Onset of Asian desertification by 22 Myr ago inferred from loess deposits in China

The initial desertification in the Asian interior is thought to be one of the most prominent climate changes in the Northern Hemisphere during the Cenozoic era. But the dating of this transition is uncertain, partly because desert sediments are usually scattered, discontinuous and difficult to date. Here we report nearly continuous aeolian deposits covering the interval from 22 to 6.2 million years ago, on the basis of palaeomagnetic measurements and fossil evidence. A total of 231 visually definable aeolian layers occur as brownish loesses interbedded with reddish soils. This new evidence indicates that large source areas of aeolian dust and energetic winter monsoon winds to transport the material must have existed in the interior of Asia by the early Miocene epoch, at least 14 million years earlier than previously thought. Regional tectonic changes and ongoing global cooling are probable causes of these changes in aridity and circulation in Asia.     

DNA sequence and comparative analysis of chimpanzee chromosome 22

Human-chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.     

Effects of atorvastatin on vascular remodeling in spontaneously hypertensive rats

OBJECTIVE: To investigate the structural changes of aorta, and evaluate the effects of atorvastatin on the remodeling of thoracic aorta in spontaneously hypertensive rats (SHR). METHODS: Twelve eight-week-old SHR were randomized into atorvastatin treated group (ATV group, n=6) and distilled water group (DW group, n=6); Wistar-Kyoto rats (WKY) were used as normal controls. Atorvastatin was administered to ATV group for 10 weeks by gavage in mixture with distilled water (1 ml); the latter two groups were given the same amount of distilled water by gavage for 10 weeks. Systolic blood pressure of caudal artery was examined before and after treatment, and serum concentrations of total cholesterol, triglycerides and HDL-C were measured. Wall thickness, media thickness, medial cross-sectional area and lumen diameter of thoracic aorta were assessed with computed video processing. RESULTS: Systolic blood pressure in ATV group was markedly lower than that in DW group (P<0.01). Compared with DW group and WKY group, serum concentrations of total cholesterol, triglycerides and HDL-C in ATV group were significantly lower (P<0.01,P<0.05). Wall thickness, media thickness, and medial cross-sectional area to lumen ratio in DW group were significantly higher than those in WKY group and ATV group (P<0.01,P<0.05), but no such difference was found between WKY group and ATV group (P>0.05). CONCLUSION: Vascular structural changes of aorta are due to the alteration of the vessel wall in early stage of SHR. Atorvastatin can markedly improve vascular remodeling.     

Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation.     

Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans

The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.     

Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.