Copper (Cu) has emerged as an important modifier of body lipid metabolism. However, how Cu contributes to the physiology of fat cells remains largely unknown. We found that adipocytes require Cu to ...establish a balance between main metabolic fuels. Differentiating adipocytes increase their Cu uptake along with the ATP7A-dependent transport of Cu into the secretory pathway to activate a highly up-regulated amino-oxidase copper-containing 3 (AOC3)/semicarbazide-sensitive amine oxidase (SSAO); in vivo, the activity of SSAO depends on the organism's Cu status. Activated SSAO oppositely regulates uptake of glucose and long-chain fatty acids and remodels the cellular proteome to coordinate changes in fuel availability and related downstream processes, such as glycolysis, de novo lipogenesis, and sphingomyelin/ceramide synthesis. The loss of SSAO-dependent regulation due to Cu deficiency, limited Cu transport to the secretory pathway, or SSAO inactivation shifts metabolism towards lipid-dependent pathways and results in adipocyte hypertrophy and fat accumulation. The results establish a role for Cu homeostasis in adipocyte metabolism and identify SSAO as a regulator of energy utilization processes in adipocytes.
The Scaly-foot Snail, Chrysomallon squamiferum, presents a combination of biomineralised features, reminiscent of enigmatic early fossil taxa with complex shells and sclerites such as sachtids, but ...in a recently-diverged living species which even has iron-infused hard parts. Thus the Scaly-foot Snail is an ideal model to study the genomic mechanisms underlying the evolutionary diversification of biomineralised armour. Here, we present a high-quality whole-genome assembly and tissue-specific transcriptomic data, and show that scale and shell formation in the Scaly-foot Snail employ independent subsets of 25 highly-expressed transcription factors. Comparisons with other lophotrochozoan genomes imply that this biomineralisation toolkit is ancient, though expression patterns differ across major lineages. We suggest that the ability of lophotrochozoan lineages to generate a wide range of hard parts, exemplified by the remarkable morphological disparity in Mollusca, draws on a capacity for dynamic modification of the expression and positioning of toolkit elements across the genome.
The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more ...severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed “mouse kidney parvovirus” (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.
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•Inclusion body nephropathy is caused by mouse kidney parvovirus (MKPV)•MKPV is widely distributed in animal facilities in Australia and North America•MKPV is highly divergent from other mouse parvoviruses•Uncontrolled MKPV infection in immunocompromised mice results in renal failure
A kidney parvovirus found in multiple laboratory mouse colonies causes spontaneous nephropathy and represents a new tool for studying chronic kidney disease.
During replication of herpesviruses, capsids escape from the nucleus into the cytoplasm by budding at the inner nuclear membrane. This unusual process is mediated by the viral nuclear egress complex ...(NEC) that deforms the membrane around the capsid by oligomerizing into a hexagonal, membrane-bound scaffold. Here, we found that highly basic membrane-proximal regions (MPRs) of the NEC alter lipid order by inserting into the lipid headgroups and promote negative Gaussian curvature. We also find that the electrostatic interactions between the MPRs and the membranes are essential for membrane deformation. One of the MPRs is phosphorylated by a viral kinase during infection, and the corresponding phosphomimicking mutations block capsid nuclear egress. We show that the same phosphomimicking mutations disrupt the NEC-membrane interactions and inhibit NEC-mediated budding
, providing a biophysical explanation for the
phenomenon. Our data suggest that the NEC generates negative membrane curvature by both lipid ordering and protein scaffolding and that phosphorylation acts as an off switch that inhibits the membrane-budding activity of the NEC to prevent capsid-less budding.
Herpesviruses are large viruses that infect nearly all vertebrates and some invertebrates and cause lifelong infections in most of the world's population. During replication, herpesviruses export their capsids from the nucleus into the cytoplasm by an unusual mechanism in which the viral nuclear egress complex (NEC) deforms the nuclear membrane around the capsid. However, how membrane deformation is achieved is unclear. Here, we show that the NEC from herpes simplex virus 1, a prototypical herpesvirus, uses clusters of positive charges to bind membranes and order membrane lipids. Reducing the positive charge or introducing negative charges weakens the membrane deforming ability of the NEC. We propose that the virus employs electrostatics to deform nuclear membrane around the capsid and can control this process by changing the NEC charge through phosphorylation. Blocking NEC-membrane interactions could be exploited as a therapeutic strategy.
Extrapulmonary small cell carcinoma (EPSCC) is a rare cancer and few studies describe its epidemiology. Our objectives were to compare the incidence and survival of EPSCC in South East England with ...small cell carcinoma of the lung (SCLC), to determine the most common anatomical presenting sites for EPSCC and to compare survival in EPSCC by disease stage and site of diagnosis.
We used data from the Thames Cancer Registry database for South East England between 1970 and 2004 to determine the incidence, most common anatomical sites, and survival by site, and stage of EPSCC. 1618 patients registered with EPSCC were identified. We calculated the age-standardised incidence rate for EPSCC using the European standard population and compared this to that for SCLC. We calculated survival using the Kaplan-Meier method for EPSCC and SCLC, and reported 3-year survival for different EPSCC anatomical sites and disease stages.
The incidence of EPSCC was much lower than for SCLC, similar in males and females, and stable throughout the study period, with incidence rates of 0.45 per 100,000 in males and 0.37 in females during 2000-2004. In general, patients with EPSCC had a better 3-year survival (19%) than SCLC (5%). The most common anatomical sites for EPSCC were oesophagus (18%), other gastrointestinal (15%), genitourinary (20%), head and neck (11%), and breast (10%). Breast EPSCC had the best 3-year survival (60%) and gastrointestinal EPSCC the worst (7%).
