A human-specific enhancer fine-tunes radial glia potency and corticogenesis.

Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications 1-3 . Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to human-specific cortical development is largely unknown 4,5 . HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development 6 . Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices containing more neurons. By measuring neural dynamics in vivo we show these anatomical features correlate with increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using live imaging, lineage analysis, and single-cell RNA sequencing. This reveals Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

A Customisable Data Acquisition System for Open-Source Hyperspectral Imaging.

Hyperspectral imagers, or imaging spectrometers, are used in many remote sensing environmental studies in fields such as agriculture, forestry, geology, and hydrology. In recent years, compact hyperspectral imagers were developed using commercial-off-the-shelf components, but there are not yet any off-the-shelf data acquisition systems on the market to deploy them. The lack of a self-contained data acquisition system with navigation sensors is a challenge that needs to be overcome to successfully deploy these sensors on remote platforms such as drones and aircraft. Our work is the first successful attempt to deploy an entirely open-source system that is able to collect hyperspectral and navigation data concurrently for direct georeferencing. In this paper, we describe a low-cost, lightweight, and deployable data acquisition device for the open-source hyperspectral imager (OpenHSI). We utilised commercial-off-the-shelf hardware and open-source software to create a compact data acquisition device that can be easily transported and deployed. The device includes a microcontroller and a custom-designed PCB board to interface with ancillary sensors and a Raspberry Pi 4B/NVIDIA Jetson. We demonstrated our data acquisition system on a Matrice M600 drone at a beach in Sydney, Australia, collecting timestamped hyperspectral, navigation, and orientation data in parallel. Using the navigation and orientation data, the hyperspectral data were georeferenced. While the entire system including the pushbroom hyperspectral imager and housing weighed 735 g, it was designed to be easy to assemble and modify. This low-cost, customisable, deployable data acquisition system provides a cost-effective solution for the remote sensing of hyperspectral data for everyone.

Apoptotic cell-derived metabolites in efferocytosis-mediated resolution of inflammation.

The resolution of inflammation, as part of standard host defense mechanism, is the process to guarantee timely termination of inflammatory responses and eventual restoration of tissue homeostasis . It is mainly achieved via efferocytosis, during which pro-resolving macrophages clear apoptotic neutrophils at the inflammatory site. Unfortunately, impaired resolution can be the leading cause of chronic inflammatory disorders and some autoimmune diseases. Existing studies have provided relatively comprehensive understandings about the recognition and uptake of apoptotic neutrophils by macrophages during early phases of efferocytosis. However, lack of information concerns macrophage metabolism of apoptotic cell-derived metabolites after being released from phagolysosomes or the relationship between such metabolism and efferocytosis. Notwithstanding, three recent studies have revealed macrophage metabolism of cholesterol, fatty acids and arginine, as well as their respective functions in the context of inflammation-resolution. This review provides an overview of the resolution of inflammation, efferocytosis and the key players involved, followed by a focus on the metabolism of apoptotic cell-derived metabolites within efferocytes. Hypotheses of more potential apoptotic cell-derived metabolites and their possible roles in the resolution are also formulated. Understanding the effect of these metabolites further advances the concept that apoptotic cells act as active players to regulate resolution, and also suggests novel therapeutic strategies for diseases driven by defective resolution and even cancer that may be treated through enhanced efferocytosis.

S5, a Withanolide Isolated from Physalis Pubescens L., Induces G2/M Cell Cycle Arrest via the EGFR/P38 Pathway in Human Melanoma A375 Cells.

S5 is a withanolide natural product isolated from Physalis pubescens L. Our previous experimental studies found that it has significant antitumor activity on renal cell carcinoma. In the present study, the anti-melanoma effect of S5 and the related molecular mechanism was first investigated. It was found that S5 induced an obvious growth inhibitory effect on human melanoma A375 cells with low toxicity to human peripheral blood cells. Furthermore, the results demonstrated that the cell death mode of S5 on A375 cells is not due to inducing apoptosis and autophagy. However, there was a significant time-dependent increase in G2/M phase after treatment of A375 with S5. Meanwhile, S5 could also decrease the protein expression of Cdc25c, Cdc2, and CyclinB1, and increased the expression of p-P53 and P21, suggesting that S5 inhibited A375 cell death through G2/M phase arrest. Moreover, the signal pathway factors P38, extracellular regulated protein kinases (ERK), and epidermal growth factor receptor (EGFR) were observed taking part in the S5-induced A375 cells growth inhibitory effect. In addition, suppressing P38 and EGFR reversed the cell proliferation inhibitory effect and G2/M cell cycle arrest induced by S5 and inhibition of EGFR enhanced the downregulation of the expression of P38 and p-P38, indicating that S5 induced A375 G2/M arrest through the EGFR/P38 pathway. Briefly, this study explained for the first time the mechanism of S5-induced A375 cell growth inhibition in order to provide the basis for its clinical application in melanoma.

