Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

A novel lncRNA associated with the prognosis of patients with colorectal cancer resists apoptosis through the LYN/BCL-2 pathway.

PURPOSE: We found a novel lncRNA named lncAC138150.2 related to the overall survival and staging of patients with colorectal cancer (CRC) by bioinformatic analysis using data from the Cancer Genome Atlas (TCGA), and the study aimed to elucidate the function of lncAC138150.2 and underlying mechanisms. METHODS: Target molecules were knocked down by transfection with antisense oligonucleotides (ASOs), siRNAs, or lentiviruses and overexpressed by transfection with plasmids. The function of lncAC138150.2 was determined using histological, cytological, and molecular biology methods. The underlying mechanism of lncAC138150.2 function was investigated using RNA-seq, bioinformatics analysis, and molecular biology methods. RESULTS: The expression of lncAC138150.2 was increased in colorectal tissues compared with paired normal tissues. The lncAC138150.2 knockdown increased apoptosis but did not change the cell proliferation, cell cycle distribution, or cell migration ability of CRC cells, while lncAC138150.2 overexpression decreased CRC apoptosis. lncAC138150.2 was mainly located in the cell nucleus, and each lncAC138150.2 transcript knockdown increased CRC apoptosis. BCL-2 pathway was significantly altered in apoptosis induced by lncAC138150.2 knockdown, which was alleviated by BAX knockdown. The expression of LYN was significantly decreased with lncAC138150.2 knockdown, LYN knockdown increased CRC apoptosis, and its overexpression completely alleviated CRC apoptosis induced by lncAC138150.2 knockdown. CONCLUSION: lncAC138150.2 significantly inhibited CRC apoptosis and affected the prognosis of patients with CRC, through the LYN/BCL-2 pathway.

Ion Steric Effect Induces Giant Enhancement of Thermoelectric Conversion in Electrolyte-Filled Nanochannels.

Ionic thermoelectricity in nanochannels has received increasing attention because of its advantages, such as high Seebeck coefficient and low cost. However, most studies have focused on dilute simple electrolytes that neglect the effects of finite ion sizes and short-range electrostatic correlation. Here, we reveal a new thermoelectric mechanism arising from the coupling of the ion steric effect due to finite ion sizes and ion thermodiffusion in electric double layers, using both theoretical and numerical methods. We show that this mechanism can significantly enhance the thermoelectric response in nanoconfined electrolytes depending on the properties of electrolytes and nanochannels. Compared to the previously known mechanisms, the new mechanism can increase the Seebeck coefficient by 100% or even 1 order of magnitude enhancement under optimal conditions. Moreover, we demonstrate that the short-range electrostatic correlation can help preserve the Seebeck coefficient enhancement in a weaker confinement or in more concentrated electrolytes.

Controlling the Nonlinear Optical Behavior and Structural Transformation with A-Site Cation in α-AZnPO4 (A = Li, K).

Regulating the crystal structure by A-site cation substitution is one of the effective methods to explore high-performance nonlinear optical (NLO) materials. Herein, two non-centrosymmetric (NCS) compounds, α-MZnPO4 (M = Li, K) with short UV absorption edges 221 and 225 nm, are obtained by performing A-site cation substitution method. It is noteworthy that α-LiZnPO4 (α-LZPO) achieves >10 times second harmonic generation (SHG) response (2.3 × KDP) enhancement compared with that of α-KZnPO4 (α-KZPO) (0.2 × KDP), which is the only case among phosphates with different A-site cations. By structural comparison, it is found that the A-site cations play important roles for anion rearrangements, and further the structure features of the two compounds by designing two suppositional crystal models as well as performing other theoretical calculations are analyzed. The study confirms the feasibility to design promising NLO materials with strengthen SHG response and structural stability in orthophosphate system.

