Catalytic Asymmetric Cyclizative Rearrangement of Anilines and Vicinal Diketones to Access 2,2-Disubstituted Indolin-3-ones.

The efficient synthesis of chiral 2,2-disubstituted indolin-3-ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one-step construction of enantioenriched 2,2-disubstituted indolin-3-ones is presented. The reaction proceeds through a self-sorted [3+2] heteroannulation/regioselective dehydration/1,2-ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3-binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine-directed regio- and enantioselective ortho-Csp2-H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well.

A Transformable Specific-Responsive Peptide for One-Step Synergistic Therapy of Bladder Cancer.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8+ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer.

Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer.

Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

Discovery of Unusual Ajmaline-Macroline Type Bisindole Alkaloids from Alstonia macrophylla by Building Blocks-Based Molecular Networking.

Three unusual ajmaline-macroline type bisindole alkaloids, alsmaphylines A-C, together with their postulated biogenetic precursors, were isolated from the stem barks and leaves of Alstonia macrophylla via the building blocks-based molecular network (BBMN) strategy. Alsmaphyline A represents a rare ajmaline-macroline type bisindole alkaloid with an S-shape polycyclic ring system. Alsmaphylines B and C are two novel ajmaline-macroline type bisindole alkaloids with N-1-C-21' linkages, and the former possesses an unconventional stacked conformation due to the presence of intramolecular noncovalent interactions. The chemical structures including absolute configurations of alsmaphylines A-C were established by comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray crystallography. In addition, a plausible biosynthetic pathway of these bisindole alkaloids as well as their ability to promote the protein synthesis on HT22 cells were discussed.

Vitrectomy for retinal detachment associated with macular hole: Prognostic factor analysis under different axial length conditions.

PURPOSE: To identify prognostic factors for complete anatomical success (CAS) under different axial length (AL) conditions after vitrectomy plus internal limiting membrane (ILM) peeling for retinal detachment associated with macular hole (MHRD). METHODS: This retrospective study included 243 patients (251 eyes) with MHRD who underwent primary vitrectomy plus ILM peeling. Multivariate logistic regression explored prognostic factors for CAS in AL <30 mm and ≥ 30 mm groups. RESULTS: Overall, 113 eyes (45.0% of 251) exhibited complete CAS after initial surgery. Eyes with CAS had greater best-corrected visual acuity improvement than eyes without CAS (p < 0.001). CAS was more common in eyes with AL < 30 mm (50.3% of 155) than in eyes with AL ≥ 30 mm (36.5%, 35/96; p = 0.032). In the AL < 30 mm group, CAS was associated with ILM insertion (odds ratio [OR], 2.824, 95% confidence interval [CI], 1.189-6.710; p = 0.019), silicone oil (SO)/perfluoropropane (C3F8) tamponade (SO: OR, 0.408, 95% CI, 0.191-0.873; C3F8: OR, 2.448, 95% CI, 1.145-5.234; p = 0.021) and staphyloma (OR, 0.318, 95% CI, 0.143-0.707; p = 0.005). In the AL ≥30 mm group, CAS was associated with ILM insertion (OR, 11.621, 95% CI, 2.557-52.813; p = 0.001), SO /C3F8 tamponade (SO: OR, 5.305, 95% CI, 1.206-23.334; C3F8: OR, 0.188, 95% CI, 0.043-0.829; p = 0.027) and age (OR, 0.928, 95% CI, 0.876-0.983; p = 0.011). CONCLUSION: Vitrectomy plus ILM peeling can effectively treat MHRD but has limited efficacy in eyes with AL ≥ 30 mm. ILM insertion was associated with more frequent CAS at any AL. C3F8 tamponade yielded better outcomes with AL < 30 mm; SO tamponade yielded better outcomes with AL ≥ 30 mm.

A bispecific glycopeptide spatiotemporally regulates tumor microenvironment for inhibiting bladder cancer recurrence.

