Structure of the ESCRT-II endosomal trafficking complex

The multivesicular-body (MVB) pathway delivers transmembrane proteins and lipids to the lumen of the endosome. The multivesicular-body sorting pathway has crucial roles in growth-factor-receptor downregulation, developmental signalling, regulation of the immune response and the budding of certain enveloped viruses such as human immunodeficiency virus. Ubiquitination is a signal for sorting into the MVB pathway, which also requires the functions of three protein complexes, termed ESCRT-I, -II and -III (endosomal sorting complex required for transport). Here we report the crystal structure of the core of the yeast ESCRT-II complex, which contains one molecule of the Vps protein Vps22, the carboxy-terminal domain of Vps36 and two molecules of Vps25, and has the shape of a capital letter 'Y'. The amino-terminal coiled coil of Vps22 and the flexible linker leading to the ubiquitin-binding NZF domain of Vps36 both protrude from the tip of one branch of the 'Y'. Vps22 and Vps36 form nearly equivalent interactions with the two Vps25 molecules at the centre of the 'Y'. The structure suggests how ubiquitinated cargo could be passed between ESCRT components of the MVB pathway through the sequential transfer of ubiquitinated cargo from one complex to the next.     

内蒙赤峰南部楼子店拆离断层系绿泥石化带的形成时代

楼子店拆离断层系是华北陆块北缘一条大型北东南西向构造，低角度倾向南东．拆离断层系中韧性剪切带的走向线理与脆性断面上的倾向擦痕表明该断层发育过程中发生了运动学上的转向．拆离断层系绿泥石化带是伸展过程中构造层次递进变浅所致的退化变质作用产物，其中发育了早期近走向和晚期倾向两组线理，记录了上盘早期向北东的韧性剪切到晚期脆性倾向下滑的运动学转向过程．因此，绿泥石矿物的定年可限定这一构造热事件及运动学转向的时间．初步的绿泥石K-Ar定年表明，楼子店拆离断层系绿泥石化带形成始于~121Ma，114—112Ma间发生了运动学的转向．     

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer

Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.     

Migration of a Late Cretaceous fish

Late Cretaceous sediments from the Western Interior of North America yield exceptionally well preserved fossils that serve as proxies for the rapidly changing climate preceding the Cretaceous/Tertiary boundary (about 67-65 Myr ago). Here we reconstruct the ontogenetic history of a Maastrichtian-age fish, Vorhisia vulpes, by using the carbon, oxygen and strontium isotope ratios of four aragonite otoliths collected from the Fox Hills Formation of South Dakota. Individuals of V. vulpes spawned in brackish water (about 70-80% seawater) and during their first year migrated to open marine waters of the Western Interior Seaway, where they remained for 3 years before returning to the estuary, presumably to spawn and die. The mean delta(18)O from the marine growth phase of V. vulpes yields a seawater temperature of 18 degrees C, which is consistent with leaf physiognomy and general-circulation-model temperature estimates for the Western Interior during the latest Maastrichtian.     

Hidden complexity in the mechanical properties of titin

Individual molecules of the giant protein titin span the A-bands and I-bands that make up striated muscle. The I-band region of titin is responsible for passive elasticity in such muscle, and contains tandem arrays of immunoglobulin domains. One such domain (I27) has been investigated extensively, using dynamic force spectroscopy and simulation. However, the relevance of these studies to the behaviour of the protein under physiological conditions was not established. Force studies reveal a lengthening of I27 without complete unfolding, forming a stable intermediate that has been suggested to be an important component of titin elasticity. To develop a more complete picture of the forced unfolding pathway, we use mutant titins--certain mutations allow the role of the partly unfolded intermediate to be investigated in more depth. Here we show that, under physiological forces, the partly unfolded intermediate does not contribute to mechanical strength. We also propose a unified forced unfolding model of all I27 analogues studied, and conclude that I27 can withstand higher forces in muscle than was predicted previously.     

Forensic Science: Current State and Perspective by a Group of Early Career Researchers

Forensic science and its influence on policing and the criminal justice system have increased since the beginning of the twentieth century. While the philosophies of the forensic science pioneers remain the pillar of modern practice, rapid advances in technology and the underpinning sciences have seen an explosion in the number of disciplines and tools. Consequently, the way in which we exploit and interpret the remnant of criminal activity are adapting to this changing environment. In order to best exploit the trace, an interdisciplinary approach to both research and investigation is required. In this paper, nine postdoctoral research fellows from a multidisciplinary team discuss their vision for the future of forensic science at the crime scene, in the laboratory and beyond. This paper does not pretend to be exhaustive of all fields of forensic science, but describes a portion of the postdoctoral fellows’ interests and skills.