The genomic origins of the Bronze Age Tarim Basin mummies.

The identity of the earliest inhabitants of Xinjiang, in the heart of Inner Asia, and the languages that they spoke have long been debated and remain contentious1. Here we present genomic data from 5 individuals dating to around 3000-2800 BC from the Dzungarian Basin and 13 individuals dating to around 2100-1700 BC from the Tarim Basin, representing the earliest yet discovered human remains from North and South Xinjiang, respectively. We find that the Early Bronze Age Dzungarian individuals exhibit a predominantly Afanasievo ancestry with an additional local contribution, and the Early-Middle Bronze Age Tarim individuals contain only a local ancestry. The Tarim individuals from the site of Xiaohe further exhibit strong evidence of milk proteins in their dental calculus, indicating a reliance on dairy pastoralism at the site since its founding. Our results do not support previous hypotheses for the origin of the Tarim mummies, who were argued to be Proto-Tocharian-speaking pastoralists descended from the Afanasievo1,2 or to have originated among the Bactria-Margiana Archaeological Complex3 or Inner Asian Mountain Corridor cultures4. Instead, although Tocharian may have been plausibly introduced to the Dzungarian Basin by Afanasievo migrants during the Early Bronze Age, we find that the earliest Tarim Basin cultures appear to have arisen from a genetically isolated local population that adopted neighbouring pastoralist and agriculturalist practices, which allowed them to settle and thrive along the shifting riverine oases of the Taklamakan Desert.

Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane.

Mitochondrial cristae are extraordinarily crowded with proteins, which puts stress on the bilayer organization of lipids. We tested the hypothesis that the high concentration of proteins drives the tafazzin-catalyzed remodeling of fatty acids in cardiolipin, thereby reducing bilayer stress in the membrane. Specifically, we tested whether protein crowding induces cardiolipin remodeling and whether the lack of cardiolipin remodeling prevents the membrane from accumulating proteins. In vitro, the incorporation of large amounts of proteins into liposomes altered the outcome of the remodeling reaction. In yeast, the concentration of proteins involved in oxidative phosphorylation (OXPHOS) correlated with the cardiolipin composition. Genetic ablation of either remodeling or biosynthesis of cardiolipin caused a substantial drop in the surface density of OXPHOS proteins in the inner membrane of the mouse heart and Drosophila flight muscle mitochondria. Our data suggest that OXPHOS protein crowding induces cardiolipin remodelling and that remodeled cardiolipin supports the high concentration of these proteins in the inner mitochondrial membrane.

Wettability-based ultrasensitive detection of amphiphiles through directed concentration at disordered regions in self-assembled monolayers.

Various forms of ecological monitoring and disease diagnosis rely upon the detection of amphiphiles, including lipids, lipopolysaccharides, and lipoproteins, at ultralow concentrations in small droplets. Although assays based on droplets' wettability provide promising options in some cases, their reliance on the measurements of surface and bulk properties of whole droplets (e.g., contact angles, surface tensions) makes it difficult to monitor trace amounts of these amphiphiles within small-volume samples. Here, we report a design principle in which self-assembled monolayer-functionalized microstructured surfaces coated with silicone oil create locally disordered regions within a droplet's contact lines to effectively concentrate amphiphiles within the areas that dominate the droplet static friction. Remarkably, such surfaces enable the ultrasensitive, naked-eye detection of amphiphiles through changes in the droplets' sliding angles, even when the concentration is four to five orders of magnitude below their critical micelle concentration. We develop a thermodynamic model to explain the partitioning of amphiphiles at the contact line by their cooperative association within the disordered, loosely packed regions of the self-assembled monolayer. Based on this local analyte concentrating effect, we showcase laboratory-on-a-chip surfaces with positionally dependent pinning forces capable of both detecting industrially and biologically relevant amphiphiles (e.g., bacterial endotoxins), as well as sorting aqueous droplets into discrete groups based on their amphiphile concentrations. Furthermore, we demonstrate that the sliding behavior of amphiphile-laden aqueous droplets provides insight into the amphiphile's effective length, thereby allowing these surfaces to discriminate between analytes with highly disparate molecular sizes.

