Carbonate uranium isotopes record global expansion of marine anoxia during the Toarcian Oceanic Anoxic Event.

The Toarcian Oceanic Anoxic Event (T-OAE; ~183 Mya) was a globally significant carbon-cycle perturbation linked to widespread deposition of organic-rich sediments, massive volcanic CO2 release, marine faunal extinction, sea-level rise, a crisis in carbonate production related to ocean acidification, and elevated seawater temperatures. Despite recognition of the T-OAE as a potential analog for future ocean deoxygenation, current knowledge on the severity of global ocean anoxia is limited largely to studies of the trace element and isotopic composition of black shales, which are commonly affected by local processes. Here, we present the first carbonate-based uranium isotope (δ238U) record of the T-OAE from open marine platform limestones of the southeastern Tethys Ocean as a proxy for global seawater redox conditions. A significant negative δ238U excursion (~0.4‰) is recorded just prior to the onset of the negative carbon isotope excursion comprised within the T-OAE, followed by a long-lived recovery of δ238U values, thus confirming that the T-OAE represents a global expansion of marine anoxia. Using a Bayesian inverse isotopic mass balance model, we estimate that anoxic waters covered ~6 to 8% of the global seafloor during the peak of the T-OAE, which represents 28 to 38 times the extent of anoxia in the modern ocean. These data, combined with δ238U-based estimates of seafloor anoxic area for other CO2-driven Phanerozoic OAEs, suggest a common response of ocean anoxia to carbon release, thus improving prediction of future anthropogenically induced ocean deoxygenation.

Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns.

AIMS/HYPOTHESIS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) are antihyperglycaemic drugs that protect the kidneys of individuals with type 2 diabetes mellitus. However, the underlying mechanisms mediating the renal benefits of SGLT2i are not fully understood. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, we hypothesised that SGLT2i induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease (DKD). METHODS: Untargeted and targeted metabolomics assays were performed on plasma samples from participants with type 2 diabetes and kidney disease (n=35, 11 women) receiving canagliflozin (CANA) 100 mg/day at baseline and 12 week follow-up. Next, a systematic snapshot of the effect of CANA on key metabolites and pathways in the kidney was obtained using db/db mice. Moreover, the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells were studied. RESULTS: Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median (interquartile range 25-75%) of 49.0 (44.0-57.0) mmol/mol (7.9%, [7.10-9.20%]) to 42.2 (39.7-47.7) mmol/mol (6.8%, [6.40-7.70%]), and reduced urinary albumin/creatinine ratio from 67.8 (45.9-159.0) mg/mmol to 47.0 (26.0-93.6) mg/mmol. The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation. The targeted metabolomics assay revealed significant upregulation of glycine. The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice. In particular, the pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys. Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels. Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. CONCLUSIONS/INTERPRETATION: In conclusion, our study shows that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway.

miRNA, lncRNA and circRNA: targeted molecules with therapeutic promises in Mycoplasma pneumoniae infection.

Mycoplasma pneumoniae (MP) is primarily recognized as a respiratory pathogen that causes community-acquired pneumonia, which can lead to acute upper and lower airway inflammation and extrapulmonary syndrome. Refractory pneumonia caused by MP can cause severe complications and even be life-threatening, particularly in infants and the elderly. It is well-known that non-coding RNAs (ncRNAs) represented by miRNAs, lncRNAs and circRNAs have been manifested to be widely involved in the regulation of gene expression. Growing evidence indicates that these ncRNAs have distinct differentiated expression in MP infection and affect multiple biological processes, playing an indispensable role in the initiation and promotion of MP infection. However, the epigenetic mechanisms involved in the development of MP infection remain unclear. This article reviews the mechanisms by which miRNAs, lncRNAs, and circRNAs mediate MP infection, such as inflammatory responses, apoptosis and pulmonary fibrosis. Focusing on miRNAs, lncRNAs and circRNAs associated with MP infection could provide new insights into this disease's early diagnosis and therapeutic approaches.

Large Phase-Transition Temperature Enhancement Achieved in a Layered Lead Iodide Hybrid Crystal by H/F Substitution.