Detrimental role of SIX1 in hepatic lipogenesis and fibrosis of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD. METHODS: Alb-Cre mice were administered the AAV9 vector for SIX1 liver-specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet-induced steatohepatitis. RESULTS: Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver-specific overexpression of SIX1 using adeno-associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD-induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor ß (LXRß), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF-ß pathway by increasing the levels of type I and II TGF-ß receptor (TGFßRI/TGFßRII) in hepatic stellate cells (HSCs). Finally, we found that liver-specific SIX1 deficiency could ameliorate diet-induced NAFLD pathogenesis. CONCLUSION: Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/ß and TGF-ß signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.

Metal-induced sensor mobilization turns on affinity to activate regulator for metal detoxification in live bacteria.

Metal detoxification is essential for bacteria's survival in adverse environments and their pathogenesis in hosts. Understanding the underlying mechanisms is crucial for devising antibacterial treatments. In the Gram-negative bacterium Escherichia coli, membrane-bound sensor CusS and its response regulator CusR together regulate the transcription of the cus operon that plays important roles in cells' resistance to copper/silver, and they belong to the two-component systems (TCSs) that are ubiquitous across various organisms and regulate diverse cellular functions. In vitro protein reconstitution and associated biochemical/physical studies have provided significant insights into the functions and mechanisms of CusS-CusR and related TCSs. Such studies are challenging regarding multidomain membrane proteins like CusS and also lack the physiological environment, particularly the native spatial context of proteins inside a cell. Here, we use stroboscopic single-molecule imaging and tracking to probe the dynamic behaviors of both CusS and CusR in live cells, in combination with protein- or residue-specific genetic manipulations. We find that copper stress leads to a cellular protein concentration increase and a concurrent mobilization of CusS out of clustered states in the membrane. We show that the mobilized CusS has significant interactions with CusR for signal transduction and that CusS's affinity toward CusR switches on upon sensing copper at the interfacial metal-binding sites in CusS's periplasmic sensor domains, prior to ATP binding and autophosphorylation at CusS's cytoplasmic kinase domain(s). The observed CusS mobilization upon stimulation and its surprisingly early interaction with CusR likely ensure an efficient signal transduction by providing proper conformation and avoiding futile cross talks.

Molecular Mechanism and Agricultural Application of the NifA-NifL System for Nitrogen Fixation.

Nitrogen-fixing bacteria execute biological nitrogen fixation through nitrogenase, converting inert dinitrogen (N2) in the atmosphere into bioavailable nitrogen. Elaborating the molecular mechanisms of orderly and efficient biological nitrogen fixation and applying them to agricultural production can alleviate the "nitrogen problem". Azotobacter vinelandii is a well-established model bacterium for studying nitrogen fixation, utilizing nitrogenase encoded by the nif gene cluster to fix nitrogen. In Azotobacter vinelandii, the NifA-NifL system fine-tunes the nif gene cluster transcription by sensing the redox signals and energy status, then modulating nitrogen fixation. In this manuscript, we investigate the transcriptional regulation mechanism of the nif gene in autogenous nitrogen-fixing bacteria. We discuss how autogenous nitrogen fixation can better be integrated into agriculture, providing preliminary comprehensive data for the study of autogenous nitrogen-fixing regulation.

Effects of fluid slippage on pressure-driven electrokinetic energy conversion in conical nanochannels.

The effects of fluid slippage on the pressure-driven electrokinetic energy conversion in conical nanochannels are systematically investigated in this paper. We present a multiphysical model that couples the Planck-Nernst-Poisson equations and the Navier-Stokes equation with a Navier slip condition to fulfill this purpose. We systematically look into the variation of various performance indicators of electrokinetic energy conversion, for example, streaming current, streaming potential, generation power, energy conversion efficiency, regulation parameter, and enchantment ratio, with the conicity of nanochannels and the slip length for two pressure differences of the same magnitude but opposite directions. Particularly, enhancement ratios related to streaming current, streaming potential, generation power, and energy conversion efficiency are defined to comprehensively measure the enhancement of the performance of electrokinetic energy conversion due to the slip length. The results demonstrate that a combination of large slip length and small conicity enhances the electrokinetic energy conversion performance significantly. Furthermore, the fluid slippage-induced enhancement of the electrokinetic energy conversion in the backward pressure difference mode is stronger than that in the forward pressure difference mode. Our results provide design and operation guidelines for pressure-driven electrokinetic energy conversion devices.