DNA-Nanostructure-Guided Assembly of Proteins into Programmable Shapes.

The development of methods to synthesize artificial protein complexes with precisely controlled configurations will enable diverse biological and medical applications. Using DNA to link proteins provides programmability that can be difficult to achieve with other methods. Here, we use DNA origami as an "assembler" to guide the linking of protein-DNA conjugates using a series of oligonucleotide hybridization and displacement operations. We constructed several isomeric protein nanostructures, including a dimer, two types of trimer structures, and three types of tetramer assemblies, on a DNA origami platform by using a C3-symmetric building block composed of a protein trimer modified with DNA handles. Our approach expands the scope for the precise assembly of protein-based nanostructures and will enable the formulation of functional protein complexes with stoichiometric and geometric control.

Enhancing intracellular mRNA precise imaging-guided photothermal therapy with a nucleic acid-based polydopamine nanoprobe.

Despite significant advancements in cancer research, real-time monitoring and effective treatment of cancer through non-invasive techniques remain a challenge. Herein, a novel polydopamine (PDA) nucleic acid nanoprobe has been developed for imaging signal amplification of intracellular mRNA and precise photothermal therapy guidance in cancer cells. The PDA nucleic acid nanoprobe (PDA@DNA) is constructed by assembling an aptamer hairpin (H1) labeled with the Cy5 fluorophore and another nucleic acid recognition hairpin (H2) onto PDA nanoparticles (PDA NPs), which have exceptionally high fluorescence quenching ability and excellent photothermal conversion properties. The nanoprobe could facilitate cellular uptake of DNA molecules and their protection from nuclease degradation. Upon recognition and binding to the intracellular mRNA target, a catalytic hairpin assembly (CHA) reaction occurs. The stem of H1 unfolds upon binding, allowing the exposed H1 to hybridize with H2, forming a flat and sturdy DNA double-stranded structure that detaches from the surface of PDA NPs. At the same time, the target mRNA is displaced and engages in a new cyclic reaction, resulting in the recovery and significant amplification of Cy5 fluorescence. Using thymidine kinase1 (TK1) mRNA as a model mRNA, this nanoprobe enables the analysis of TK1 mRNA with a detection limit of 9.34 pM, which is at least two orders of magnitude lower than that of a non-amplifying imaging nucleic acid probe. Moreover, with its outstanding performance for in vitro detection, this nanoprobe excels in precisely imaging tumor cells. Through live-cell TK1 mRNA imaging, it can accurately distinguish between tumor cells and normal cells. Furthermore, when exposed to 808-nm laser irradiation, the nanoprobe fully harnesses exceptional photothermal conversion properties of PDA NPs. This results in a localized temperature increase within tumor cells, which ultimately triggers apoptosis in these tumor cells. The integration of PDA@DNA presents innovative prospects for tumor diagnosis and image-guided tumor therapy, offering the potential for high-precision diagnosis and treatment of tumors.

Development and in vitro/in vivo evaluation of famotidine hydrochloride bioadhesive sustained release suspension.

To develop a new kind of famotidine-resin microcapsule for gastric adhesion sustained release by screening out suitable excipients and designing reasonable prescriptions to improve patient drug activities to achieve the expected therapeutic effect. The famotidine drug resin was prepared using the water bath method with carbomer 934 used as coating material. Microcapsules were prepared using the emulsified solvent coating method and appropriate excipients were used to prepare famotidine sustained release suspension. Pharmacokinetics of the developed microcapsules were studied in the gastrointestinal tract of rats. The self-made sustained-release suspension of famotidine hydrochloride effectively reduced the blood concentration and prolonged the action time. The relative bioavailability of the self-made suspension of the famotidine hydrochloride to the commercially available famotidine hydrochloride was 146.44%, with an average retention time of about 5h longer, which indicated that the new suspension had acceptable adhesion properties. The findings showed that the newly developed famotidine-resin microcapsule increased the bioavailability of the drug with a significant sustained-release property.