Organic-inorganic hybrid metal halides with structural flexibility and solution processability have been widely investigated for different application scenarios. However, the effective construction of phase-transition materials with a high phase-transition temperature (Ttr) for potential practical applications remains a great challenge, and reports on the regulation of Ttr with significant enhancement have been rare. In this manuscript, we have realized a large Ttr increase of 148 K in a layered hybrid lead iodide crystal (4-FTMBA)4Pb3I10 (4-FTMBA = 4-fluoro-N,N,N-trimethylbenzenaminium) by the H/F substitution strategy. Compared to the parent (TMBA)4Pb3I10 (TMBA = N,N,N-trimethylbenzenaminium), H/F substitution preserves the structural framework and crystal symmetry in (4-FTMBA)4Pb3I10. The introduction of heavier fluorine will significantly increase the motion barrier for the order-disorder transition, resulting in the remarkably improved Ttr. Temperature-dependent crystal structures, Raman spectra, and dielectric analyses well support the phase-transition behavior. In addition, evident thermochromism with a tunable direct band gap in (4-FTMBA)4Pb3I10 has been observed using UV-vis spectra. To the best of our knowledge, the achieved Ttr enhancement of 148 K by H/F substitution is the highest among the organic-inorganic hybrid lead halide phase-transition materials. This finding would greatly inspire the rational design of functional materials with high performance.

Efficient production of α-monoglucosyl hesperidin by cyclodextrin glucanotransferase from Bacillus subtilis.

α-Monoglucosyl hesperidin is a promising food additive with various activities. However, there are a few reports about the production of α-monoglucosyl hesperidin. Here, to develop a practical and safe process for α-monoglucosyl hesperidin synthesis, we used nonpathogenic Bacillus subtilis as a host to express cyclodextrin glucanotransferase (CGTase) from Bacillus sp. A2-5a. The promoters and signal peptides were screened to optimize the transcription and secretion of CGTase in B. subtilis. The results of optimization showed that the best signal peptide and promoter were YdjM and PaprE, respectively. Finally, the enzyme activity increased to 46.5 U mL-1, 8.7 times that of the enzyme expressed from the strain containing pPHpaII-LipA, and the highest yield of α-monoglucosyl hesperidin was 2.70 g L-1 by enzymatic synthesis using the supernatant of the recombinant B. subtilis WB800 harboring the plasmid pPaprE-YdjM. This is the highest α-monoglucosyl hesperidin production level using recombinant CGTase to date. This work provides a generally applicable method for the scaled-up production of α-monoglucosyl hesperidin. KEY POINTS: • A three-step procedure was created for high throughput signal peptide screening. • YdjM and PaprE were screened from 173 signal peptides and 13 promoters. • α-Monoglucosyl hesperidin was synthesized by CGTase with a yield of 2.70 g L-1.

Application of a Tele-Ultrasound Robot During COVID-19 Pandemic: A Feasibility Study.

OBJECTIVE: To investigate the accuracy of ultrasonic diagnosis using the tele-ultrasound robot in Leishen Shan Hospital. METHOD: Twenty-two patients with novel coronavirus pneumonia from Leishen Shan Hospital voluntarily participated in this study. Their thyroids, neck vessels, hepatobiliaries and kidneys were scanned by both a tele-ultrasound robot manufactured by Imabot Co., Ltd, Wuhan and conventional method. The ultrasound diagnosis of each patient was compared, and the ultrasound images obtained by the two methods were mixed together and double-blindly diagnosed by an experienced ultrasound radiologist. RESULTS: There were 44 positive lesions in 110 sites of 22 patients. Of which the two methods, 40 positive lesions were detected by the robotic method with 4 lesions missed (2 small polyps of gallbladder, 1 small hemangioma of liver and 1 small cyst of kidney) and 1 lesion misdiagnosed (normal carotid artery was misdiagnosed as carotid atherosclerotic plaque); 44 positive lesions were detected by conventional method with 1 small cyst of the liver was missed. There was no statistically significant difference in the accuracy rate between the robotic method and the conventional method using the chi-square test of the four-grid data (P>.05). CONCLUSION: The application of tele-ultrasound robot meets the standard of patient care during the pandemic. The method is feasible to provide adequate ultrasound information to diagnose common abdominal, vascular, superficial organ pathologies in patients with COVID-19 with acceptable accuracy compared with a conventional ultrasound scan.

A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC50) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

Establishment of RNA Interference Genetic Transformation System and Functional Analysis of FlbA Gene in Leptographium qinlingensis.