Acid-Tolerant Sulfate Tetrahedral Cages from Anion-Coordination-Driven Assembly.

Supramolecular cages have been constructed by anion-coordination-driven assembly (ACDA) in recent years and have shown unique host-guest interactions. However, most of the reported cages are made of the phosphate ion (PO4 3- ); other anions have rarely been explored. Here we show for the first time that the sulfate ion (SO4 2- ) is also able to form the A4 L4 tetrahedral motif with tris-bis(urea) ligands, but this is dependent on the stoichiometry of the sulfate ion (in solution). Notably, the sulfate cages display enhanced resistance for both Brønsted (pH as low as 4.3 in acetone containing 15 % water) and Lewis acids (metal complexes) compared to the corresponding phosphate cages, and thus could find applications where an acidic (proton or metals) environment is required.

Structural features and electrostatic energy storage of electric double layers in confined polyelectrolyte solutions under low-salt conditions.

An electric double layer (EDL) in a polyelectrolyte solution plays a crucial role in diverse fields ranging from physical and life sciences to modern technologies. Due to the nonnegligible excluded volume effects, chain connectivity and complex intermolecular interactions, the EDLs in (confined) polyelectrolyte solutions display distinct features compared to those in simple electrolyte solutions. Here, we conducted a systematic study on the characteristics of EDLs in confined polyelectrolyte solutions for salt-free and low salt concentration systems using self-consistent field theory. Results suggest that the characteristic length scales measuring the EDL structures are different for positively and negatively charged surfaces. The former is the same as in the electrolyte solutions, while the latter is smaller due to the accumulation of oppositely charged polyelectrolytes near the surface. Furthermore, for low surface charge densities, a scaling law for the electrostatic energy stored in polyelectrolyte EDLs (in units of mJ m-2) was found to be U ∝ |σ|ν with ν ∼ 2-2.7, which differs from the electrolyte EDLs with ν ∼ 2; however, such a scaling law breaks down for high surface charge densities.

Light-Triggered High-Affinity Binding of Tetramethylammonium over Potassium Ions by [18]crown-6 in a Tetrahedral Anion Cage.

An azobenzene-functionalized bis-bis(urea) ligand (Lazo ) and phosphate anion assemble to give the first photoactive "aniono" constructs, tetrahedron (A4 L6 ) and helicate (A2 L3 ), which readily undergo interconversion through cis-trans isomerization of the azo group under irradiation/heating. Most strikingly, the tetrahedral cage can accommodate an [18]crown-6 molecule, which can capture two tetramethylammonium (TMA+ ) ions with an unusually high affinity, even capable of replacing K+ in [K([18]crown-6)]+ to form a {(TMA)2⊂ ([18]crown-6)} ⊂ cage "Russian doll" structure. Thus, the current work may provide a model for the light-driven binding and exchange of the biologically important K+ and TMA+ ions.

A Hydrogen-Bonded Ravel Assembled by Anion Coordination.

Anion-coordination-driven assembly (ACDA) is showing increasing power in the construction of anionic supramolecular architectures. Herein, by expanding the anion centers from oxoanion (phosphate or sulfate) to organic tris-carboxylates, an Archimedean solid (truncated tetrahedron) and a highly entangled, double-walled tetrahedron featuring a ravel topology have been assembled with tris-bis(urea) ligands. The results demonstrate the promising ability of tris-carboxylates as new anion coordination centers in constructing novel topologies with increasing complexity and diversity compared to phosphate or sulfate ions on account of the modifiable size and easy functionalization character of these organic anions.

Pipette-Tip-Enabled Digital Nucleic Acid Analyzer for COVID-19 Testing with Isothermal Amplification.