Safety assessment, whole genome sequence, and metabolome analysis of Streptococcus thermophilus CICC 20372 for bone cement fermentation.

Bone is a kind of meat processing by-product with high nutritional value but low in calorie, which is a typical food in China and parts of East Asian countries. Microbial fermentation by lactic acid bacteria showed remarkable advantages to increase the absorption of nutrients from bone cement by human body. Streptococcus thermophilus CICC 20372 is proven to be a good starter for bone cement fermentation. No genes encoding virulence traits or virulence factors were found in the genome of S. thermophilus CICC 20372 by a thorough genomic analysis. Its notable absence of antibiotic resistance further solidifies the safety. Furthermore, the genomic analysis identified four types of gene clusters responsible for the synthesis of antimicrobial metabolites. A comparative metabolomic analysis was performed by cultivating the strain in bone cement at 37 °C for 72 h, with the culture in de Man, Rogosa, and Sharpe (MRS) medium as control. Metabolome analysis results highlighted the upregulation of pathways involved in 2-oxocarboxylic acid metabolism, ATP-binding cassette (ABC) transporters, amino acid synthesis, and nucleotide metabolism during bone cement fermentation. S. thermophilus CICC 20372 produces several metabolites with health-promoting function during bone cement fermentation, including indole-3-lactic acid, which is demonstrated ameliorative effects on intestinal inflammation, tumor growth, and gut dysbiosis. In addition, lots of nucleotide and organic acids were accumulated at higher levels, which enriched the fermented bone cement with a variety of nutrients. Collectively, these features endow S. thermophilus CICC 20372 a great potential strain for bone food processing.

Potential micro-/nano-encapsulation systems for improving stability and bioavailability of anthocyanins: An updated review.

Anthocyanins (ACNs) are notable hydrophilic compounds that belong to the flavonoid family, which are available in plants. They have excellent antioxidants, anti-obesity, anti-diabetic, anti-inflammatory, anticancer activity, and so on. Furthermore, ACNs can be used as a natural dye in the food industry (food colorant). On the other hand, the stability of ACNs can be affected by processing and storage conditions, for example, pH, temperature, light, oxygen, enzymes, and so on. These factors further reduce the bioavailability (BA) and biological efficacy of ACNs, as well as limit ACNs application in both food and pharmaceutics field. The stability and BA of ACNs can be improved via loading them in encapsulation systems including nanoemulsions, liposomes, niosomes, biopolymer-based nanoparticles, nanogel, complex coacervates, and tocosomes. Among all systems, biopolymer-based nanoparticles, nanohydrogels, and complex coacervates are comparatively suitable for improving the stability and BA of ACNs. These three systems have excellent functional properties such as high encapsulation efficiency and well-stable against unfavorable conditions. Furthermore, these carrier systems can be used for coating of other encapsulation systems (such as liposome). Additionally, tocosomes are a new system that can be used for encapsulating ACNs. ACNs-loaded encapsulation systems can improve the stability and BA of ACNs. However, further studies regarding stability, BA, and in vivo work of ACNs-loaded micro/nano-encapsulation systems could shed a light to evaluate the therapeutic efficacy including physicochemical stability, target mechanisms, cellular internalization, and release kinetics.

An updated and comprehensive review on the potential health effects of curcumin-encapsulated micro/nanoparticles.

