Potentiating effect of distant sites in non-phosphorylated cyclic peptide antagonists of the Grb2-SH2 domain

Without the presence of a phosphotyrosyl group, a phage library derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain attributed its high affinity and specificity to well-defined and highly favored interactions of its structural elements with the binding pocket of the protein. We have disclosed a significant compensatory role of the Glu(2-) sidechain for the absence of the phosphate functionality on Tyr(0) in the peptide ligand, cyclo(CH(2)CO-Glu(2-)-Leu-Tyr(0)-Glu-Asn-Val-Gly-Met(5+)-Tyr-Cys)-amide (termed G1TE). In this study, we report the importance of hydrophobic residue at the Tyr+5 site in G1TE. Both acidic and basic amino acid substitutes are disfavored at this position, and replacement of Met with beta-tert-butyl-Ala was found to improve the antagonist properties. Besides, the polarity of the cyclization linkage was implicated as important in stabilizing the favored binding conformation. Oxidation of the thioether linkage into sulfoxide facilitated the binding to Grb2-SH2 markedly. Simultaneous modification of the three distant sites within G1TE provided the best agent with an IC(50) of 220 nM, which is among the most potent non-phosphorous- and non-phosphotyrosine-mimic containing Grb2-SH2 domain inhibitors yet reported. This potent peptidomimetic provides a novel template for the development of chemotherapeutic agents for the treatment of erbB2-related cancer. Biological assays on G1TE(Gla(2-)) in which the original residue of Glu(2-) was substituted by gamma-carboxyglutamic acid (Gla) indicated that it could inhibit the interaction between activated GF receptor and Grb2 protein in cell homogenates of MDA-MB-453 breast cancer cells at the 2 microM level. More significantly, both G1TE(Gla(2-)) alone and the conjugate of G1TE(Gla(2-)) with a peptide carrier can effectively inhibit intracellular association of erbB2 and Grb2 in the same cell lines with IC(50) of 50 and 2 microM, respectively.     

Global convergence properties in multilocus viability selection models: the additive model and the Hardy-Weinberg law

A natural coordinate system is introduced for the analysis of the global stability of the Hardy-Weinberg (HW) polymorphism under the general multilocus additive viability model. A global convergence criterion is developed and used to prove that the HW polymorphism is globally stable when each of the loci is diallelic, provided the loci are overdominant and the multilocus recombination is positive. As a corollary the multilocus Hardy-Weinberg law for neutral selection is derived.Research supported in part by NIH grants GM 39907-01, GM 10452-26 and NSF Grant DMS 86-06244Research supported in part by a US-Israel Binational Science Foundation grant 85-00021 and NIH grant GM 28016     

Protective effect of melatonin against transient global cerebral ischemia-induced neuronal cell damage via inhibition of matrix metalloproteinase-9

Aims

Melatonin possesses various pharmacological effects including neuroprotective effects against brain ischemia. Post-ischemic increases in matrix metalloproteinase-9 (MMP-9) expression and activity mainly contribute to neuronal damage by degradation of the extracellular matrix. This study was designed to examine whether melatonin has a neuroprotective effect and an influence on MMP-9 in transient global brain ischemia.

Main methods

Mice were subjected to 20 min of global brain ischemia and sacrificed 72 h later. Melatonin (30 mg/kg) was administered 30 min before and 2 h after ischemia as well as once daily until sacrifice.

Key findings

Hippocampal pyramidal cell damage after ischemia was significantly decreased by melatonin. As observed by zymography, melatonin inhibited the increase of MMP-9 activity after ischemia. In the brain sections, the increased gelatinase activity was mainly observed in the hippocampus after ischemia and melatonin also reduced gelatinase activity. The laminin and NeuN expression levels were reduced in the hippocampal CA1 and CA2 regions after ischemia, and melatonin reduced laminin degradation and neuronal loss. A TUNEL assay demonstrated that there were TUNEL-positive cells in the hippocampus and the number of TUNEL-positive cells was significantly decreased by melatonin. There was no difference in the ischemia-induced hippocampal neuronal damage between the vehicle- and melatonin-treated groups of MMP-9 knock-out mice.

Significance

These data demonstrate that melatonin suppressed the occurrence of neuronal injury, which might be partly due to its inhibitory effects on MMP-9 in addition to its anti-oxidative effects. MMP-9 may be an important key target of melatonin in neuroprotection against global ischemia.     