Herein, a pipette-tip-enabled digital nucleic acid analyzer for high-performance COVID-19 testing is demonstrated. This is achieved by digital loop-mediated isothermal amplification (digital LAMP or dLAMP) using common laboratory equipment and materials. It is shown that simply fixing a glass capillary inside conventional pipette tips enables the generation of monodisperse, water-in-oil microdroplets with benchtop centrifugation. It is shown that using LAMP, the ORF1a/b gene, a standard test region for COVID-19 screening, can be amplified without a thermal cycler. The amplification allows counting of fluorescent microdroplets so that Poisson analysis can be performed to allow quantification with a limit of detection that is 1 order of magnitude better than those of nondigital techniques and comparable to those of commercial dLAMP platforms. It is envisioned that this work will inspire studies on ultrasensitive digital nucleic acid analyzers demanding both sensitivity and accessibility, which is pivotal to their large-scale applications.

Intelligent Multidimensional Purity Analysis and Confirmation Tool for Multiple Attribute Analysis.

Chiral active pharmaceutical ingredients (APIs) are known to bind to chiral biological targets with better on-target specificity than achiral ones. However, the methods of synthesizing such APIs stereoselectively require the exhaustive optimization of multiple quality attributes of an asymmetric synthesis, wherein all critical quality attributes (for example, chemical and stereochemical purity of the API) are to be optimized in parallel and ideally from the beginning of the drug development program. A multidimensional liquid chromatographic tool capable of simultaneously measuring multiple quality attributes from a single analytical injection is reported. The tool is designed for the recirculation of chromatographic eluent bearing an analyte of interest through one or more stationary phases using a new and uniquely designed heart-cut valve. The iterative measurement of a target analyte from just one single injection will help scientists identify whether an unknown impurity is formed during reaction or during analysis. This chromatographic tool is particularly useful in the discovery of on-analysis artifacts, which is a resource-intensive exercise involving the identification, synthesis, and injection of impurity standards, all of which delay the drug development program.

Numerical investigation of the solute dispersion in finite-length microchannels with the interphase transport.

This paper utilizes a combined approach of the convection-diffusion theory and the moment analysis to conduct a comprehensive investigation of the solute dispersion under the influence of the interphase transport in finitely long inner coated microchannels. The present work has threefold novel contributions: (1) The 2D solute concentration contours in the stationary phase are calculated for the first time to facilitate the understanding the role of the interphase transport in the solute dispersion in the mobile phase. (2) The skewness of the elution curves is investigated to guide the control of solute band shape at the channel outlet. (3) The 2D diffusion-convection theory and zero-dimensional (0D) moment analysis complement each other to present a characterization of the solute dispersion behaviors more comprehensive than that by either of the two methods alone. Parametric studies are performed to clarify the effects of four major parameters related to the interphase transport (i.e., stationary phase Péclet number, interphase transport rate, partition coefficient, and stationary phase thickness) on the solute dispersion characteristics. The results from this study provide a straightforward understanding of the effects of interphase transport on the solute dispersion in finitely long microchannels and are of potential relevance to the design and operation of the microfluidics-based analytical devices.

Radial basis function interpolation supplemented lattice Boltzmann method for electroosmotic flows in microchannel.

Large gradients of physical variables near the channel walls are characteristic of EOF. The previous numerical simulations of EOFs with the lattice Boltzmann method (LBM) utilize uniform lattice and are not efficient, especially when the electric double layer (EDL) thickness is significantly smaller than the channel height. The efficient LBM simulation of EOF in microchannel calls for a nonuniform mesh which is dense in the EDL region and sparse in the bulk region. In this article, we formulate a radial basis function (RBF)-based interpolation supplemented LBM (ISLBM) to solve the governing equations of EOF, that is, the Poisson, Nernst-Planck, and Navier-Stokes equations, in a nonuniform mesh system. Unlike the conventional ISLBM, the RBF-ISLBM determines the prestreaming distribution functions by using the local RBF-based interpolation over circular supporting regions and is particularly suitable for nonuniform meshes. The RBF-ISLBM is validated by the EOFs in infinitely long and finitely long microchannels. The results show that the RBF-ISLBM possesses excellent robustness and accuracy. Finally, we use the RBF-ISLBM to simulate the EOFs with the hitherto highest electrokinetic parameter, κa, defined by the ratio of channel height a to EDL thickness κ-1 , in LBM simulations of EOF.

