Post-natal heart adaptation in a knock-in mouse model of calsequestrin 2-linked recessive catecholaminergic polymorphic ventricular tachycardia

Cardiac calsequestrin (CASQ2) contributes to intracellular Ca²⁺ homeostasis by virtue of its low-affinity/high-capacity Ca²⁺ binding properties, maintains sarcoplasmic reticulum (SR) architecture and regulates excitation–contraction coupling, especially or exclusively upon β-adrenergic stimulation. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in children or young adults. Recessive CPVT variants are due to mutations in the CASQ2 gene. Molecular and ultra-structural properties were studied in hearts of CASQ2^R33Q/R33Q and of CASQ2^−/− mice from post-natal day 2 to week 8. The drastic reduction of CASQ2-R33Q is an early developmental event and is accompanied by down-regulation of triadin and junctin, and morphological changes of jSR and of SR-transverse-tubule junctions. Although endoplasmic reticulum stress is activated, no signs of either apoptosis or autophagy are detected. The other model of recessive CPVT, the CASQ2^−/− mouse, does not display the same adaptive pattern. Expression of CASQ2-R33Q influences molecular and ultra-structural heart development; post-natal, adaptive changes appear capable of ensuring until adulthood a new pathophysiological equilibrium.     

Prokaryotes in the WAIS Divide ice core reflect source and transport changes between Last Glacial Maximum and the early Holocene

We present the first long‐term, highly resolved prokaryotic cell concentration record obtained from a polar ice core. This record, obtained from the West Antarctic Ice Sheet (WAIS) Divide (WD) ice core, spanned from the Last Glacial Maximum (LGM) to the early Holocene (EH) and showed distinct fluctuations in prokaryotic cell concentration coincident with major climatic states. The time series also revealed a ~1,500‐year periodicity with greater amplitude during the Last Deglaciation (LDG). Higher prokaryotic cell concentration and lower variability occurred during the LGM and EH than during the LDG. A sevenfold decrease in prokaryotic cell concentration coincided with the LGM/LDG transition and the global 19 ka meltwater pulse. Statistical models revealed significant relationships between the prokaryotic cell record and tracers of both marine (sea‐salt sodium [ssNa]) and burning emissions (black carbon [BC]). Collectively, these models, together with visual observations and methanosulfidic acid (MSA) measurements, indicated that the temporal variability in concentration of airborne prokaryotic cells reflected changes in marine/sea‐ice regional environments of the WAIS. Our data revealed that variations in source and transport were the most likely processes producing the significant temporal variations in WD prokaryotic cell concentrations. This record provided strong evidence that airborne prokaryotic cell deposition differed during the LGM, LDG, and EH, and that these changes in cell densities could be explained by different environmental conditions during each of these climatic periods. Our observations provide the first ice‐core time series evidence for a prokaryotic response to long‐term climatic and environmental processes.     

Age‐specific reproduction and disposable soma in an urban population of Common Blackbirds Turdus merula

The mechanism of senescence is an important subject of current research, but our knowledge of the factors influencing the rate of ageing in naturally occurring populations remains rudimentary. Evolutionary theories of senescence predict that investment in reproduction in early life should come at the cost of reduced somatic maintenance and thus result in earlier or more rapid senescence. We use data on the complete reproductive histories of 431 Common Blackbirds (222 males and 209 females) collected during a 19‐year study of the ecology of an urban population of this species to test the main hypotheses addressing the issue of senescence. On average, the birds in this population survived for 3.7 (± 1.9 sd) years. Reproductive success in females peaked at the age of 4, but in males remained stable until the 5th year of life. We observed declines in reproductive success, indicative of senescence, after the peak years in both sexes. The mechanism of age‐related changes in the reproduction of females confirms the individual improvement and selective disappearance hypotheses. In the case of males, the increase in reproductive performance comes as a consequence of the disappearance of poor reproducers. The parental investment associated with early life fecundity (the first two breeding seasons in males and females) impairs the breeding success of females later on. Contrary to expectations, there was no negative impact of high early life fecundity on either mortality or lifespan. Individuals of both sexes with a high early life fecundity had a higher lifetime reproductive success than those in which early life fecundity was low. Hence, the most profitable strategy is to maximize reproductive effort in the early stages of life. This yields the highest lifetime reproductive success, despite the increased impact of senescence, especially in females. These results are consistent with the disposable soma hypothesis.     