Curcumin (CUR) is a natural hydrophobic compound, which is available in turmeric rhizome. It has several bioactivities including antioxidant, anti-obesity, anti-diabetic, cardioprotective, anti-inflammatory, antimicrobial, anticancer, and other activities. Despite its medical and biological benefits, it is using in limitations because of its hydrophobicity and sensitivity. These unfavorable conditions further reduced the bioavailability (BA) and biological efficacy of CUR. This review summarizes the stability and BA of free- and encapsulated-CUR, as well as comprehensively discusses the potential biological activity of CUR-loaded various micro-/nano-encapsulation systems. The stability and BA of CUR can be improved via loading in different encapsulation systems, including nanoemulsions, liposomes, niosomes, biopolymer-based nanoparticles, nano-hydrogel, and others. Biopolymer-based nanoparticles (especially poly lactic-co-glycolic acid (PLGA), zein, and chitosan) and nano-gels are the best carriers for encapsulating and delivering CUR. Both delivery systems are suitable because of their excellent functional properties such as high encapsulation efficiency, well-stability against unfavorable conditions, and can be coated using other encapsulation systems. Based on available evidences, encapsulated-CUR exerted greater biological activities especially anticancer (breast cancer), antioxidant, antidiabetic, and neuroprotective effects.

Mechanically Strong and Tough Poly(urea-urethane) Thermosets Capable of Being Degraded under Mild Condition.

The development of degradable polymeric materials such as degradable polyurethane or polyurea has been much highlighted for resource conservation and environmental protection. Herein, a facile strategy of constructing mechanically strong and tough poly(urea-urethane) (PUU) thermosets that can be degraded under mild conditions by using triple boron-urethane bonds (TBUB) as cross-linkers is demonstrated. By tailoring the molecular weight of the soft segment of the prepolymers, the mechanical performance can be finely controlled. Based on the cross-linking of TBUB units and hydrogen-binding interactions between TBUB linkages, the as-prepared PUU thermosets have excellent mechanical strength of ≈40.2 MPa and toughness of ≈304.9 MJ m-3 . Typically, the PBUU900 strip can lift a barbell with 60 000 times its own weight, showing excellent load-bearing capacity. Meanwhile, owing to the covalent cross-linking of TBUB units, all the PUU thermosets show initial decomposition temperatures over 290 °C, which are comparable to those of the traditional thermosets. Moreover, the TBUB cross-linked PUU thermosets can be easily degraded in a mild acid solution. The small pieces of the PBUU sample can be fully decomposed in 1 m HCl/THF solution for 3.5 h at room temperature.

Snoring in patients with chronic rhinosinusitis after endoscopic sinus surgery.

PURPOSES: In patients with chronic rhinosinusitis (CRS), we assessed quality of life (QOL) of chronic rhinosinusitis (CRS) patients with different self-reported snoring frequencies after endoscopic sinus surgery (ESS), and explored factors associated with pre-ESS snoring and post-ESS snoring reduction. METHODS: This prospective cohort study was conducted in a tertiary referral center in Chengdu, China. Adult patients with medically recalcitrant CRS receiving initial ESS were engaged. Self-reported snoring was measured at baseline and 3-year follow-up, along with Sino-Nasal Outcome Test-22 and snoring visual analog scale assessment. Mouth breathing (MB), demographics, behavior, comorbidity factors, and objective CRS severity were considered. RESULTS: In 210 patients who completed this study, 63 (30%) patients reported pre-ESS habitual snoring, and post-operative habitual snoring was observed in 52 (25%) patients. The presence of self-reported snoring was correlated with worse CRS QOL at baseline and 3-year follow-up. Obesity (odds ratio [OR] = 4.30; 95% confidence interval [CI], 1.64-11.28; p < 0.01) and posterior-to-anterior ethmoid sinus ratio greater than one (PE/AE, OR = 0.32; 95% CI, 0.10-0.99; p = 0.05) were associated with pre-ESS snoring in univariable and multivariable analysis. The post-operative reduction of snoring frequency was related with patient age over 65 (OR = 11.55; 95%CI, 1.35-98.79; p = 0.03) and bilateral opacification in the Lund-Mackay system (OR = 8.04; 95%CI, 1.24-51.90; p = 0.03) in multivariable analysis. Pre-operative snoring and MB were associated with increased risk of post-operative snoring (p < 0.01 for each comparison). CONCLUSIONS: Post-ESS, self-reported snoring was associated with worse CRS QOL. Obesity and PE/AE > 1 were risk factors of pre-operative snoring. Advanced age and bilateral opacification were associated with greater improvement of snoring after ESS.