Selection signatures in Shetland ponies

Shetland ponies were selected for numerous traits including small stature, strength, hardiness and longevity. Despite the different selection criteria, Shetland ponies are well known for their small stature. We performed a selection signature analysis including genome‐wide SNPs of 75 Shetland ponies and 76 large‐sized horses. Based upon this dataset, we identified a selection signature on equine chromosome (ECA) 1 between 103.8 Mb and 108.5 Mb. A total of 33 annotated genes are located within this interval including the IGF1R gene at 104.2 Mb and the ADAMTS17 gene at 105.4 Mb. These two genes are well known to have a major impact on body height in numerous species including humans. Homozygosity mapping in the Shetland ponies identified a region with increased homozygosity between 107.4 Mb and 108.5 Mb. None of the annotated genes in this region have so far been associated with height. Thus, we cannot exclude the possibility that the identified selection signature on ECA1 is associated with some trait other than height, for which Shetland ponies were selected.     

Using niche modelling and human influence index to indicate conservation priorities for Atlantic forest deer species

To prioritise conservation actions and management strategies for threatened forest deer species at the Atlantic forest, we aimed to identify and describe the most suitable habitat areas for forest deer species and to indicate conservation measures for state agents and local communities. We adopt an approach based on ecological niche modelling, key variable thresholds and spatial analyses. In addition, we associated our approach with a human influence index, an invasive species dataset of occurrences, protected area cover and IUCN category. We indicate 2 % (484 km²) of the Atlantic forest cover as conservation priority areas (CPAs). Of these, 56.8 % are outside protected areas, 20.7 % are inside IUCN categories i, ii and iii protected areas, 19.9 % are inside IUCN categories iv, v, and vi protected areas, and 2.6 % are inside indigenous areas. Also, we indicate the most relevant protected areas for deer conservation in the Atlantic forest. The CPAs were classified into more human-influenced areas (MHIA) and less human-influenced areas (LHIA), and we identified 21 significant (greater than120 km²) continuous CPAs outside protected areas. We highlight actions in several perspectives of human influence, governance levels and law protection that would rationalise the use of funds and human resources.     

“2020年后全球生物多样性框架”进展及展望

“2020年后全球生物多样性框架”是当前《生物多样性公约》谈判的焦点议题之一。本文阐述了框架制定的背景, 介绍了“2020年后全球生物多样性框架”不限成员名额工作组(Open Ended Working Group, OEWG),的谈判过程, 综合分析了缔约方在各有关磋商进程中的观点, 以及目前缔约方对框架各个要素的共识和分歧, 评估了框架的制定进展, 并就框架的设计提出四点展望: (1)阐明转型变革的具体实施路径; (2)平衡反映公约三大目标; (3)加强与其他全球治理进程的协同; (4)强化框架对全球及缔约方履约进展的评估和审查。最后提出对我国的建议: (1)及时更新国家生物多样性战略与行动计划(National Biodiversity Strategies and Action Plans, NBSAP); (2)加强国内生物多样性工作的协调; (3)继续加强生态环境执法和责任机制。为缔约方更好参与框架制定进程, 深入了解框架及其磋商进展提供参考, 并为下一步框架制定提供参考。     

Kinetic models for the dynamical behavior of polyacrylamide (PAAm)–κ-carrageenan (κC) composite gels

A fluorescence method was employed for studying the drying and swelling of PAAm–κC composite gels, which were formed from acrylamide (AAm) and N, N’- methylenebisacrylamide (BIS) with various κ–carrageenan (κC) contents by free radical crosslinking copolymerization in water. Composite gels were prepared at 80 °C with pyranine (Py) as a fluorescence probe. Scattered light, I_sc, and fluorescence emission intensities, I_em, were monitored during drying and swelling of these gels. The fluorescence intensity of pyranine increased and decreased as drying and swelling time are increased, respectively, for all gel samples. The Stern–Volmer equation combined with moving boundary and Li-Tanaka models were used to explain the behavior of I_em during drying and swelling processes respectively. It is found that the desorption coefficient D_d decreased as κC contents were increased for a given temperature during drying. However, the cooperative diffusion coefficient, D_s presented exactly the opposite case. Conventional gravimetrical and volumetric experiments were also carried out during drying and swelling of PAAm–κC composite gels. It was observed that D_d and D_s values measured with the fluorescence method were found to be much larger than they were measured with the conventional methods.     