Wearable Mixed-Reality Holographic Navigation Guiding the Management of Penetrating Intracranial Injury Caused by a Nail.

Penetrating brain injury caused by a nail is an extremely rare neurosurgical emergency that poses a challenge for neurosurgeons. Nail entering the brain from the orbit and lodging within the cranial cavity is even more unusual. A 53-year-old male was found unconscious at a construction site, and brain CT revealed not only the presence of a nail beneath the inner table of the parietal bone, but also traumatic intracerebral hematoma. Consequently, accurate localization of the nail and hematoma was mandatory for surgical plan. During surgical planning, computational model reconstruction and trajectory calculation were completed using preoperative CT in 3D Slicer. Under the guidance of a head-mounted mixed-reality holographic computer, the neurosurgeon was able to visualize and interact with the hologram of the surgical plan, and intraoperative findings demonstrated that our low-cost portable wearable mixed-reality holographic navigation assisted precise localization of the nail and intracerebral hematoma, assuring less injury to the already compromised brain. After the surgery, the patient could obey commands, and postoperative imaging ruled out the possibility of brain abscess during follow-up. To the best of our knowledge, this is the first report on using a low-cost wearable mixed-reality holographic navigation to guide the management of penetrating intracranial injury caused by a nail.

Series of Crystals with Giant Optical Anisotropy: A Targeted Strategic Research.

The main commercially used birefringent oxides α-BaB2 O4 and YVO4 have the birefringences of 0.12 and 0.22. We propose a targeted high-throughput screening system to search birefringence-active functional modules (FMs) and large birefringent materials. A series of π-conjugated C-O units [C2 O4 ]2- , [C2 O6 ]2- , [C4 O4 ]2- , and [C6 O6 ]2- are discovered to be birefringence-active FMs. Theoretical and experimental studies on the crystals with C-O units confirm the feasibility of strategy. Based on this, the C-O containing compounds ranging from deep-ultraviolet to near-infrared region with large birefringence from 0.1 to 1.35 are found, and most of them break through the birefringent limit of oxides. The (NH4 )2 C2 O4 ⋅H2 O crystal is grown and its experimental birefringence is 0.248 at 546 nm, which is identified as a promising UV birefringent crystal. The A-site cations play significant roles in optical properties by influencing the density and arrangement of the C-O units.

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine-Chemical Manufacturing.

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine-chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors. This requires innovative approaches to sampling and analysis from flowing media to maintain the integrity of the reactor content and the analyte of interest. The following Review discusses examples of PAT tools implemented in flow chemistry for the preparation of small organic molecules, and applications of self-optimization tools.

Fine-Tuning the Spring-Like Motion of an Anion-Based Triple Helicate by Tetraalkylammonium Guests.

Supramolecular springs are a class of molecular devices that may provide implications to the macroscopic spring behavior from the molecular level. Helical structures are suitable molecular springs because the specific twisting of the helical strands can cause spring-like (extension-contraction) movement along the axis upon external stimuli. Herein we report an anion-based triple-helicate spring, which can undergo reversible contraction-extension motion through introduction and removal of tetraalkylammonium cations, including TMA+ and analogous irregular tetrahedral cations bearing different alkyl chains, while the relative orientation of the two phosphate ions changes to facilitate guest inclusion. Notably, the degree of contraction (shortening of the helical pitch) can be fine-tuned by varying the shape and size of guest cation. However, with the larger cations (TEA+ , TPA+ and TBA+ ), the meso-helicate configuration is obtained, which interconverts with the helicate by addition/removal of TMA+ ion.