Up to 75% of bladder cancer patients suffer from recurrence due to postoperative tumor implantation. However, clinically used Bacillus Calmette-Guerin (BCG) treatment failed to inhibit the recurrence. Here, we report a bispecific glycopeptide (bsGP) that simultaneously targets CD206 on tumor-associated macrophages (TAMs) and CXCR4 on tumor cells. bsGP repolarizes protumoral M2-like TAMs to antitumor M1-like that mediated cytotoxicity and T cell recruitment. Meanwhile, bsGP is cleaved by the MMP-2 enzyme to form nanostructure for the long-term inhibition of CXCR4 downstream signaling, resulting in reduced tumor metastasis and promoted T cell infiltration. In orthotopic bladder tumor models, bsGP reduced the postoperative recurrence rate to 22%. In parallel, the recurrence rates of 89 and 78% were treated by doxycycline and BCG used in clinic, respectively. Mechanistic studies reveal that bsGP reduces the matrix microenvironment barrier, increasing the spatially redirected CD8+ T cells to tumor cells. We envision that bis-targeting CD206 and CXCR4 may pave the way to inhibit tumor metastasis and recurrence.

Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells promotes functional recovery in patients with spontaneous intracerebral hemorrhage: phase I clinical trial.

Animal experiments have shown that injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can promote recovery from spinal cord injury. To investigate whether injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can be used to treat spontaneous intracerebral hemorrhage, this non-randomized phase I clinical trial recruited patients who met the inclusion criteria and did not meet the exclusion criteria of spontaneous intracerebral hemorrhage treated in the Characteristic Medical Center of Chinese People's Armed Police Force from May 2016 to December 2020. Patients were divided into three groups according to the clinical situation and patient benefit: control (n = 18), human umbilical cord-derived mesenchymal stem cells (n = 4), and combination (n = 8). The control group did not receive any transplantation. The human umbilical cord-derived mesenchymal stem cells group received human umbilical cord-derived mesenchymal stem cell transplantation. The combination group received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells. Patients who received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells had more remarkable improvements in activities of daily living and cognitive function and smaller foci of intracerebral hemorrhage-related encephalomalacia. Severe adverse events associated with cell transplantation were not observed. Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells appears to have great potential treating spontaneous intracerebral hemorrhage.

A Self-Disguised Nanospy for Improving Drug Delivery Efficiency via Decreasing Drug Protonation.

Nanoscale drug carriers play a crucial role in reducing side effects of chemotherapy drugs. However, the mononuclear phagocyte system (MPS) and the drug protonation after nanoparticles (NPs) burst release still limit the drug delivery efficiency. In this work, a self-disguised Nanospy is designed to overcome this problem. The Nanospy is composed of: i) poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) loading doxorubicin is the core structure of the Nanospy. ii) CD47 mimic peptides (CD47p) is linked to NPs which conveyed the "don't eat me" signal. iii) 4-(2-aminoethyl) benzenesulfonamide (AEBS) as the inhibitor of Carbonic anhydrase IX (CAIX) linked to NPs. Briefly, when the Nanospy circulates in the bloodstream, CD47p binds to the regulatory protein α (SIRPα) on the surface of macrophages, which causes the Nanospy escapes from phagocytosis. Subsequently, the Nanospy enriches in tumor and the AEBS reverses the acidic microenvironment of tumor. Due to above characteristics, the Nanospy reduces liver macrophage phagocytosis by 25% and increases tumor in situ DOX concentration by 56% compared to PLGA@DOX treatment. In addition, the Nanospy effectively inhibits tumor growth with a 63% volume reduction. This work presents a unique design to evade the capture of MPS and overcomes the influence of acidic tumor microenvironment (TME) on weakly alkaline drugs.

Giant spin ensembles in waveguide magnonics.

The dipole approximation is usually employed to describe light-matter interactions under ordinary conditions. With the development of artificial atomic systems, 'giant atom' physics is possible, where the scale of atoms is comparable to or even greater than the wavelength of the light they interact with, and the dipole approximation is no longer valid. It reveals interesting physics impossible in small atoms and may offer useful applications. Here, we experimentally demonstrate the giant spin ensemble (GSE), where a ferromagnetic spin ensemble interacts twice with the meandering waveguide, and the coupling strength between them can be continuously tuned from finite (coupled) to zero (decoupled) by varying the frequency. In the nested configuration, we investigate the collective behavior of two GSEs and find extraordinary phenomena that cannot be observed in conventional systems. Our experiment offers a new platform for 'giant atom' physics.

The Potential of Parapanteles hyposidrae and Protapanteles immunis (Hymenoptera: Braconidae) as Biocontrol Agents for the Tea Grey Geometrid Ectropis grisescens (Lepidoptera).

