with the concentrations ranged from ND (not detected) to 24.78 µg/kg ww (wet weight). Eggs exhibited the highest residual level of all detected metals (13.70 ± 14.70 µg/kg ww in sum), while the lowest concentrations were observed in vegetables (0.53 ± 0.17 µg/kg ww in sum). Sn accounting for more than 50% of the total trace metals concentration in both terrestrial and aquatic animal origin foods. In terrestrial plant origin foods, Sn and Ir were the most abundant elements. Hf and Au were the most abundant elements in egg samples. In addition, Sb and Ir showed a clear trophic dilution effect in terrestrial environments, while in aquatic ecosystems, Sn, Hf, and Au exhibited obvious trophic amplification effects. The calculated average estimated daily intake (EDI) via food consumption in five regions of China was 0.09 µg/(kg·day), implying the health risk of aforementioned elements was acceptable.

[Research progress of electrospinning polyurethane fiber in the field of biomedical tissue engineering].

Polyurethane materials have good biocompatibility, blood compatibility, mechanical properties, fatigue resistance and processability, and have always been highly valued as medical materials. Polyurethane fibers prepared by electrostatic spinning technology can better mimic the structure of natural extracellular matrices (ECMs), and seed cells can adhere and proliferate better to meet the requirements of tissue repair and reconstruction. The purpose of this review is to present the research progress of electrostatically spun polyurethane fibers in bone tissue engineering, skin tissue engineering, neural tissue engineering, vascular tissue engineering and cardiac tissue engineering, so that researchers can understand the practical applications of electrostatically spun polyurethane fibers in tissue engineering and regenerative medicine.

Stereocontrolled Radical Thiophosphorylation.

The first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P-chiral products, which can be further diversified (with conventional 2e- chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

Core-shell structured hollow copper sulfide@metal-organic framework for magnetic resonance imaging guided photothermal therapy in second near-infrared biological window.

Multifunctional core-shell hybrids formed by integration of metal-organic framework (MOF) and functional materials have attracted extensive attention as promising theranostic nanoplatforms due to their combined novel properties and enhanced therapeutic efficacy. Recently, the second near-infrared (NIR-II, 1000-1700 nm) laser-induced photothermal therapy (PTT) as compared to the NIR-I(700-950 nm) laser-induced PTT has displayed improved therapeutic effects owing to its merits that include deeper tissue penetration and increased maximum permissible exposure. Herein, a novel core-shell hollow copper sulfide@metal-organic framework (HCuS@MIL-100) has been successfully fabricated by a layer-by-layer technique for the first time and their collective theranostic effects are investigated in vitro and in vivo. In this platform, the inner HCuS was applied as the NIR-II photothermal agent with excellent NIR-II absorption feature, leading to impressive photothermal effects under irradiation by 1064 nm light. With MIL-100 as the shell, HCuS@MIL-100 not only displayed optimal biocompatibility but also presented superior T2 magnetic resonance imaging (MRI) ability. In the current study multifunctional hollow core-shell HCuS@MIL-100 are fabricated for the MRI-guided PTT. This study also offers a facile and effective strategy for the development of novel theranostic platforms with high efficiency through the integration of MOFs and functional materials.

M2 tumor-associated macrophage mediates the maintenance of stemness to promote cisplatin resistance by secreting TGF-ß1 in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly gastrointestinal malignancy, and chemotherapy resistance is a key factor leading to its poor prognosis. M2 tumor-associated macrophages (M2-TAMs) may be an important cause of chemoresistance in ESCC, but its exact mechanism is still unclear. METHODS: In order to study the role of M2-TAMs in ESCC chemoresistance, CCK-8, clone formation assay, flow cytometric apoptosis assay, qRT-PCR, western blotting, and serum-free sphere formation assays were used. In vivo animal experiments and human ESCC tissues were used to confirm the findings. RESULTS: In vitro and in vivo animal experiments, M2-TAMs reduced the sensitivity of ESCC cells to cisplatin. Mechanistically, M2-TAMs highly secreted TGF-ß1 which activated the TGFßR1-smad2/3 pathway to promote and maintain the stemness characteristic of ESCC cells, which could inhibit the sensitivity to cisplatin. Using TGFß signaling inhibitor SB431542 or knockdown of TGFßR1 could reverse the cisplatin resistance of ESCC cells. In 92 cases of human ESCC tissues, individuals with a high density of M2-TAMs had considerably higher levels of TGF-ß1. These patients also had worse prognoses and richer stemness markers. CONCLUSION: TGF-ß1 secreted from M2-TAMs promoted and maintained the stemness characteristic to induce cisplatin resistance in ESCC by activating the TGFß1-Smad2/3 pathway.