Leptographium qinlingensis is a pathogenic fungus of Pinus armandii that is epidemic in the Qinling Mountains. However, an effective gene interference strategy is needed to characterize the pathogenic genes in this fungus on a functional level. Using the RNA silencing vector pSilent-1 as a template, we established an RNA interference genetic transformation system mediated by Agrobacterium tumefaciens GV3101, which is suitable for the gene study for Leptographium qinlingensis by homologous recombination and strain interference system screening. The LqFlbA gene was silenced using the RNA interference approach described above, and the resulting transformants displayed various levels of silencing with a gene silencing effectiveness ranging from 41.8% to 91.4%. The LqFlbA-RNAi mutant displayed altered colony morphology, sluggish mycelium growth, and diminished pathogenicity toward the host P. armandii in comparison to the wild type. The results indicate that this method provides a useful reverse genetic system for studying the gene function of L. qinlingensis, and that LqFlbA plays a crucial role in the growth, development, and pathogenicity of L. qinlingensis.

LncRNA GAS5 Attenuates Cardiac Electrical Remodeling Induced by Rapid Pacing via the miR-27a-3p/HOXa10 Pathway.

Previous studies indicated long non-coding RNAs (lncRNAs) participated in the pathogenesis of atrial fibrillation (AF). However, little is known about the role of lncRNAs in AF-induced electrical remodeling. This study aimed to investigate the regulatory effect of lncRNA GAS5 (GAS5) on the electrical remodeling of neonatal rat cardiomyocytes (NRCMs) induced by rapid pacing (RP). RNA microarray analysis yielded reduced GAS5 level in NRCMs after RP. RT-qPCR, western blot, and immunofluorescence yielded downregulated levels of Nav1.5, Kv4.2, and Cav1.2 after RP, and whole-cell patch-clamp yielded decreased sodium, potassium, and calcium current. Overexpression of GAS5 attenuated electrical remodeling. Bioinformatics tool prediction analysis and dual luciferase reporter assay confirmed a direct negative regulatory effect for miR-27a-3p on lncRNA-GAS5 and HOXa10. Further analysis demonstrated that either miR-27a-3p overexpression or the knockdown of HOXa10 further downregulated Nav1.5, Kv4.2, and Cav1.2 expression. GAS5 overexpression antagonized such effects in Nav1.5 and Kv4.2 but not in Cav1.2. These results indicate that, in RP-treated NRCMs, GAS5 could restore Nav1.5 and Kv4.2 expression via the miR-27a-3p/HOXa10 pathway. However, the mechanism of GAS5 restoring Cav1.2 level remains unclear. Our study suggested that GAS5 regulated cardiac ion channels via the GAS5/miR-27a-3p/HOXa10 pathway and might be a potential therapeutic target for AF.

Mechanic Insight into the Distinct and Common Roles of Ovariectomy Versus Adrenalectomy on Adipose Tissue Remodeling in Female Mice.

Dysfunctions of the ovaries and adrenal glands are both evidenced to cause aberrant adipose tissue (AT) remodeling and resultant metabolic disorders, but their distinct and common roles are poorly understood. In this study, through biochemical, histological and RNA-seq analyses, we comprehensively explored the mechanisms underpinning subcutaneous (SAT) and visceral adipose tissue (VAT) remodeling, in response to ovariectomy (OVX) versus adrenalectomy (ADX) in female mice. OVX promoted adipocyte differentiation and fat accumulation in both SAT and VAT, by potentiating the Pparg signaling, while ADX universally prevented the cell proliferation and extracellular matrix organization in both SAT and VAT, likely by inactivating the Nr3c1 signaling, thus causing lipoatrophy in females. ADX, but not OVX, exerted great effects on the intrinsic difference between SAT and VAT. Specifically, ADX reversed a large cluster of genes differentially expressed between SAT and VAT, by activating 12 key transcription factors, and thereby caused senescent cell accumulation, massive B cell infiltration and the development of selective inflammatory response in SAT. Commonly, both OVX and ADX enhance circadian rhythmicity in VAT, and impair cell proliferation, neurogenesis, tissue morphogenesis, as well as extracellular matrix organization in SAT, thus causing dysfunction of adipose tissues and concomitant metabolic disorders.

Efficacy of Immunization against a Novel Synthetic 13-Amino Acid Betaglycan-Binding Peptide Sequence of Inhibin α Subunit on Promoting Fertility in Female Rats.