Determinants of knowledge translation from health technology assessment to policy-making in China: From the perspective of researchers.

BACKGROUND: For health technology assessment (HTA) to be more policy relevant and for health technology-related decision-making to be truly evidence-based, promoting knowledge translation (KT) is of vital importance. Although some research has focused on KT of HTA, there is a dearth of literature on KT determinants and the situation in developing countries and transitional societies remains largely unknown. OBJECTIVE: To investigate the determinants of HTA KT from research to health policy-making from the perspective of researchers in China. DESIGN: Cross-sectional study. METHODS: A structured questionnaire which focused on KT was distributed to HTA researchers in China. KT activity levels in various fields of HTA research were compared, using one-way ANOVA. Principal component analysis was performed to provide a basis to combine similar variables. To investigate the determinants of KT level, multiple linear regression analysis was performed. RESULTS: Based on a survey of 382 HTA researchers, it was found that HTA KT wasn't widespread in China. Furthermore, results showed that no significant differences existed between the various HTA research fields. Factors, such as attitudes of researchers toward HTA and evidence utilization, academic ranks and linkages between researchers and policy-makers, had significant impact on HTA KT (p-values<0.05). Additionally, collaboration between HTA researchers and policy-makers, policy-relevance of HTA research, practicality of HTA outcomes and making HTA reports easier to understand also contributed to predicting KT level. However, academic nature of HTA research was negatively associated with KT level. CONCLUSION: KT from HTA to policy-making was influenced by many factors. Of particular importance were collaborations between researchers and policy-makers, ensuring policy relevance of HTA and making HTA evidence easier to understand by potential users.

Realizing a finite array of dipole sources with high acoustic transmission directivity at low frequency.

A finite array of dipole sources is used to enhance the directivity and radiation gains of sound. This letter demonstrates that this idea can be realized as several sub-wavelength slits in a plate with periodic Helmholtz resonators. Moreover, the array gain of this structure can be further improved by adjusting the effective boundary impedance. The directivity of the dipole array is compared with that of a point array, and the advantages of the dipole array are revealed. Prospective applications of this mechanism include achieving directional radiation in high-gain loudspeakers and ultrasonic medical instrumentation.

Acoustic radiation force on a sphere in a progressive and standing zero-order quasi-Bessel-Gauss beam.

By means of series expansion theory, the incident quasi-Bessel-Gauss beam is expanded using spherical harmonic functions, and the beam coefficients of the quasi-Bessel-Gauss beam are calculated. According to the theory, the acoustic radiation force function, which is the radiation force per unit energy on a unit cross-sectional surface on a sphere made of diverse materials and immersed in an ideal fluid along the propagation axis of zero-order quasi-Bessel-Gauss progressive and standing beams, is investigated. The acoustic radiation force function is calculated as a function of the spherical radius parameter ka and the half-cone angle ß with different beam widths in a progressive and standing zero-order Bessel-Gauss beam. Simulation results indicate that the acoustic radiation forces with different waist radii demonstrate remarkably different features from those found in previous studies. The results are expected to be useful in potential applications such as acoustic tweezers.

Combined oridonin with cetuximab treatment shows synergistic anticancer effects on laryngeal squamous cell carcinoma: involvement of inhibition of EGFR and activation of reactive oxygen species-mediated JNK pathway.

Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is expressed at high levels in a large proportion of laryngeal squamous cell carcinoma (LSCC). Cetuximab (Cet), an anti-EGFR monoclonal antibody, has limited clinical outcome for patients with head and neck squamous cell carcinoma. Our previous studies showed that oridonin (ORI), a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens, inhibited cell growth in HEp-2 cells through inhibition of EGFR phosphorylation. The aim of the present study was to determine whether ORI could improve the anticancer efficacy of Cet on LSCC. We observed that the combination with Cet and ORI synergistically inhibited cell growth associated with Fas-mediated apoptosis and G2/M phase arrest in two LSCC cell lines (HEp-2 and Tu212 cells). Moreover, combination treatment caused cell death associated with suppression of p-EGFR and activation of reactive oxygen species (ROS)-mediated JNK pathway. In nude mice bearing HEp-2 xenografts, ORI plus Cet caused a significant tumor regression through induction of apoptosis and inhibition of proliferation with no side-effect. Together, our findings suggest that the combination of ORI and Cet has the potential to enhance tumor responses and may significantly improve therapeutic outcomes in LSCC.

