Protein Kinase A Activity Is Necessary for Fission and Fusion of Golgi to Endoplasmic Reticulum Retrograde Tubules

It is becoming increasingly accepted that together with vesicles, tubules play a major role in the transfer of cargo between different cellular compartments. In contrast to our understanding of the molecular mechanisms of vesicular transport, little is known about tubular transport. How signal transduction molecules regulate these two modes of membrane transport processes is also poorly understood. In this study we investigated whether protein kinase A (PKA) activity regulates the retrograde, tubular transport of Golgi matrix proteins from the Golgi to the endoplasmic reticulum (ER). We found that Golgi-to-ER retrograde transport of the Golgi matrix proteins giantin, GM130, GRASP55, GRASP65, and p115 was impaired in the presence of PKA inhibitors. In addition, we unexpectedly found accumulation of tubules containing both Golgi matrix proteins and resident Golgi transmembrane proteins. These tubules were still attached to the Golgi and were highly dynamic. Our data suggest that both fission and fusion of retrograde tubules are mechanisms regulated by PKA activity.     

Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy

Alzheimer''s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706) prevents accumulation of Aβ species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD). Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP), resulting in the accumulation of immature APP (iAPP) in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aβ production in vivo.     

SPECIES‐SPECIFIC DIFFERENCES IN ADAPTIVE PHENOTYPIC PLASTICITY IN AN ECOLOGICALLY RELEVANT TROPHIC TRAIT: HYPERTROPHIC LIPS IN MIDAS CICHLID FISHES

The spectacular species richness of cichlids and their diversity in morphology, coloration, and behavior have made them an ideal model for the study of speciation and adaptive evolution. Hypertrophic lips evolved repeatedly and independently in African and Neotropical cichlid radiations. Cichlids with hypertrophic lips forage predominantly in rocky crevices and it has been hypothesized that mechanical stress caused by friction could result in larger lips through phenotypic plasticity. To test the influence of the environment on the size and development of lips, we conducted a series of breeding and feeding experiments on Midas cichlids. Full‐sibs of Amphilophus labiatus (thick‐lipped) and Amphilophus citrinellus (thin‐lipped) each were split into a control group which was fed food from the water column and a treatment group whose food was fixed to substrates. We found strong evidence for phenotypic plasticity on lip area in the thick‐lipped species, but not in the thin‐lipped species. Intermediate phenotypic values were observed in hybrids from thick‐ and thin‐lipped species reared under “control” conditions. Thus, both a genetic, but also a phenotypic plastic component is involved in the development of hypertrophic lips in Neotropical cichlids. Moreover, species‐specific adaptive phenotypic plasticity was found, suggesting that plasticity is selected for in recent thick‐lipped species.     

Explosive evolution of an ancient group of Cyphophthalmi (Arachnida: Opiliones) in the Balkan Peninsula

Aim  To investigate the phylogeny of the genus Cyphophthalmus in the Balkan Peninsula and to test the current recognition of 'phyletic lines' and phylogenetic groups proposed in previous studies in order to elucidate the biogeographical history of the region.
Location  Europe, Balkan Peninsula, Adria microplate.
Methods  Two mitochondrial (cytochrome c oxidase subunit I and 16S rRNA) and two nuclear (28S rRNA and 18S rRNA) markers were used to infer the phylogenetic history of the group. Molecular dating with relaxed molecular clocks was used to elucidate the relative time of diversification within the genus Cyphophthalmus and its constituent lineages.
Results  Our analyses confirm the monophyly of the genus Cyphophthalmus , and that of the Aegean and gjorgjevici lineages, whereas the 'Dinaric lineage' appears paraphyletic.
Main conclusions  We show that the genus Cyphophthalmus is an old endemic from the Balkan biogeographical region, which gave origin to at least three main lineages. Those lineages have diversified within overlapping ranges. According to our molecular dating, they have also diversified within the same timeframe. The Dinaric Alps, although presenting a large number of species, cannot be inferred as the centre of origin of the group. Instead, the biogeographical evolution of the genus could be related to the palaeogeographic history of the Adria microplate.     

A phylogeny of Vetigastropoda and other “archaeogastropods”: re-organizing old gastropod clades

Abstract. The phylogenetic relationships among the “archaeogastropod” clades Patellogastropoda, Vetigastropoda, Neritimorpha, and Neomphalina are uncertain; the phylogenetic placement of these clades varies across different analyses, and particularly among those using morphological characteristics and those relying on molecular data. This study explores the relationships among these groups using a combined analysis with seven molecular loci (18S rRNA, 28S rRNA, histone H3, 16S rRNA, cytochrome c oxidase subunit I [COI], myosin heavy-chain type II, and elongation factor-1α [EF-1α]) sequenced for 31 ingroup taxa and eight outgroup taxa. The deep evolutionary splits among these groups have made resolution of stable relationships difficult, and so EF-1α and myosin are used in an attempt to re-examine these ancient radiation events. Three phylogenetic analyses were performed utilizing all seven genes: a single-step direct optimization analysis using parsimony, and two-step approaches using parsimony and maximum likelihood. A single-step direct optimization parsimony analysis was also performed using only five molecular loci (18S rRNA, 28S rRNA, histone H3, 16S rRNA, and COI) in order to determine the utility of EF-1α and myosin in resolving deep relationships. In the likelihood and POY optimal phylogenetic analyses, Gastropoda, Caenogastropoda, Neritimorpha, Neomphalina, and Patellogastropoda were monophyletic. Additionally, Neomphalina and Pleurotomariidae fell outside the remaining vetigastropods, indicating the need for further investigation into the relationship of these groups with other gastropods.     