The tea grey geometrid Ectropis grisescens has long been a significant insect pest of tea plants in China. Two parasitoids, Parapanteles hyposidrae and Protapanteles immunis (Hymenoptera: Braconidae: Microgastrinae), are the most important parasitoids in the larval stage of E. grisescens. Yet, the potential of these two parasitoids for controlling the tea grey geometrid is not known. Here, we studied the parasitism performance of these two parasitoid species on different host densities under different temperatures as well as the interference effect of parasitoid density. The results showed that both parasitoid species, Pa. hyposidrae and Pr. immunis, exhibited a Type II functional response towards the tea grey geometrid E. grisescens at four tested temperatures. With increasing the density of E. grisescens larvae, the number of parasitized larvae increased until a maximum was reached. The highest number of hosts parasitized by Pa. hyposidrae or Pr. immunis reached 14.5 or 14.75 hosts d-1 at 22 °C, respectively. The estimated values of instantaneous searching efficiency (a) and handling time (h) for Pa. hyposidrae or Pr. immunis were 1.420 or 3.621 and 0.04 or 0.053 at 22 °C, respectively. Pr. immunis performed better than Pa. hyposidrae under higher temperatures. The parasitism rate by a single female parasitoid decreased with increasing parasitoid density at different temperatures, resulting in a reduction of searching efficiency. The findings of this study showed that Pr.immunis could be a better effective biocontrol agent than Pa. hyposidrae against the tea grey geometrid.

Enhanced laccase production by mutagenized Myrothecium verrucaria using corn stover as a carbon source and its potential in the degradation of 2-chlorophen.

Chlorophenols are widely used in industry and are known environmental pollutants. The degradation of chlorophenols is important for environmental remediation. In this study, we evaluated the biodegradation of 2-chlorophenol using crude laccase produced by Myrothecium verrucaria. Atmospheric and room temperature plasma technology was used to increase laccase production. The culture conditions of the M-6 mutant were optimized. Our results showed that corn stover could replace glucose as a carbon source and promote laccase production. The maximum laccase activity of 30.08 U/mL was achieved after optimization, which was a 19.04-fold increase. The biodegradation rate of 2-chlorophenol using crude laccase was 97.13%, a positive correlation was determined between laccase activity and degradation rate. The toxicity of 2-CP was substantially reduced after degradation by laccase solution. Our findings show the feasibility of the use of corn stover in laccase production by M. verrucaria mutant and the subsequent biodegradation of 2-chlorophenol using crude laccase.

A high-quality genome of the dobsonfly Neoneuromus ignobilis reveals molecular convergences in aquatic insects.

Neoneuromus ignobilis is an archaic holometabolous aquatic predatory insect. However, a lack of genomic resources hinders the use of whole genome sequencing to explore their genetic basis and molecular mechanisms for adaptive evolution. Here, we provided a high-contiguity, chromosome-level genome assembly of N. ignobilis using high coverage Nanopore and PacBio reads with the Hi-C technique. The final assembly is 480.67 MB in size, containing 12 telomere-ended pseudochromosomes with only 17 gaps. We compared 42 hexapod species genomes including six independent lineages comprising 11 aquatic insects, and found convergent expansions of long wavelength-sensitive and blue-sensitive opsins, thermal stress response TRP channels, and sulfotransferases in aquatic insects, which may be related to their aquatic adaptation. We also detected strong nonrandom signals of convergent amino acid substitutions in aquatic insects. Collectively, our comparative genomic analysis revealed the evidence of molecular convergences in aquatic insects during both gene family evolution and convergent amino acid substitutions.

[Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome]. / å¼‚åŸºå› é€ è¡€å¹²ç»†èƒžç§»æ¤æ²»ç–—å„¿ç«¥é«˜IgM综合征的临床分析.

OBJECTIVES: To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM). METHODS: A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT. RESULTS: After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04). CONCLUSIONS: Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

An Ultrasound-Induced Self-Clearance Hydrogel for Male Reversible Contraception.