Defining criteria and indicators for a sustainability label of local public services

The assessment of sustainability of public services is an important issue, especially at local level, taken into account the central role of local governments as a major public employer and provider of a diversity of services. Local governments are close to citizens and are moving faster than other public sector levels with regard to the integration of sustainability principles in their operations and strategies. A sustainability label to communicate public service performance enables to disclose information directly to service users. However, there is a dearth of research about labels addressing specific sustainability criteria for local services. The main aim of this research was the development of a conceptual framework to define a sustainability label, as a tool to assess and communicate sustainability of local public services. The approach was developed taking into account criteria of the European Union Ecolabel and indicators of the Global Reporting Initiative guidelines. The ecolabel is a relatively well-known voluntary instrument in Europe and has the potential for application in public service activities and operations, but only assess the environmental component of sustainability. The Global Reporting Initiative, in particular the Sector Supplement for Public Agencies, was then used to integrate the other sustainability components. Thirty-six (36) criteria and respective indicators were adapted for the proposed sustainability label conceptual framework. A Portuguese local public service was used as an exploratory case study to test the proposed conceptual model into practice. The overall results demonstrate that few criteria were accomplished in this local public service, stressing that new practices and public policies need to be adopted to invert the current trend, especially through the application of assessment systems. This exploratory case study research has shown how useful can be a sustainability label to support local governments in evaluating and communicating the sustainability performance of their public services. This case could drive and support other government levels, including central and regional public administration, in adopting and exploring public service labels and their associated performance approaches.     

Laccase from Aspergillus niger: A novel tool to graft multifunctional materials of interests and their characterization

In the present study, we propose a green route to prepare poly(3-hydroxybutyrate) [(P(3HB)] grafted ethyl cellulose (EC) based green composites with novel characteristics through laccase-assisted grafting. P(3HB) was used as a side chain whereas, EC as a backbone material under ambient processing conditions. A novel laccase obtained from Aspergillus niger through its heterologous expression in Saccharomyces cerevisiae was used as a green catalyst for grafting purposes without the use of additional initiator and/or cross-linking agents. Subsequently, the resulting P(3HB)-g-EC composites were characterized using a range of analytical and imagining techniques. Fourier transform infrared spectroscopy (FT-IR) spectra showed an increase in the hydrogen-bonding type interactions between the side chains of P(3HB) and backbone material of EC. Evidently, X-ray diffraction (XRD) analysis revealed a decrease in the crystallinity of the P(3HB)-g-EC composites as compared to the pristine individual polymers. A homogeneous P(3HB) distribution was also achieved in case of the graft composite prepared in the presence of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) as a mediator along with laccase as compared to the composite prepared using pure laccase alone. A substantial improvement in the thermal and mechanical characteristics was observed for grafted composites up to the different extent as compared to the pristine counterparts. The hydrophobic/hydrophilic properties of the grafted composites were better than those of the pristine counterparts.     

Insight into the biological impact of COVID-19 and its vaccines on human health

COVID-19 (coronavirus disease-2019) is a contagious illness that has been declared a global epidemic by the World Health Organization (WHO). The coronavirus causes diseases ranging in severity from the common cold to severe respiratory diseases and death. Coronavirus primarily affects blood pressure by attaching to the angiotensin converting enzyme 2 (ACE 2) receptor. This virus has an impact on multiple organ systems, including the central nervous system, immune system, cardiovascular system, peripheral nervous system, gastrointestinal tract, endocrine system, urinary system, skin, and pregnancy. For the prevention of COVID-19, various vaccines such as viral-like particle vaccines, entire inactivated virus vaccines, viral vector vaccines, live attenuated virus vaccines, subunit vaccines, RNA vaccines, and DNA vaccines are now available. Some of the COVID-19 vaccines are reported to cause a variety of adverse effects that range from mild to severe in nature. SARS-CoV-2 replication is controlled by the RNA-Dependent RNA-Polymerase enzyme (RdRp). The availability of FDA-approved anti-RdRp drugs (Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir) as potent drugs against SARS-CoV-2 that tightly bind to its RdRp may aid in the treatment of patients and reduce the risk of the mysterious new form of COVID-19 viral infection. RdRp inhibitors, such as remdesivir (an anti-Ebola virus experimental drug) and favipiravir (an anti-influenza drug), inhibit RdRp and thus slow the progression of COVID-19 and associated clinical symptoms, as well as significantly shorten recovery time. Molnupiravir, an orally active RdRp inhibitor and noval broad spectrum antiviral agent, is an isopropyl pro-drug of EIDD-1931 for emergency use. Galidesivir's in vitro and in vivo activities are limited to RNA of human public health concern. Top seeds for antiviral treatments with high potential to combat the SARS-CoV-2 strain include guanosine derivatives (IDX-184), setrobuvir, and YAK. The goal of this review is to compile scattered information on available COVID-19 vaccines and other treatments for protecting the human body from their harmful effects and to provide options for making better choices in a timely manner.