Inhibins suppress the FSH production in pituitary gonadotrope cells by robustly antagonizing activin signaling by competitively binding to activin type II receptors (ACTR II). The binding of inhibin A to ACTR II requires the presence of its co-receptor, namely, betaglycan. In humans, the critical binding site for betaglycan to inhibin A was identified on the inhibin α subunit. Through conservation analysis, we found that a core 13-amino-acid peptide sequence within the betaglycan-binding epitope on human inhibin α subunit is highly conserved across species. Based on the tandem sequence of such a conserved 13-amino-acid betaglycan-binding epitope (INHα13AA-T), we developed a novel inhibin vaccine and tested its efficacy in promoting female fertility using the female rat as a model. Compared with placebo-immunized controls, INHα13AA-T immunization induced a marked (p < 0.05) antibody generation, enhanced (p < 0.05) ovarian follicle development, and increased ovulation rate and litter sizes. Mechanistically, INHα13AA-T immunization promoted (p < 0.05) pituitary Fshb transcription and increased (p < 0.05) serum FSH and 17ß-estradiol concentrations. In summary, active immunization against INHα13AA-T potently increased FSH levels, ovarian follicle development, ovulation rate and litter sizes, thus causing super-fertility in females. Therefore, immunization against INHα13AA is a promising alternative to the conventional approach of multiple ovulation and super-fertility in mammals.

A Homochiral Fulgide Organic Ferroelectric Crystal with Photoinduced Molecular Orbital Breaking.

Thermally triggered spatial symmetry breaking in traditional ferroelectrics has been extensively studied for manipulation of the ferroelectricity. However, photoinduced molecular orbital breaking, which is promising for optical control of ferroelectric polarization, has been rarely explored. Herein, for the first time, we synthesized a homochiral fulgide organic ferroelectric crystal (E)-(R)-3-methyl-3-cyclohexylidene-4-(diphenylmethylene)dihydro-2,5-furandione (1), which exhibits both ferroelectricity and photoisomerization. Significantly, 1 shows a photoinduced reversible change in its molecular orbitals from the 3 π molecular orbitals in the open-ring isomer to 2 π and 1 σ molecular orbitals in the closed-ring isomer, which enables reversible ferroelectric domain switching by optical manipulation. To our knowledge, this is the first report revealing the manipulation of ferroelectric polarization in homochiral ferroelectric crystal by photoinduced breaking of molecular orbitals. This finding sheds light on the exploration of molecular orbital breaking in ferroelectrics for optical manipulation of ferroelectricity.

Emerging roles of Sodium-glucose cotransporter 2 inhibitors in Diabetic kidney disease.

Diabetic kidney disease (DKD), a severe microvascular complication of diabetes mellitus, is the primary cause of end stage renal disease (ESRD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of novel anti-diabetic drugs for DKD, which have the potential to prevent renal function from failing. The involved mechanisms have garnered considerable attention. Besides hypoglycemic effect, it seems that various glucose-independent nephroprotective mechanisms also have a role. Among them, improvement in tubuloglomerular feedback is considered as the main reason, followed by reduced intraglomerular pressure and fluid load. In addition, reduced blood pressure, anti-inflammatory effects, nutrient deprivation signaling as well as improved endothelial function are also important. In the future, clinical trials and mechanistic studies might further complement the current knowledge on SGLT2 inhibitors and facilitate to translate these agents to clinical use. Here, we review these mechanisms of SGLT2 inhibitors with an emphasis on kidney protective effects.

Anodal tDCS Over the Left Frontal Eye Field Improves Sustained Visual Search Performance.

Monotonous and repetitive tasks cause vigilance, or sustained attention decrement, which possibly leads to irreparable accident consequences in the aerospace and nuclear industry. Buffering the decrement of vigilance in visual search tasks is essential for cognitive enhancement and ergonomic research. This study aimed to evaluate the efficacy of anodal transcranial direct current stimulation (tDCS) applied to the left frontal eye field (FEF) to improve the performance of the sustained visual search. Twenty-seven healthy participants received anodal and sham tDCS of 2 mA for 28.8 min and completed a visual search task lasting for approximately 40 min without any break. For the online effect, results showed that the d' hit rate and accuracy under anodal tDCS were significantly higher than those under sham conditions during 0-19.2 min time intervals. For the after-effect, compared with sham, anodal tDCS caused significantly higher d' in the 10 min after completing the tDCS. Our findings suggest that anodal tDCS over the left FEF could effectively mitigate the decline of visual vigilance performance by buffering cognitive resource depletion.