This study suggests that EPSCC has a stable incidence and confirms that it presents widely, but most commonly in the oesophagus and breast. Site and extent of disease influence survival, with breast EPSCC having the best prognosis. Further studies using standardised diagnosis, prospective case registers for uncommon diseases and European cancer registries are needed to understand this disease.
The chiral spiroborate anions B
(Sal)
and B
(Sal)
, (
and
subscripts indicate boron stereochemistry) have been isolated as 1 : 1 quininium and 1 : 2 sparteinium salts, HQuinB
(Sal)
and H
SpaB
(Sal)
...
respectively, by either cation metathesis or a simple one-pot synthesis involving reaction of boric and salicylic acids with the alkaloid base. Circular dichroism (CD) spectroscopy shows that the B-based chirality is stable in polar aprotic media, such as DMF or DMSO, though labile in protic solutions. Enantiopure salts with achiral counter-cations such as NBu
B
(Sal)
may then be prepared by exchange, so these B-chiral anions may have use in metathesis-based resolutions. Due to a site disorder the anion in H
SpaB
(Sal)
is limited to 70% ee, however an enantiopure analogue H
SpaB
(5-Cl-Sal)
is readily formed using 5-chlorosalicylic acid. This also indicates a wide family of stable enantiopure B-chiral anions may be isolated by this approach.
Spiroborate anions have potential for crystallization or resolution and chiral bis(mandelato)borate anions can be used for the efficient resolution of a diverse range of racemic cations via ...diastereomeric salt formation. The syntheses, X‐ray crystal structures and solubilities of three chiral bis(mandelato)borate salts, namely polyaqua‐μ3‐bis(R)‐mandelatoborato‐lithium(I) monohydrate, Li(C16H12BO6)(H2O)n or LiB(R‐Man)2·H2O, (1), ammonium bis(R)‐mandelatoborate, NH4+·C16H12BO6− or NH4B(R‐Man)2, (2), and tetra‐n‐butylammonium bis(R)‐mandelatoborate, C16H36N+·C16H12BO6− or NBu4B(R‐Man)2, (3), are reported. They all have a BS configuration and show a reasonably well‐conserved anion geometry. The main conformational variation is the orientation of the two phenyl groups, supporting the idea that B(Man)2− is a semi‐rigid anion. The salts are differentially soluble in a range of solvents, meaning they could be useful as reagents for resolution via a metathesis crystallization approach.
The preparation and structures of three simple salts of the bis(R)‐mandelatoborate anion that could be used for the resolution of racemic cations by metathesis crystallization are reported.
The mushroom Ganoderma lucidum (G. lucidum) has been consumed in China as a medicine for promoting health and longevity for thousands of years. Due to its paramount and multiple pharmaceutical ...effects, G. lucidum has received considerable attention from researchers and its chemical constituents as well as their respective functions were gradually unveiled by using modern research methods. Herein, we reported the isolation of a protein (Ganoderma lucidum ribonuclease, GLR) with anti-colorectal cancer activities from G. lucidum. This protein is a 17.4-kDa RNA degrading enzyme (ribonuclease) and was purified by using liquid chromatography procedures. GLR manifested potent anti-proliferative and anti-colony formation activities on HT29 and HCT116 colorectal cancer cells by inducing cell cycle arrest in G1 phase through the regulation of cyclin D1 and P53 expression. GLR was demonstrated to induce cell apoptosis in HCT116 cells by activating unfolded protein response and caspase-9 regulated pathways. Besides, the ability to undergo autophagy which is a stress adaption mechanism to cope with metabolic crisis was significantly suppressed by GLR treatment in HCT116 cells. The activation of apoptosis in GLR-treated HT29 cells was, however, independent of caspase-9 and the suppression of autophagy was also relatively minor. Thus the apoptosis of HT29 cells triggered by GLR was much milder than that in HCT116 cells. Our findings show that the RNase from G. lucidum may be one of the bioactive components that contribute to the anti-colorectal cancer activity of G. lucidum.
Cordymin, an antifungal peptide with a molecular mass of 10,906
Da and an N-terminal amino acid sequence distinct from those of previously reported proteins, was purified from the medicinal mushroom
...Cordyceps militaris. The isolation protocol comprised ion exchange chromatography of the aqueous extract on SP-Sepharose and Mono S and gel filtration on Superdex 75 by a fast protein liquid chromatography system. Cordymin was adsorbed on both cation exchangers. The peptide inhibited mycelial growth in
Bipolaris maydis,
Mycosphaerella arachidicola,
Rhizoctonia solani and
Candida albicans with an IC
50 of 50
μM, 10
μM, 80
μM, and 0.75
mM, respectively. However, there was no effect on
Aspergillus fumigatus,
Fusarium oxysporum and
Valsa mali when tested up to 2
mM. The antifungal activity of the peptide was stable up to 100
°C and in the pH range 6–13, and unaffected by 10
mM Zn
2+ and 10
mM Mg
2+. Cordymin inhibited HIV-1 reverse transcriptase with an IC
50 of 55
μM. Cordymin displayed antiproliferative activity toward breast cancer cells (MCF-7) but there was no effect on colon cancer cells (HT-29). There was no mitogenic activity toward mouse spleen cells and no nitric oxide inducing activity toward mouse macrophages when tested up to 1
mM.
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