Nearly half of pregnancies worldwide are unintended mainly due to failure of contraception, resulting in negative effects on women's health. Male contraception techniques, primarily condoms and vasectomy, play a crucial role in birth control, but cannot be both highly effective and reversible at the same time. Herein, an ultrasound (US)-induced self-clearance hydrogel capable of real-time monitoring is utilized for in situ injection into the vas deferens, enabling effective contraception and noninvasive recanalization whenever needed. The hydrogel is composed of (i) sodium alginate (SA) conjugated with reactive oxygen species (ROS)-cleavable thioketal (SA-tK), (ii) titanium dioxide (TiO2), which can generate a specific level of ROS after US treatment, and (iii) calcium chloride (CaCl2), which triggers the formation of the hydrogel. For contraception, the above mixture agents are one-time injected into the vas deferens, which can transform from liquid to hydrogel within 160 s, thereby significantly physically blocking the vas deferens and inhibiting movability of sperm. When fertility is needed, a noninvasive remedial ultrasound can make TiO2 generate ROS, which cleaves SA-tK to destroy the network of the hydrogel. Owing to the recanalization, the refertility rate is restored to 100%. Meanwhile, diagnostic ultrasound (D-US, 22 MHz) can monitor the occlusion and recanalization process in real-time. In summary, the proposed hydrogel contraception can be a reliable, safe, and reversible male contraceptive strategy that addresses an unmet need for men to control their fertility.

Risk assessment of malignancy in solitary pulmonary nodules in lung computed tomography: a multivariable predictive model study.

BACKGROUND: Computed tomography images are easy to misjudge because of their complexity, especially images of solitary pulmonary nodules, of which diagnosis as benign or malignant is extremely important in lung cancer treatment. Therefore, there is an urgent need for a more effective strategy in lung cancer diagnosis. In our study, we aimed to externally validate and revise the Mayo model, and a new model was established. METHODS: A total of 1450 patients from three centers with solitary pulmonary nodules who underwent surgery were included in the study and were divided into training, internal validation, and external validation sets (n = 849, 365, and 236, respectively). External verification and recalibration of the Mayo model and establishment of new logistic regression model were performed on the training set. Overall performance of each model was evaluated using area under receiver operating characteristic curve (AUC). Finally, the model validation was completed on the validation data set. RESULTS: The AUC of the Mayo model on the training set was 0.653 (95% confidence interval [CI]: 0.613-0.694). After re-estimation of the coefficients of all covariates included in the original Mayo model, the revised Mayo model achieved an AUC of 0.671 (95% CI: 0.635-0.706). We then developed a new model that achieved a higher AUC of 0.891 (95% CI: 0.865-0.917). It had an AUC of 0.888 (95% CI: 0.842-0.934) on the internal validation set, which was significantly higher than that of the revised Mayo model (AUC: 0.577, 95% CI: 0.509-0.646) and the Mayo model (AUC: 0.609, 95% CI, 0.544-0.675) (P < 0.001). The AUC of the new model was 0.876 (95% CI: 0.831-0.920) on the external verification set, which was higher than the corresponding value of the Mayo model (AUC: 0.705, 95% CI: 0.639-0.772) and revised Mayo model (AUC: 0.706, 95% CI: 0.640-0.772) (P < 0.001). Then the prediction model was presented as a nomogram, which is easier to generalize. CONCLUSIONS: After external verification and recalibration of the Mayo model, the results show that they are not suitable for the prediction of malignant pulmonary nodules in the Chinese population. Therefore, a new model was established by a backward stepwise process. The new model was constructed to rapidly discriminate benign from malignant pulmonary nodules, which could achieve accurate diagnosis of potential patients with lung cancer.

Removal of sticky silicone oil adhered to the retinal surface: comparison of methodological safety and effectiveness.