Culture and in situ H2O2-mediated electrochemical study of cancer cells using three-dimensional scaffold based on graphene foam coated with Fe3O4 nanozyme.

For real-time evaluation of the cell behavior and function under in vivo-like 3D environment, the 3D functionalized scaffolds simultaneously integrate the function of 3D cell culture, and electrochemical sensing is a convincing candidate. Herein, Fe3O4 nanoparticles as the nanozyme (peroxide oxidase mimics) were modified on graphene foam scaffold to construct a 3D integrated platform. The platform displayed a wide linear range of 100 nM to 20 µM and a high sensitivity of 53.2 nA µM-1 toward detection of hydrogen peroxide (H2O2) under the working potential of + 0.6 V (vs. Ag/AgCl). The obtained 3D scaffold also displayed satisfactory selectivity toward the possible interferents that appeared in the cell culture environment. Furthermore, the cells still maintained high cell viability (almost 100%) after their growth and proliferation on the scaffold for 7 days. With the superior performance on cell culture and electrochemical monitoring, the functions on the 3D culture of MCF-7 or HeLa cells and in situ monitoring of cell-released H2O2 was easily achieved on this 3D platform, which show its great application prospects on further cancer-related disease diagnosis or drug screening. A nanozyme-based three-dimensional graphene scaffold was successfully constructed for cell culture and identification of cancer cells through in situ electrochemical monitoring of the cell-released H2O2.

Elevated atmospheric CO2 enhances the phytoremediation efficiency of tall fescue (Festuca arundinacea) in Cd-polluted soil.

With the economic development of society, concentrations of atmospheric CO2 and heavy metals in soils have been increasing. The physiological responses of plants to the interaction between soil pollution and climatic change need to be understood. Pot experiments were designed to assess variations in Festuca arundinacea dry weight, leaf type, chlorophyll content, antioxidase activities, and Cd accumulation ability, under different atmospheric CO2 treatments. The results showed that the total dry weights increased with increasing CO2, and Cd concentrations in falling leaf tissues increased with raised atmospheric CO2, before reaching a peak at 600 ppm, above which they remained constant. Compared with the control (400 ppm), 600, 650, and 700 ppm CO2 treatments increased the proportions of the falling tissues by 1.7%, 3.3%, and 4.5%, respectively. Antioxidant enzyme activities in plant leaves increased with increasing atmospheric CO2 levels. The concentration of H2O2 in leaf tissues increased with increasing CO2, reaching a peak at 600 ppm, and then decreased significantly as the CO2 content increased further, to 700 ppm. The results in this study suggest that F. arundinacea could be regarded as a potential candidate for phytoremediation of Cd-polluted soil; especially if senescent and dead leaf tissues could be harvested, and that raised atmospheric CO2 levels could improve its soil remediation efficiency.Novelty statement Extrapolation of results from experiments of environmental impacts in greenhouse to real scale field requires to be considered cautiously. External factors such as water, temperature, humidity, and pollution are variable in real field. Plants will face a lot of beneficial or detrimental conditions which will influence the magnitude of the results. However, the elevation of CO2 is an inevitable phenomenon in future. Therefore, findings from experiments under artificial conditions are sometime a good choice to obtain knowledge about elevated CO2 related impacts on phytoremediation efficiency of a specific plant. The final goal of this work is to find a suitable CO2 fumigation strategy optimized for soil remediation. We report on that elevated atmospheric CO2 can increase the phytoremediation efficiency of Festuca arundinacea for Cd. This is significant because the combined influences of elevated atmospheric CO2 and metal pollution in terms of biomass yield, pollutant uptake, and phytoremediation efficiency would be more complex than the effects of each individual factor.

Impacts of root pruning intensity and direction on the phytoremediation of moderately Cd-polluted soil by Celosia argentea.