Physalin A induces G2/M phase cell cycle arrest in human non-small cell lung cancer cells: involvement of the p38 MAPK/ROS pathway.

Physalin A (PA) is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has long been used for the treatment of sore throat, hepatitis, and tumors in China. In the present study, we firstly investigated the effects of PA on proliferation and cell cycle distribution of the human non-small cell lung cancer (NSCLC) A549 cell line, and the potential mechanisms involved. Here, PA inhibited cell growth in dose- and time-dependent manners. Treatment of A549 cells with 28.4 µM PA for 24 h resulted in approximately 50 % cell death. PA increased the amount of intracellular ROS and the proportion of cells in G2/M. G2/M arrest was attenuated by the addition of ROS scavenger NAC. ERK and P38 were triggered by PA through phosphorylation in a time-dependent manner. The phosphorylation of ERK and P38 were not attenuated by the addition of NAC, but the use of the p38 inhibitor could reduce, at least in part, PA-induced ROS and the proportion of cells in G2/M. PA induces G2/M cell cycle arrest in A549 cells involving in the p38 MAPK/ROS pathway. This study suggests that PA might be a promising therapeutic agent against NSCLC.

Cost effectiveness of dipeptidyl peptidase-4 inhibitors for type 2 diabetes.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs used for treating type 2 diabetes mellitus. While many studies have reported on the cost-effectiveness of DPP-4 inhibitors for treating type 2 diabetes, a systematic review of economic evaluations of DPP-4 inhibitors is currently lacking. OBJECTIVES: The aim of this systematic review was to assess the cost effectiveness of DPP-4 inhibitors for patients with type 2 diabetes. DATA SOURCES: MEDLINE, EMBASE, National Health Service Economic Evaluation Database (NHS EED), Web of Science, EconLit databases, and the Cochrane Library were searched in November 2013. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Studies assessing the cost effectiveness of DPP-4 inhibitors for type 2 diabetes were eligible for analysis. DPP-4 inhibitor monotherapy or combinations with other antidiabetic agents were included in the review. The DPP-4 inhibitors were all marketed drugs. Two reviewers independently reviewed titles, abstracts, and articles sequentially to select studies for data abstraction based on the inclusion and exclusion criteria. Disagreements were resolved by consensus. STUDY APPRAISAL AND SYNTHESIS METHODS: The quality of included studies was assessed according to the 24-item checklist of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. The costs reported by the included studies were converted to US dollars via purchasing power parities (PPP) in the year 2013 using the CCEMG-EPPI-Center Cost Converter. RESULTS: A total of 11 published studies were selected for inclusion; all were cost-utility analyses. Nine studies were conducted from a payer perspective and one used a societal perspective; however, the perspective of the other study was unclear. Four studies were of good quality, six were of moderate quality, and one was of low quality. Of the seven studies comparing DPP-4 inhibitors plus metformin with sulfonylureas plus metformin, six concluded that DPP-4 inhibitors were cost effective in patients with type 2 diabetes who were no longer adequately controlled by metformin monotherapy. Five studies compared DPP-4 inhibitors with thiazolidinediones, and whether DPP-4 inhibitors were cost effective was uncertain. Only two economic evaluations provided data to compare DPP-4 inhibitors versus insulin, and the results favored the use of DPP-4 inhibitors as second-line therapy. LIMITATIONS: Synthesis of the data was impossible because of heterogeneity in the methodology and data sources of the economic evaluations, and the inclusion criteria excluded conference abstracts. It was difficult to find reliable weightings for each of the items of the CHEERS checklist, and the ratings were dichotomous. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This study provides the first systematic evaluation of DPP-4 inhibitors for patients with type 2 diabetes. It found that, in patients with type 2 diabetes who do not achieve glycemic targets with antidiabetic monotherapy, DPP-4 inhibitors as add-on treatment may represent a cost-effective option compared with sulfonylureas and insulin. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

Differences in evaluating health technology assessment knowledge translation by researchers and policy makers in China.

