Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gammaaminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. Furthermore, there is now evidence suggesting that neural network activity is aberrantly increased in AD patients and animal models due to functional deficits in and decreased activity of GABA inhibitory interneurons, contributing to cognitive deficits. Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.

A novel and efficient Pd-catalyzed C-H acetoxylation is described. The approach uses R2(O)P as a directing group to synthesize various substituted 2'-phosphorylbiphenyl-2-OAc compounds. Notably, the reaction exhibits smooth operation under mild conditions and shows good functional group tolerance. Products are obtained with high selectivity and yields.

Multi-modal pre-training models have been intensively explored to bridge vision and language in recent years. However, most of them explicitly model the cross-modal interaction between image-text pairs, by assuming that there exists strong semantic correlation between the text and image modalities. Since this strong assumption is often invalid in real-world scenarios, we choose to implicitly model the cross-modal correlation for large-scale multi-modal pretraining, which is the focus of the Chinese project 'Wen-Lan' led by our team. Specifically, with the weak correlation assumption over image-text pairs, we propose a twotower pre-training model called BriVL within the crossmodal contrastive learning framework. Unlike OpenAI CLIP that adopts a simple contrastive learning method, we devise a more advanced algorithm by adapting the latest method MoCo into the cross-modal scenario. By building a large queue-based dictionary, our BriVL can incorporate more negative samples in limited GPU resources. We further construct a large Chinese multi-source imagetext dataset called RUC-CAS-WenLan for pre-training our BriVL model. Extensive experiments demonstrate that the pre-trained BriVL model outperforms both UNITER and OpenAI CLIP on various downstream tasks.

Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeletonrelated proteins were also detected. The results showed that Hcy (300 -500 M) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time-and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an ␣5␤1-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocytederived resistin, which provides further evidence of the adiposevascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.adipose-vascular interaction; insulin resistance; cytoskeleton

Cypermethrin is a widely used synthetic pyrethroid insecticide. Previous studies showed that cypermethrin significantly decreased the fertility and reduced the number of implantation sites and viable fetuses in females impregnated by males exposed to cypermethrin. As yet, little is known about the mechanism of cypermethrin-induced reproductive toxicity. In the present study, we investigated the effects of cypermethrin exposure during puberty on steroidogenesis in mice. Young male mice were administered with cypermethrin (25 mg/kg) by gavage daily from postnatal day (PND) 35 to PND70. Results showed that the level of serum and testicular testosterone (T) was markedly decreased in cypermethrin-treated mice. Additional experiment showed that cypermethrin exposure during puberty markedly downregulated mRNA level of steroidogenic acute regulatory protein (StAR) in testes. Correspondingly, protein level of testicular StAR was significantly decreased in cypermethrin-treated mice. Cypermethrin exposure during puberty did not affect the number of Leydig cells in testes. Although cypermethrin exposure during puberty did not affect the weight of testes and epididymides, the number of sperm in the cauda epididymides was significantly decreased in cypermethrin-treated mice. Taken together, these results indicate that cypermethrin exposure during puberty significantly disrupts T synthesis via downregulating the expression of testicular StAR. The decreased T synthesis might be associated with cypermethrin-induced impairment in spermatogenesis in mice.

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Hedgehog (Hh) signaling emerges as a potential pathway contributing to fat formation during postnatal development. In this report, we found that Patched 1 (Ptc1), a negative regulator of Hh signaling, was expressed in the epididymal fat pad of adult mice. Reduced total white fat mass and epididymal adipocyte cell size were observed in naturally occurring spontaneous mesenchymal dysplasia (mes) adult mice (Ptc1 mes/mes ), which carry a deletion of Ptc1 at the carboxyl-terminal cytoplasmic region. Increased expression of truncated Ptc1, Ptc2 and Gli1, the indicators of ectopic activation of Hh signaling, was observed in epididymal fat pads of adult Ptc1 mes/mes mice. In contrast, expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, adipocyte P2 and adipsin were reduced in epididymal fat pads of adult Ptc1 mes/mes mice. Taken together, our results indicate that deletion of carboxyl-terminal tail of Ptc1 can lead to the reduction of white fat mass during postnatal development.

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