Root pruning can impact the physiological functions of various plants, which influence phytoremediation. A series of root pruning treatments with different combinations of direction (two-side pruning and four-side pruning) and intensity (10, 25, and 33% pruning) were performed on Celosia argentea L. All two-side pruning treatments, regardless of intensity, decreased the dry biomass of the C. argentea roots at the end of the experiment relative to that of the control. However, the two-side-10% and two-side-25% pruning treatments stimulated the growth rate of the plant leaves significantly by 58.6 and 41.4%, respectively, relative to that of the control, and even offset the weight loss of the plant roots. Contrastingly, the two-side-33% pruning treatment reduced the biomass yield of leaves by 24.1%. For the four-side pruning treatments, the low intensity increased the dry weight of both the plant roots and leaves, while both decreased under high-intensity root pruning. The dry weight, Cd content, pigment level, and photosynthetic efficiency in the four-side-10% treatment were higher than those in the other treatments during the experiment. This study indicates that root pruning with a suitable combination of direction and intensity can positively influence the Cd removal ability of C. argentea.

Our study suggests that a suitable root pruning pattern can significantly increase the phytoremediation effect of Celosia argentea L. Compared with chemical and biological regulation including plant hormone application, chemical reagent spraying, and endophytes inoculation which might introduce unpredictable risks into the ecological system, root pruning can be considered as an environmentally friendly physical trigger to modulate physiological features and to induce advantages in plants. This finding can be extrapolated into the real-world easily since root pruning is an established, convenient, and feasible method. We believe readers would be interested in this method.

Neuroprotective effects of voluntary exercise and Yisaipu after traumatic brain injury in mice.

The mechanisms underlying exercise-induced neuroprotective effects after traumatic brain injury (TBI) remained elusive, and there is a lack of effective treatments for TBI. In this study, we investigated the effects of an integrative approach of exercise and Yisaipu (TNFR-IgG fusion protein, TNF inhibitor) in a mouse TBI model. Male C57BL/6J mice were randomly assigned to a sedentary group or a group that followed a voluntary exercise regimen. The effects of 6-week prophylactic preconditioning exercise (PE) alone or in combination with post-TBI Yisaipu treatment on moderate TBI associated deficits were examined. The results showed that combined treatments of PE and post-TBI Yisaipu were superior to single treatments on reducing sensorimotor and gait dysfunctions in mice. These functional improvements were accompanied by reduced systemic inflammation largely via decreased serum TNF-α, boosted autophagic flux, and mitigated lesion volume after TBI. Given these neuroprotective effects, composite approaches such as a combination of exercise and TNF inhibitor may be a promising strategy for facilitating functional recovery from TBI and are worth further investigation.

In Situ Self-Assembly of Bispecific Peptide for Cancer Immunotherapy.

Precise and effective manipulation of protein functions still faces tremendous challenges. Herein we report a programmable peptide molecule, consisted of targeting and self-assembly modules, that enables specific and highly efficient assembly governed by targeting receptor proteins. Upon binding to the cell membrane receptor, peptide conformation is somewhat stabilized along with decreased self-assembly activation energy, promoting peptide-protein complex oligomerization. We first design a GNNQQNY-RGD peptide (G7-RGD) to recognize integrin αV ß3 receptor for proof-of-concept study. In the presence of αV ß3 protein, the critical assembly concentration of free G7-RGD decreases from 525 to 33 µM and the resultant G7-RGD cluster drives integrin receptor oligomerization. Finally, a bispecific assembling peptide antiCD3-G7-RGD is rationally designed for cancer immunotherapy, which validates CD3 oligomerization and concomitant T cell activation, leading to T cell-mediated cancer cell cytolysis.

In Situ Constructed Nano-Drug Depots through Intracellular Hydrolytic Condensation for Chemotherapy of Bladder Cancer.

Intravesical administration of first-line drugs has shown failure in the treatment of bladder cancer owing to the poor tumor retention time of chemotherapeutics. Herein, we report an intracellular hydrolytic condensation (IHC) system to construct long-term retentive nano-drug depots in situ, wherein sustained drug release results in highly efficient suppression of bladder cancer. Briefly, the designed doxorubicin (Dox)-silane conjugates self-assemble into silane-based prodrug nanoparticles, which condense into silicon particle-based nano-drug depots inside tumor cells. Significantly, we demonstrate that the IHC system possesses highly potent antitumor efficacy, which leads to the regression and eradication of large established tumors and simultaneously extends the overall survival of air pouch bladder cancer mice compared with that of mice treated with Dox. The concept of intracellular hydrolytic condensation can be extended via conjugating other chemotherapeutic drugs, which may facilitate rational design of novel nanomedicines for augmentation of chemotherapy.