Targeting BET proteins inhibited the growth of non-small cell lung carcinoma through downregulation of Met expression.

Hepatocyte growth factor receptor (HGFR or Met) upregulation has been proven to play important roles in non-small cell lung carcinoma (NSCLC). Interestingly, chemoresistance against epidermal growth factor receptor (EGFR) inhibitors including erlotinib and gefitinib was also related to Met. Targeting bromodomain and extra terminal domain (BET) proteins, especially BRD4, has shown inhibitory effects on lung cancer, but the mechanism is unclear. Herein, we found that JQ1 (BET inhibitor) suppressed NSCLC cell growth, reduced the Met expression, and contributed to inactivation of PI3K/Akt and MAPK/ERK pathways. Moreover, another BET protein inhibitor I-BET151, or BRD4 depletion, also inhibited NSCLC cell growth and downregulated Met. JQ1 inhibited HGF-induced cell growth and Met/PI3K/Akt activation, also inhibited A549 tumor growth in xenograft mouse models, in parallel with Met downregulation. Moreover, JQ1 inhibited the growth of paired erlotinib-sensitive and resistant HCC827 cells in parallel with Met downregulation and PI3K/Akt signaling inactivation. JQ1 also exerted inhibitory influences on the growth of erlotinib-sensitive and resistant HCC827 tumors in xenograft mouse models. These results suggested that targeting BET proteins inhibited NSCLC via downregulating Met and inactivating PI3K/AKT pathway. Our findings reveal a novel mechanism of BET proteins implicated in NSCLC progression with Met taken into consideration.

Release Mechanism of Short- and Medium-Chain Chlorinated Paraffins from PVC Materials under Thermal Treatment.

Chlorinated paraffins (CPs) as plasticizers are massively added to polyvinyl chloride (PVC) products, during whose life cycle CPs can be continuously released especially under thermal stress. In this study, a PVC cable sheath was adopted as a representative kind of PVC material to investigate the release behaviors of short- and medium-chain CPs (SCCPs and MCCPs) under thermal treatment. Release percentages of CPs with increasing temperature followed a Gaussian-like curve. At the unmolten stage of 80 °C, heating for 10 min caused 0.051% of added SCCPs and 0.029% of added MCCPs to be released. At the molten stage of 270 °C, accumulative release rates of SCCPs and MCCPs within 10 min were up to 30 and 14%, respectively. The developed emission model indicated that material-gas partitioning and internal diffusion simultaneously governed the release of CPs. During thermal treatment, the release of CPs could be remarkably affected by the thermal expansion of the PVC material and the formation of breakage and micropores. Congener group profiles of released CPs indicated a slight fractionation effect for SCCPs during the release process. Furthermore, the release risk of CPs from the whole life cycle of PVC products was preliminarily evaluated.

Health Risks Posed by Dermal and Inhalation Exposure to High Concentrations of Chlorinated Paraffins Found in Soft Poly(vinyl chloride) Curtains.

Chlorinated paraffins (CPs) are used in many products, including soft poly(vinyl chloride) curtains, which are used in many indoor environments. Health hazards posed by CPs in curtains are poorly understood. Here, chamber tests and an indoor fugacity model were used to predict CP emissions from soft poly(vinyl chloride) curtains, and dermal uptake through direct contact was assessed using surface wipes. Short-chain and medium-chain CPs accounted for 30% by weight of the curtains. Evaporation drives CP migration, like for other semivolatile organic plasticizers, at room temperature. The CP emission rate to air was 7.09 ng/(cm2 h), and the estimated short-chain and medium-chain CP concentrations were 583 and 95.3 ng/m3 in indoor air 21.2 and 172 µg/g in dust, respectively. Curtains could be important indoor sources of CPs to dust and air. The calculated total daily CP intakes from air and dust were 165 ng/(kg day) for an adult and 514 ng/(kg day) for a toddler, and an assessment of dermal intake through direct contact indicated that touching just once could increase intake by 274 µg. The results indicated that curtains, which are common in houses, could pose considerable health risks through inhalation of and dermal contact with CPs.