PURPOSE: To compare safety and effectiveness among methods to remove sticky silicone oil bubbles adhered to the retinal surface. METHODS: This retrospective nonrandomised case series included 14 eyes of 14 patients who had sticky silicone oil residue during silicone oil removal surgery. For small sticky silicone oil bubbles (< 2-disc diameter), aspiration was performed with a 23-gauge vitreous cutter. Residual tiny oil bubbles were then removed with a silicone-tipped flute needle or internal limiting membrane (ILM) peeling. For large sticky silicone oil bubbles (≥ 2-disc diameter) that could not be removed with a 23-gauge vitreous cutter, we devised a more efficient active removal method involving a modified 22-gauge venous indwelling cannula device. RESULTS: The mean preoperative best-corrected visual acuity (BCVA; logarithm of the minimum angle of resolution [logMAR]) significantly improved from 1.28 ± 0.63 logMAR to 0.77 ± 0.58 logMAR (p = 0.014). The postoperative BCVA and improvement in BCVA were significantly better in the ILM peeling group than in the non-ILM peeling group (p = 0.004 and p = 0.045, respectively). Postoperative complications included residual sticky silicone oil bubbles in seven eyes without ILM peeling (50.0%), retinal neuroepithelial layer damage in two eyes (14.3%), and temporary hypotony in five eyes (35.7%). CONCLUSION: Various methods can safely and efficiently remove sticky silicone oil bubbles adhered to the retinal surface. A 22-gauge venous indwelling cannula enabled simple and safe removal of large sticky silicone oil bubbles, while small residual sticky silicone oil bubbles could be completely removed by ILM peeling.

A Near-Infrared Peptide Probe with Tumor-Specific Excretion-Retarded Effect for Image-Guided Surgery of Renal Cell Carcinoma.

Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvß3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.

Intraperitoneal Administration of Monoclonal Antibody Against Pathologic Aß42 Aggregates Alleviated Cognitive Deficits and Synaptic Lesions in APP/PS1 Mice.

Alzheimer's disease (AD) is the most common form of dementia, characterized by amyloid-ß peptide (Aß) aggregates, phosphorylated tau protein (p-tau), and progressive neurodegeneration. Amyloid-ß peptide 42 (Aß42) is considered an early trigger of AD pathogenesis. We have previously reported that Aß N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aß in the brains of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1ΔE9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 treatment group had a shorter escape latency than the control groups in the place navigation test and the probe trial (p < 0.05). Moreover, immunohistochemistry showed decreased levels of both Aß and p-tau in the brains of APP/PS1 mice. Regarding Aß levels, western blot results showed that Aß42 oligomer (p < 0.01) but not Aß40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231) (p < 0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (p < 0.01) density of synapses and a reduction of abnormally enlarged mitochondria (p < 0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade.

A new variety of Didymocarpus (Gesneriaceae) from Guangdong, China.

A new variety of Didymocarpus, D.heucherifoliusvar.gamosepalus from Guangdong, China, is described and illustrated with photographs. It closely resembles the more widespread D.heucherifolius within a number of morphological characters. However, it can be easily distinguished from the latter according to the new taxon: calyx base connate, 5-lobed from middle to above middle, larger flowers (up to 5 cm long) and glabrous corolla.

Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice.

Sigma-1 receptor (Sig-1R) activation has been shown to decrease infarct volume and enhance neuronal survival after brain ischemia-reperfusion (IR) in rodent models. The present study aims to investigate first the effect of Sig-1R activation on blood-brain barrier (BBB) disruption during experimental stroke. Male C57BL/6 mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 15 min, and the worst BBB leakage was observed on the 7th day after brain IR. To confirm the BBB protective role of Sig-1R, mice were divided into five groups (sham group, BCCAO group, PRE084 group, BD1047 group, PRE084 and BD1047 group; 29-35 mice for each group), and treated with agonist PRE084 (1 mg/kg) and/or antagonist BD1047 (1 mg/kg) for 7 days intraperitoneally once a day after BCCAO. Interestingly, PRE084 administration significantly improved neurobehavioral performance as well as healing of neuron damage and white matter lesions. PRE084 also reduced the leakage of Evans blue and IgG and attenuated the disassembly of BBB structural proteins, while the neuroprotective and BBB protective functions of PRE084 were blocked by BD1047. Furthermore, in Sig-1R knockout (Sig-1R KO) mice, brain IR produced more serious IgG leakage and degradation of BBB structural proteins than in wild-type model mice. In addition, the protective effect of PRE084 against the BBB was lost in Sig-1R KO mice after brain IR. Finally, treatment with PRE084 significantly increased the expression of Sig-1R in brain microvascular endothelial cells of mice that were subjected to brain IR and increased translocation of Sig-1R to the cell plasmalemma. Thus, we identified a previously unexplored role of Sig-1R in alleviating BBB disruption in stroke processes and have demonstrated that reversing BBB rupture through Sig-1R activation may be another promising method for cerebral protection against IR injury.