胃癌发展相关阶段中E-cadherin基因启动子甲基化及蛋白表达的研究

为了研究E cadherin基因启动子甲基化在胃癌发生及发展阶段中的作用 ,我们采用甲基化特异性PCR和免疫组化的方法对异型增生 (2 3例 )、早期胃癌 (2 0例 )和进展期胃癌 (2 0例 )石蜡标本进行启动子甲基化状态及蛋白表达的分析。结果表明E cadherin基因启动子在异型增生、早期胃癌和进展期胃癌中均有甲基化 ,其阳性率分别为78 3% ,80 %和 90 % ,经χ2 检验各病例组与正常组 (30 % )比较均有差异 (P <0 0 5 ) ,但各病例组间没有差异 (P >0 0 5 ) ;进展期胃癌E cadherin蛋白表达全部阴性 ,早期胃癌 70 %阴性 ,异型增生中无蛋白阴性 ,在早期胃癌和进展期胃癌 34例蛋白表达阴性的标本中 31例有启动子甲基化 (91 2 % ) ,蛋白表达与启动子甲基化呈明显负相关 (P <0 0 1)。表明E cadherin启动子甲基化是胃癌发生的早期事件 ,也是胃癌发生、进展的重要事件     

Ultrastructure of some Cambrian palynomorphs from the Bright Angel Shale, Arizona, USA

Palynomorphs with complex resistant walls have been recovered from several Cambrian deposits in the continental United States. Those recovered from the Bright Angel Shale of Arizona typically preserve both a primary wall, and an outer envelope (synoecosporal wall) that encloses multiple spore-like bodies within. At least three distinct types of primary walls, are recognized with the TEM: 1) a unilaminate wall with a smooth inner surface and a sculptured outer surface, 2) a wall of three unornamented laminae of very uniform thickness, and, 3) a thicker wall with multiple thin, lightly-staining layers embedded in a darker matrix. This third type of primary wall bears a strong resemblance to those of certain Lower Devonian hilate cryptospore monads from the Welsh Borderlands. No extant algae produce spores with walls as thick or as complex, suggesting that these Cambrian palynomorphs were the desiccation-resistant spores of cryptogams belonging to the charophyte–embryophyte lineage. Multilaminate spore walls, which are characteristic of some extant liverworts and Paleozoic cryptospores, may have evolved via the fusion of separate, multiple laminae. This appears to be the primitive plant sporoderm type, but it may have evolved asynchronously with respect to the evolution of the embryophytic development of the sporophyte in land plants.     

Human cytomegalovirus immediate early proteins and cell growth control

It is widely accepted that small DNA tumor viruses, such as adenovirus, simian virus 40 and papillomavirus, push infected cells into S-phase to facilitate the replication of their genome. Until recently, it was believed that the large DNA viruses (i.e. herpesviruses) functioned very differently in this regard by inducing a G₁ arrest in infected cells as part of their replication process. However, studies over the last 6–8 years have uncovered striking parallels (and differences) between the functions of the major immediate early (IE) proteins of at least one herpesvirus, human cytomegalovirus (HCMV) and IE equivalents encoded by small DNA tumor viruses, such as adenovirus. Similarities between the HCMV major IE proteins and adenovirus IE proteins include targeting of members of the RB and p53 families and an ability of these viral factors to induce S-phase in quiescent cells. However, unlike the small DNA tumor virus proteins, individual HCMV IE proteins target different RB family members. HCMV also encodes several other IE gene products as well as virion tegument proteins that act early during infection to prevent an infected cell from replicating its host genome and from undergoing apoptosis. Here, we review the specifics of several HCMV IE proteins, two virion components, and their functions in relation to cell growth control.     