A multilocus approach to harvestman (Arachnida: Opiliones) phylogeny with emphasis on biogeography and the systematics of Laniatores

The internal phylogeny of the arachnid order Opiliones is investigated by including molecular data from five molecular markers for ca. 140 species totalling 43 families of Opiliones. The phylogenetic analyses consisted of a direct optimization (DO) approach using POY v. 4 and sophisticated tree search algorithms as well as a static alignment analysed under maximum likelihood. The four Opiliones suborders were well‐supported clades, but subordinal relationships did not receive support in the DO analysis, with the exception of the monophyly of Palpatores (=Eupnoi + Dyspnoi). Maximum‐likelihood analysis strongly supported the traditional relationship of Phalangida and Palpatores: (Cyphophthalmi ((Eupnoi + Dyspnoi) Laniatores)). Relationships within each suborder are well resolved and largely congruent between direct optimization and maximum‐likelihood approaches. Age estimates for the main Opiliones lineages suggest a Carboniferous diversification of Cyphophthalmi, while its sister group, Phalangida, diversified in the Early Devonian. Diversification of all suborders predates the Triassic, and most major lineages predate the Cretaceous. The following taxonomic changes are proposed. Dyspnoi: Hesperonemastoma is transferred to Sabaconidae. Insidiatores: Sclerobunidae stat. nov. is erected as a family for Zuma acuta. © The Willi Hennig Society 2009.     

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

Background

Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study.

Methods

From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors.

Results

Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk.

Conclusions

We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.     

The Prevalence and Drug Sensitivity of Tuberculosis among Patients Dying in Hospital in KwaZulu-Natal,South Africa: A Postmortem Study

Background

Tuberculosis is the leading cause of death in South Africa by death notification, but accurate diagnosis of tuberculosis is challenging in this setting of high HIV prevalence. We conducted limited autopsies on young adults dying in a single public hospital in the province of KwaZulu-Natal between October 2008 and August 2009 in order to estimate the magnitude of deaths attributable to tuberculosis.

Methods and Findings

We studied a representative sample of 240 adult inpatients (aged 20–45 years) dying after admission to Edendale Hospital. Limited autopsies included collection of respiratory tract secretions and tissue by needle core biopsies of lung, liver, and spleen. Specimens were examined by fluorescent microscopy for acid-fast bacilli and cultured in liquid media; cultures positive for M. tuberculosis were tested for drug susceptibility to first- and second-line antibiotics. Ninety-four percent of our study cohort was HIV seropositive and 50% of decedents had culture-positive tuberculosis at the time of death. Fifty percent of the participants were on treatment for tuberculosis at the time of death and 58% of these treated individuals remained culture positive at the time of death. Of the 50% not receiving tuberculosis treatment, 42% were culture positive. Seventeen percent of all positive cultures were resistant to both isoniazid and rifampin (i.e., multidrug resistant); 16% of patients dying during the initiation phase of their first ever course of tuberculosis treatment were infected with multidrug-resistant bacilli.

Conclusions

Our findings reveal the immense toll of tuberculosis among HIV-positive individuals in KwaZulu-Natal. The majority of decedents who remained culture positive despite receiving tuberculosis treatment were infected with pan-susceptible M. tuberculosis, suggesting that the diagnosis of tuberculosis was made too late to alter the fatal course of the infection. There is also a significant burden of undetected multidrug-resistant tuberculosis among HIV-coinfected individuals dying in this setting. New public health approaches that improve early diagnosis of tuberculosis and accelerate the initiation of treatment are urgently needed in this setting. Please see later in the article for the Editors'' Summary     

Instability of copronecrophagous beetle assemblages (Coleoptera: Scarabaeinae) in a mountainous tropical landscape of Mexico

We analyzed changes over time in species composition and functional guild structure (temporal beta diversity) for natural assemblages and those modified by humans in a fragmented, tropical mountain landscape. The assemblages belong to cloud forests (the original vegetation type), secondary forests, traditional shaded coffee plantations, commercial shaded coffee plantations, and a cattle pasture. Copronecrophagous beetles, subfamily Scarabaeinae (Insecta: Coleoptera: Scarabaeidae), were used as the indicator group. This group has been used in previous studies and other tropical forests and has been found to be a good indicator of the effects of anthropogenic change. For each assemblage, we compared samples that were collected several years apart. Changes were found in species composition, order of abundance, and in the proportion that a given species is present in the different functional groups. The changes that occurred between samplings affected the less abundant species in the cloud forest and in the pasture. In the other vegetation types, both abundant and less abundant species were affected. Their order of abundance and proportion in the different guilds also changed. This study shows that, although landscape richness remains relatively constant, richness at the local level (alpha diversity) changes notably even over short lapses of time. This could be a characteristic of landscapes with intermediate degrees of disturbance (such as those that have been partially modified for human use), where assemblage composition is very fluid.     

Molecular evidence that human immunodeficiency virus type 1 dissemination in a small Brazilian city was already taking place in the early 1990s

We recently performed a molecular epidemiology survey of human immunodeficiency virus type 1 (HIV-1) infection in Miracema, a small city in Southeast Brazil, and found multiple monophyletic clusters, consistent with independent introductions and spread of different viral lineages in the city. Here we apply Bayesian coalescent-based methods to the two largest subtype B clusters and estimate that the most recent common ancestors that gave rise to these two transmission chains were in circulation around 1991-1992. The finding that HIV-1 spread in this Brazilian small city was already taking place at a time Aids was considered a problem restricted to large urban centers may have important public health implications.