Current strategies for drug discovery have reached a bottleneck where the paradigm is generally "one gene, one drug, one disease." However, using holistic and systemic views, network pharmacology may be the next paradigm in drug discovery. Based on network pharmacology, a combinational drug with two or more compounds could offer beneficial synergistic effects for complex diseases. Interestingly, traditional chinese medicine (TCM) has been practicing holistic views for over 3,000 years, and its distinguished feature is using herbal formulas to treat diseases based on the unique pattern classification. Though TCM herbal formulas are acknowledged as a great source for drug discovery, no drug discovery strategies compatible with the multidimensional complexities of TCM herbal formulas have been developed. In this paper, we highlighted some novel paradigms in TCM-based network pharmacology and new drug discovery. A multiple compound drug can be discovered by merging herbal formula-based pharmacological networks with TCM pattern-based disease molecular networks. Herbal formulas would be a source for multiple compound drug candidates, and the TCM pattern in the disease would be an indication for a new drug.

Lead acetate can cause testicular damage in males. In this study, we assessed the repairing effects of human umbilical cord mesenchymal stem cells (MSCs) on testicular injury caused by lead acetate in mice. MSCs were injected into mice with testicular injury by intraperitoneal injection, and the organ coefficient of reproductive organs, sperm motility, hormone level and antioxidant index of mice were tested. Compared with the normal group, the coefficient of reproductive organs and sperm motility were reduced in the model group, and histopathology showed obvious testicular injury, proving successful modeling. Compared with the model group, the reproductive organ coefficient and sperm motility were improved in the experimental group, and histopathology showed that the testicular injury could be significantly improved. Sex hormone secretion tends to be normal, and the antioxidant index increased. Sequencing results showed that there were 485 upregulated genes and 172 downregulated genes between the model group and the control group, and 210 upregulated genes and 482 downregulated genes between the experimental group and the model group. Differentially expressed genes are mainly concentrated in AMP-activated protein kinase (AMPK) signaling pathway, apoptosis signaling pathway, and arginine biosynthesis signaling pathway. Overall, MSCs can significantly improve the degree of damages to mice testis caused by lead acetate and have a certain repairing effect.

Meiosis 1 arresting protein (M1ap) is a novel vertebrate gene expressed exclusively in germ cells of the embryonic ovary and the adult testis. In male mice, M1ap expression, which is present from spermatogonia to secondary spermatocytes, is evolutionarily conserved and has a specific spatial and temporal pattern suggestive of a role during germ cell development. To test its function, mice deficient in M1ap were created. Whereas females had histologically normal ovaries, males exhibited reduced testicular size and a myriad of tubular defects, which led to severe oligozoospermia and infertility. Although some germ cells arrested at the zygotene/pachytene stages, most cells advanced to metaphase I before arresting and entering apoptosis. Cells that reached metaphase I were unable to properly align their chromosomes at the metaphase plate due to abnormal chromosome synapses and failure to form crossover foci. Depending on the state of tubular degeneration, all germ cells, with the exemption of spermatogonia, disappeared; with further deterioration, tubules displaying only Sertoli cells reminiscent of Sertoli cell-only syndrome in humans were observed. Our results uncovered an essential role for M1ap as a novel germ cell gene not previously implicated in male germ cell development and suggest that mutations in M1AP could account for some cases of nonobstructive oligozoospermia in men.

To investigate the effects of lead exposure and IGF1R inhibitor AG1024 on the expression of IGF1R and IGFBP3 in PC12 cells. It is clear that the mechanism of the related proteins inducing AD is regulated by them, thus providing theoretical guidance for the prevention and treatment of lead poisoning.

Heavy metal detection has become very important for the protection of water resource. In this work, a novel controllable probe is presented for the sensitive detection of Pb2+ in aqueous solutions. The probe was synthesized via the immobilization of surface functionalized carbon dots (named as CAEA-Hs) into the shell of the spherical polyelectrolyte brushes (SPB). The fluorescence of CAEA-H was firstly "turned off" via electrostatic interaction induced quenching. Based on the aggregation induced emission enhancement (AIEE), the fluorescence of the immobilized CAEA-H could be specifically turned on via the aggregation of the SPB particles. This fluorescence "turn on" sensor could selectively detect Pb2+ among five different metal ions with a relatively wide detecting range (0-1.67 mM) and good linear relationship (R 2 = 0.9958). Moreover, the aggregating behavior and nano-structure of CAEA-H loaded SPB have been systematically analyzed via small angle X-ray scattering, turbidity titration, and Zeta-potential measurement. Based on a series of control experiments, we finally gain an insight into the sensing mechanism of this novel sensing probe. This contributed a proof of concept demonstration that sensitive and selective chemical detection can be achieved via a C-dot/SPB synergistic platform.