Long-term efficacy of GPi DBS for craniofacial dystonia: a retrospective report of 13 cases.

This study evaluated the long-term efficacy of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of craniofacial dystonia (Meige syndrome) and investigated the correlation between the volume of tissue activated (VTA) in the GPi and each subregion and movement score improvement. We retrospectively analyzed the clinical data of 13 patients with drug-refractory Meige syndrome who were treated with GPi DBS. The pre- and postoperative Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores were compared. The relationships between the preoperative baseline variables and improvement in the BFMDRS-Movement (BFMDRS-M) score were analyzed. LEAD-DBS software was used for the three-dimensional reconstruction of the GPi and implanted electrodes. The correlations between the GPi-VTA and score improvement were analyzed. The average follow-up period was 36.6 ± 11.0 months (18-55 months). At 3 months after the stimulation and the final follow-up visit, the improvements in the BFMDRS-M score were 58.2 and 54.6%, and the improvements in the BFMDRS-Disability (BFMDRS-D) score were 53.6 and 51.7%, respectively. At the final follow-up visit, the improvements in the BFMDRS-M scores of the eye, mouth, and speech/swallowing were significant (P < 0.001). Age was an independent predictor of improvement in the BFMDRS-M score after DBS (P = 0.005). A decrease in the BFMDRS-M score was significantly positively correlated with the GPi-VTA (r = 0.757, P = 0.003). GPi DBS is an effective method for treating drug-refractory Meige syndrome. LEAD-DBS software can be used as an effective aid for visualization programming after DBS.

Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment.

Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood-brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.

Recent Advances in Polymer Flooding in China.

Polymer flooding is drawing lots of attention because of the technical maturity in some reservoirs. The first commercial polymer flooding in China was performed in the Daqing oilfield and is one of the largest applications in the world. Some laboratory tests from Daqing researchers in China showed that the viscoelasticity of high molecular weight polymers plays a significant role in increasing displacement efficiency. Hence, encouraged by the conventional field applications and new findings on the viscoelasticity effect of polymers on residual oil saturation (ROS), some high-concentration high-molecular-weight (HCHMW) polymer-flooding field tests have been conducted. Although some field tests were well-documented, subsequent progress was seldom reported. It was recently reported that HCHMW has a limited application in Daqing, which does not agree with observations from laboratory core flooding and early field tests. However, the cause of this discrepancy is unclear. Thus, a systematic summary of polymer-flooding mechanisms and field tests in China is necessary. This paper explained why HCHMW is not widely used when considering new understandings of polymer-flooding mechanisms. Different opinions on the viscoelasticity effect of polymers on ROS reduction were critically reviewed. Other mechanisms of polymer flooding, such as wettability change and gravity stability effect, were discussed with regard to widely reported laboratory tests, which were explained in terms of the viscoelasticity effects of polymers on ROS. Recent findings from Chinese field tests were also summarized. Salt-resistance polymers (SRPs) with good economic performance using produced water to prepare polymer solutions were very economically and environmentally promising. Notable progress in SRP flooding and new amphiphilic polymer field tests in China were summarized, and lessons learned were given. Formation blockage, represented by high injection pressure and produced productivity ability, was reported in several oil fields due to misunderstanding of polymers' injectivity. Although the influence of viscoelastic polymers on reservoir conditions is unknown, the injection of very viscous polymers to displace medium-to-high viscosity oils is not recommended. This is especially important for old wells that could cause damage. This paper clarified misleading notions on polymer-flooding implementations based on theory and practices in China.

Reversible Control of Gelatin Hydrogel Stiffness by Using DNA Crosslinkers*.