Native brook trout and invasive rainbow trout respond differently to seasonal weather variation: Spawning timing matters

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Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Endocytosis and intracellular sorting of transforming growth factor-β (TGF-β) receptors play an important regulatory role in TGF-β signaling. Two major endocytic pathways, clathrin- and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors. In this study, we demonstrate that the clathrin- and caveolae-mediated endocytic pathways can converge during TGF-β receptor endocytic trafficking. By tracking the intracellular dynamics of fluorescently-labeled TGF-β type I receptor (TβRI), we found that after mediating TβRI internalization, certain clathrin-coated vesicles and caveolar vesicles are fused underneath the plasma membrane, forming a novel type of caveolin-1 and clathrin double-positive vesicles. Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TβRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). We further showed that the caveolin-1-positive early endosomes are positive for Smad3/SARA, Rab11 and Smad7/Smurf2, and may act as a multifunctional device for TGF-β signaling and TGF-β receptor recycling and degradation. Therefore, these findings uncover a novel scenario of endocytosis, the direct fusion of clathrin-coated and caveolae vesicles during TGF-β receptor endocytic trafficking, which leads to the formation of the multifunctional sorting device, caveolin-1-positive early endosomes, for TGF-β receptors.     

Pathogenesis of ER Storage Disorders: Modulating Russell Body Biogenesis by Altering Proximal and Distal Quality Control

In many protein storage diseases, detergent‐insoluble proteins accumulate in the early secretory compartment (ESC). Protein condensation reflects imbalances between entry into (synthesis/translocation) and exit from (secretion/degradation) ESC, and can be also a consequence of altered quality control (QC) mechanisms. Here we exploit the inducible formation of Russell bodies (RB), dilated ESC cisternae containing mutant Ig‐µ chains, as a model to mechanistically dissect protein condensation. Depending on the presence or absence of Ig‐L chains, mutant Ig‐µ chains lacking their first constant domain (Ch 1) accumulate in rough or smooth RB (rRB and sRB), dilations of the endoplasmic reticulum (ER) and ER‐Golgi intermediate compartment (ERGIC), respectively, reflecting the proximal and distal QC stations in the stepwise biogenesis of polymeric IgM. Either weakening ERp44‐dependent distal QC or facilitating ER‐associated degradation (ERAD) inhibits RB formation. Overexpression of PDI or ERp44 inhibits µΔCh 1 secretion. However, PDI inhibits while ERp44 promotes µΔCh 1 condensation. Both Ero1α silencing and overexpression prevent RB formation, demonstrating a strict redox dependency of the phenomenon. Altogether, our findings identify key controllers of protein condensation along the ESC as potential targets to handle certain storage disorders.     

Natural pathology of the captive chimpanzee (Pan troglodytes): A 35‐year review

We present the spontaneous pathological lesions identified as a result of necropsy or biopsy for 245 chimpanzees (Pan troglodytes) over a 35‐year period. A review of the pathology database was performed for all diagnoses on chimpanzees from 1980 to 2014. All morphologic diagnoses, associated system, organ, etiology, and demographic information were reviewed and analyzed. Cardiomyopathy was the most frequent lesion observed followed by hemosiderosis, hyperplasia, nematodiasis, edema, and hemorrhage. The most frequently affected systems were the gastrointestinal, cardiovascular, urogenital, respiratory, and lymphatic/hematopoietic systems. The most common etiology was undetermined, followed by degenerative, physiologic, neoplastic, parasitic, and bacterial. Perinatal and infant animals were mostly affected by physiologic etiologies and chimpanzee‐induced trauma. Bacterial and physiologic etiologies were more common in juvenile animals. Degenerative and physiologic (and neoplastic in geriatric animals) etiologies predominated in adult, middle aged, and geriatric chimpanzees.