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.

Electromechanical coupling in piezoelectric materials allows direct conversion of electrical energy into mechanical energy and vice versa. Here, we demonstrate lead-free (K x Na1-x )NbO3 single crystals with an ultrahigh large-signal piezoelectric coefficient d 33* of 9000 pm V-1, which is superior to the highest value reported in state-of-the-art lead-based single crystals (~2500 pm V-1). The enhanced electromechanical properties in our crystals are realized by an engineered compositional gradient in the as-grown crystal, allowing notable reversible non-180° domain wall motion. Moreover, our crystals exhibit temperature-insensitive strain performance within the temperature range of 25°C to 125°C. The enhanced temperature stability of the response also allows the materials to be used in a wider range of applications that exceed the temperature limits of current lead-based piezoelectric crystals.

Some histone deacetylase (HDAC) isoforms contribute to ischaemia/reperfusion (IR) injury (IRI). Here, we examined whether LP342, the lead candidate of a new generation of hydrazide-based HDAC inhibitors (HDACi), decreases hepatic IRI.

Human infections with the H7N9 virus could lead to lung damage and even multiple organ failure, which is closely associated with a high mortality rate. However, the metabolic basis of such systemic alterations remains unknown.

Hatching is crucial for mammalian embryo implantation, since difficulties during this process can lead to implantation failure, ectopic pregnancy and consequent infertility. Despite years of intensive researches, how internal and external factors affecting embryo hatch are still largely unclear.

The mounting evidence that osteoclasts play an important role in osteoarthritis (OA) pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K, on pain behaviour and joint pathology in a model of OA pain.

Homonymous hemianopia (HH) is an anisotropic visual impairment characterized by the binocular inability to see one side of the visual field. Patients with HH often misperceive visual space. Here we investigated how HH affects visual motor control.

Several biclustering algorithms have been proposed to identify biclusters, in which genes share similar expression patterns across a number of conditions. However, different algorithms would yield different biclusters and further lead to distinct conclusions. Therefore, some testing and comparisons between these algorithms are strongly required.

Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.

Intermittent hypoxia (IH) is a key element of obstructive sleep apnea (OSA) that can lead to disorders in the liver. In this study, IH was established in a rat model to examine its effects on the expression of hepatic cytochrome P450 (CYP) and CYP regulators, including nuclear receptors.

Mutations affecting cardiac structural genes can lead to congenital heart diseases (CHDs). Axonemal Central Pair Apparatus Protein (HYDIN) is a ciliary protein previously linked to congenital cardiomyopathy. However, the role of HYDIN in the aetiology of CHDs is thus far unknown. Herein, we explore the function of HYDIN in heart development and CHDs.

Osteoporosis is a metabolic bone disease characterized by decreased bone mineral density and abnormal bone quality. Monocytes can secret cytokines for bone resorption, resulting in bone mass loss. However, the mechanism by which monocytes subpopulations lead to osteoporosis remains unclear. The aim of this study was to identify genes associated with osteoporosis in monocytes subsets.

Vendors in the health care industry produce diagnostic systems that, through a secured connection, allow them to monitor performance almost in real time. However, challenges exist in analyzing and interpreting large volumes of noisy quality control (QC) data. As a result, some QC shifts may not be detected early enough by the vendor, but lead a customer to complain.

Cellphone use while driving (CUWD) is a frequent source of distraction for young drivers. These distractions commonly lead to motor vehicle crashes and, in some cases, death. Crash risk differs depending on if the driver is engaging in handheld or hands-free CUWD. This pilot study sought to investigate the differences between handheld versus hands-free CUWD behaviors in younger drivers and the attitudes and social norms that inform them.

Neonatal hypoxia ischemia (HI) is an injury that can lead to neurological impairments such as behavioral and learning disabilities. Granulocyte-colony stimulating factor (G-CSF) has been demonstrated to be neuroprotective in ischemic stroke however it has also been shown to induce neutrophilia, ultimately exacerbating neuronal injury. Our hypothesis is that coadministration of anti-neutrophil antibody (Ab) with G-CSF will decrease blood neutrophil counts thereby reducing infarct volume and improving neurological function post HI brain injury.