Biomaterials with dynamically tunable properties are critical for a range of applications in regenerative medicine and basic biology. In this work, we show the reversible control of gelatin methacrylate (GelMA) hydrogel stiffness through the use of DNA crosslinkers. We replaced some of the inter-GelMA crosslinks with double-stranded DNA, allowing for their removal through toehold-mediated strand displacement. The crosslinks could be restored by adding fresh dsDNA with complementary handles to those on the hydrogel. The elastic modulus (G') of the hydrogels could be tuned between 500 and 1000 Pa, reversibly, over two cycles without degradation of performance. By functionalizing the gels with a second DNA strand, it was possible to control the crosslink density and a model ligand in an orthogonal fashion with two different displacement strands. Our results demonstrate the potential for DNA to reversibly control both stiffness and ligand presentation in a protein-based hydrogel, and will be useful for teasing apart the spatiotemporal behavior of encapsulated cells.

In situ growth of electroactive polymers via ATRP to construct a biosensing interface for tumor marker.

A novel biosensing interface for tumor markers was designed based on the atom transfer radical polymerization (ATRP) of poly(isopropenylphenol) (PPPL) in situ initiated by the fixing of p-chloromethyl benzoic acid on the surface of amino-modified electrodes. It was found that the electrochemical activity of PPPL itself can provide sufficient signals for these biosensors, which can avoid signal leakage and streamline the interface modification process. Cu(II) ions absorbed on the carbon spheres and then were released via acid stimulation to act as a catalyst to participate in the interface polymerization with ATRP. As the concentration of targets increased, more Cu(II) ions were released, and the electrochemical signal of polymers was enhanced. Therefore, the sensitive detection of carbohydrate antigen 19-9 (CA19-9) as a model target was achieved, with an ultralow limit of detection of 39 µU mL-1 and wide detection range from 100 µU mL-1 to 100 U mL-1 under optimal conditions. Furthermore, this method achieved satisfying performance in human blood serum with good inter-assay precision (RSD < 6%) and satisfactory recovery of ~ 99-105%. According to the results, this work is of great significance for constructing biosensor interfaces via in situ polymerization. A novel biosensing interface for tumor marker was designed based on atom transfer radical polymerization (ATRP), which poly(isopropenylphenol) with electrochemical signal was fabricated in situ on electrode.

Combined Transcriptomic and Metabolomic Analysis Reveals the Role of Phenylpropanoid Biosynthesis Pathway in the Salt Tolerance Process of Sophora alopecuroides.

Salt stress is the main abiotic stress that limits crop yield and agricultural development. Therefore, it is imperative to study the effects of salt stress on plants and the mechanisms through which plants respond to salt stress. In this study, we used transcriptomics and metabolomics to explore the effects of salt stress on Sophora alopecuroides. We found that salt stress incurred significant gene expression and metabolite changes at 0, 4, 24, 48, and 72 h. The integrated transcriptomic and metabolomic analysis revealed that the differentially expressed genes (DEGs) and differential metabolites (DMs) obtained in the phenylpropanoid biosynthesis pathway were significantly correlated under salt stress. Of these, 28 DEGs and seven DMs were involved in lignin synthesis and 23 DEGs and seven DMs were involved in flavonoid synthesis. Under salt stress, the expression of genes and metabolites related to lignin and flavonoid synthesis changed significantly. Lignin and flavonoids may participate in the removal of reactive oxygen species (ROS) in the root tissue of S. alopecuroides and reduced the damage caused under salt stress. Our research provides new ideas and genetic resources to study the mechanism of plant responses to salt stress and further improve the salt tolerance of plants.

Mechano-Informed Biomimetic Polymer Scaffolds by Incorporating Self-Powered Zinc Oxide Nanogenerators Enhance Motor Recovery and Neural Function.