OBJECTIVES: The aim of this study was to examine the gaps between researchers and policy makers in perceptions and influencing factors of knowledge translation (KT) of health technology assessment (HTA) in China. METHODS: A sample of 382 HTA researchers and 112 policy makers in China were surveyed using structured questionnaires. The questionnaires contained two sections: perceptions of HTA research and assessments of six-stage KT activities. Wilcoxon rank sum test was applied to compare the differences in these two sections between HTA researchers and policy makers. Multivariate linear regression was performed to explore KT determinants of HTA for researchers and policy makers separately. RESULTS: Policy makers and researchers differed in their perceptions of HTA research in all items except collaboration in research development and presentation of evidence in easy-to-understand language. Significant differences in KT activities existed in all the six stages except academic translation. Regarding KT determinants, close contact between research unit and policy-making department, relevance of HTA to policy making, and importance of HTA on policy making were considered facilitators by both groups. For researchers, practicality of HTA report and presentation of evidence in easy-to-understand language can facilitate KT. Policy makers, on the other hand, considered an overly pedantic nature of HTA research as an obstacle to effective KT. CONCLUSIONS: Substantial gaps existed between HTA researchers and policy makers regarding the perceptions of HTA research and KT activities. There are also some differences in KT determinants by these two groups. Enhancing collaboration, promoting practicality and policy relevance of HTA research, and making HTA findings easily understood are likely to further the KT of HTA evidence.

[Microclimate and comfortable degree of Shanghai urban open spaces in summer].

Based on the observation data of air temperature, relative humidity, wind speed, and solar radiation from May to August 2006, the regulation effects of five types of open spaces (square, fountain, grassplot, corridor, and woodland) in Shanghai urban districts on the microclimate were analyzed, and discomfort index (DI) was introduced to evaluate the effects of these five types of open spaces on human body' s comfortable degree. The results showed that there existed definite differences in the air temperature and relative humidity among the open spaces, with the mean temperature decreased in the order of square > grassplot > fountain > corridor > woodland, and the mean relative humidity decreased in the order of woodland > corridor > fountain > grassplot > square. The area of the square, the wind speed and direction near the fountain, the grass species on the grass-plot, the width and tree coverage of the corridor, and the tree coverage and canopy height of the woodland had significant correlations with the microclimate parameters of corresponding open spaces. Comparing with other three types of open spaces, woodland and corridor had better regulation effects on the microclimate via shading, decreasing air temperature, and increasing relative humidity.

Negative birefraction of acoustic waves in a sonic crystal.

Optical birefringence and dichroism are classical and important effects originating from two independent polarizations of optical waves in anisotropic crystals. Furthermore, the distinct dispersion relations of transverse electric and transverse magnetic polarized electromagnetic waves in photonic crystals can lead to birefringence more easily. However, it is impossible for acoustic waves in the fluid to show such a birefringence because only the longitudinal mode exists. The emergence of an artificial sonic crystal (SC) has significantly broadened the range of acoustic materials in nature that can give rise to acoustic bandgaps and be used to control the propagation of acoustic waves. Recently, negative refraction has attracted a lot of attention and has been demonstrated in both left-handed materials and photonic crystals. Similar to left-handed materials and photonic crystals, negative refractions have also been found in SCs. Here we report, for the first time, the acoustic negative-birefraction phenomenon in a two-dimensional SC, even with the same frequency and the same 'polarization' state. By means of this feature, double focusing images of a point source have been realized. This birefraction concept may be extended to other periodic systems corresponding to other forms of waves, showing great impacts on both fundamental physics and device applications.

Contact acoustic nonlinearity in a bonded solid-solid interface.

We have conducted research on the contact acoustic nonlinearity (CAN) produced by a bonded solid-solid interface in order to find a nondestructive and quantitative method to evaluate the bonding strength of the interface. A CAN model is used to depict a bonded state from the relationship between the CAN parameter and the bonding strength and the crack width in the interface. According to this model, a nondestructive evaluation of the bonding strength can be established. When the CAN parameter and the crack width are measured, the bonding strength can be calculated from the model. In this paper, the bonding strengths of some samples are evaluated based on the CAN method. The results well agree with the bonding strengths measured by hanging clogs (weights) to destroy their interfaces.

Acoustic backward-wave negative refractions in the second band of a sonic crystal.

Acoustic negative refractions with backward-wave (BW) effects were both theoretically and experimentally established in the second band of a two-dimensional (2D) triangular sonic crystal (SC). Intense Bragg scatterings result in the extreme deformation of the second band equifrequency surface (EFS) into two classes: one around the K point and the other around the point of the reduced Brillouin zone. The two classes can lead to BW negative refractions (BWNRs) but with reverse negative refraction dependences on frequencies and incident angles. Not only BWNR but BW positive refraction can be present at EFSs around the K point, so it is possible to enhance the resolution of acoustic waves with a subdiffraction limit regardless of refractions, which is no analogy in both left-handed material and SCs' first band. These abundant characters make refractions in the second band distinguished.