To initiate infection many viruses enter their host cells by triggering endocytosis following receptor engagement. The mechanisms by which non-enveloped viruses escape the endosome are however poorly understood. Here we present near-atomic resolution cryoEM structures for feline calicivirus (FCV) both undecorated and labelled with a soluble fragment of its cellular receptor feline junctional adhesion molecule A (fJAM-A). We show that VP2, a minor capsid protein encoded by all caliciviruses 1,2 , forms a large portal-like assembly at a unique threefold symmetry axis following receptor engagement. This feature, which was not detected in undecorated virions, is formed of twelve copies of VP2 arranged with their hydrophobic N-termini pointing away from the virion surface. Local rearrangement at the portal site leads to opening of a pore in the capsid shell. We hypothesise that the portal-like assembly functions as a channel for delivery of the calicivirus genome through the endosomal membrane into the cytoplasm of a host cell to initiate infection. While VP2 was known to be critical for the production of infectious virus 3 , its structure and function were hitherto undetermined. Our findings therefore represent a major step forward in our understanding of the Caliciviridae.

Aldehyde-alcohol dehydrogenase (AdhE) is a key enzyme in bacterial fermentation, converting acetyl-CoA to ethanol, via two consecutive catalytic reactions. Here, we present a 3.5 Å resolution cryo-EM structure of full-length AdhE revealing a high-order spirosome architecture. The structure shows that the aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) active sites reside at the outer surface and the inner surface of the spirosome respectively, thus topologically separating these two activities. Furthermore, mutations disrupting the helical structure abrogate enzymatic activity, implying that formation of the spirosome structure is critical for AdhE activity. In addition, we show that this spirosome structure undergoes conformational change in the presence of cofactors. This work presents the atomic resolution structure of AdhE and suggests that the high-order helical structure regulates its enzymatic activity.

To initiate the infectious process, many viruses enter their host cells by triggering endocytosis following receptor engagement. The mechanism by which non-enveloped viruses, such as the caliciviruses, escape the endosome is however poorly understood. The Caliciviridae include many important human and animal pathogens, most notably norovirus, the cause of winter vomiting disease. Here we show that VP2, a minor capsid protein encoded by all caliciviruses, forms a large portal assembly at a unique three-fold symmetry axis following receptor engagement. This feature surrounds an open pore in the capsid shell. We hypothesise that the VP2 portal complex is the means by which the virus escapes the endosome, penetrating the endosomal membrane to release the viral genome into the cytoplasm. Cryogenic electron microscopy (cryoEM) and asymmetric reconstruction were used to investigate structural changes in the capsid of feline calicivirus (FCV) that occur when the virus binds to its cellular receptor junctional adhesion molecule-A (fJAM-A). Near atomic-resolution structures were calculated for the native virion alone and decorated with soluble receptor fragments. We present atomic models of the major capsid protein VP1 in the presence and absence of fJAM-A, revealing the contact interface and conformational changes brought about by the interaction. Furthermore, we have calculated an atomic model of the portal protein VP2 and revealed the structural changes in VP1 that lead to pore formation. While VP2 was known to be critical for the production of infectious virus, its function has been hitherto undetermined. Our finding that VP2 assembles a portal that is likely responsible for endosome escape represents a major step forward in our understanding of both the Caliciviridae and icosahedral RNA containing viruses in general.

The circadian system in the human body responds to daily environmental changes to optimise behaviour according to the biological clock and also influences various physiological processes. The suprachiasmatic nuclei are located in the anterior hypothalamus of the brain, and they synchronise to the 24 h light/dark cycle. Human physiological functions are highly dependent on the regulation of the internal circadian clock. Skeletal muscles comprise the largest collection of peripheral clocks in the human body. Both central and peripheral clocks regulate the interaction between the musculoskeletal system and energy metabolism. The skeletal muscle circadian clock plays a vital role in lipid and glucose metabolism. The pathogenesis of osteoporosis is related to an alteration in the circadian rhythm. In the present review, we discuss the disturbance of the circadian rhythm and its resultant effect on the musculoskeletal system. We also discuss the nutritional strategies that are potentially effective in maintaining the system’s homeostasis. Active collaborations between nutritionists and physiologists in the field of chronobiological and chrononutrition will further clarify these interactions. This review may be necessary for successful interventions in reducing morbidity and mortality resulting from musculoskeletal disturbances.

Mental illness, particularly depression, is an increasing health problem for many people from all walks of life. Both conventional and non-convventional therapies for mental illnesses including depression have been and are still being put to practice. An alternative method for treatment of depressed patients, particularly Muslims, is through the combination of Cognitive Behavioural Therapy with Islamic values, which is known as Islamic Integrated Cognitive Behavioural Therapy. This review discusses the benefits, limitations and future propects of Islamic Integrated Cognitive Behavioural Therapy particularly in treating Muslims with depression.