Piezoelectric materials can produce electrical power from the mechanical stimulation and thus, they may accelerate electroactive tissue healing as a promising treatment for traumatic peripheral nerve injuries. In this study, a piezoelectric zinc oxide nanogenerator scaffold is manufactured by 3D injectable multilayer biofabrication. The piezoelectric polymeric scaffold displays desirable mechanical and physical characteristics, such as aligned porosity, high elasticity, scaffold stiffness, surface energy, and excellent shear behavior. In addition, its biocompatibility supplies Schwann cells with an adhesive, proliferative, and angiogenic interface, as is reflected by higher expression of functional proteins including nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). In vivo mechanical stimuli by treadmill practice contribute to the comprehensive reparative therapy. The piezoelectric conduit accelerates nerve conducting velocity, promotes axonal remyelination, and restores motor function by recovering endplate muscles. Moreover, the piezoelectric nanogenerator scaffold creates biomimetic electrically conductive microenvironment without causing noticeable toxicity to functioning organs and improves peripheral nerve restoration by the multifunctional characteristics. Therefore, the mechano-informed biomimetic piezoelectric scaffold may have enormous potential in the neuroengineering for regenerative medicine.

Initiation of sodium polystyrene sulphonate and the risk of gastrointestinal adverse events in advanced chronic kidney disease: a nationwide study.

BACKGROUND: Despite long-standing clinical use of sodium polystyrene sulphonate (SPS) for hyperkalaemia management in chronic kidney disease (CKD), its safety profile remains poorly investigated. METHODS: We undertook an observational analysis of nephrology-referred adults with incident CKD Stage 4+ in Sweden during 2006-16 and with no previous SPS use. We studied patterns of use and adverse events associated to SPS initiation during follow-up. Patterns of SPS use were defined by chronicity of treatment and by prescribed dose. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with SPS initiation (time-varying exposure) for the risk of severe (intestinal ischaemia, thrombosis or ulceration/perforation) and minor (de novo dispensation of laxatives or anti-diarrheal drugs) gastrointestinal (GI) events. RESULTS: Of 19 530 SPS-naïve patients with CKD, 3690 initiated SPS during follow-up. A total of 59% took SPS chronically, with an average of three dispensations/year. The majority (85%) were prescribed lower dosages than specified on the product label. During follow-up, 202 severe and 1149 minor GI events were recorded. SPS initiation was associated with a higher incidence of severe adverse events [adjusted HR 1.25 95% CI 1.05-1.49)], particularly in those receiving per label doses [1.54 (1.09-2.17)] and mainly attributed to ulcers and perforations. SPS initiation was also associated with higher incidence of minor GI events [adjusted HR 1.11 (95% CI 1.03-1.19)], regardless of dose, and mainly accounted for by de novo dispensation of laxatives. CONCLUSIONS: Initiation of SPS in patients with advanced CKD is associated with a higher risk of severe GI complications as well as the initiation of GI-related medications, particularly when prescribed at per label doses.

Enhancement of sciatic nerve regeneration with dual delivery of vascular endothelial growth factor and nerve growth factor genes.

BACKGROUND: Peripheral nerve injury is one common clinical disease worldwide, in which sciatic nerve is anatomically the most challenging to regenerate given its length and large cross-sectional area. For the present, autologous nerve grafting remains to be the most ideal strategy when treating with sciatic nerve injury. However, this method sacrifices healthy nerves and requires highly intensive surgery, still calling for other advanced alternatives for nerve grafting. RESULTS: In this study, we utilized previously well-established gene delivery system to dually deliver plasmid DNA (pDNA) encoding vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), exploring therapeutics for sciatic nerve injury. Low-molecular-weight branched polyethylenimine (bPEI) was constructed as the backbone structure of gene vectors, and it was further crosslinked to synthesize degradable polycations via the conjugation of dialdehydes. Potential synergistic effect between VEGF and NGF proteins were observed on rat sciatic nerve crush injury model in this study. CONCLUSIONS: We concluded that dual delivery of plasmid VEGF and NGF as gene therapy could enhance sciatic nerve regeneration.