99 research outputs found
Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis
Peer reviewedPublisher PD
Long splenic flexure carcinoma requiring laparoscopic extended left hemicolectomy with CME and transverse-rectal anastomosis: technique for a modified partial Deloyers in 5 steps to achieve enough reach and preserving middle colic vessels.
Funder: Università degli Studi dell'InsubriaINTRODUCTION: This How-I-Do-It article presents a modified Deloyers procedure by mean of the case of a 67-year-old female with adenocarcinoma extending for a long segment and involving the splenic flexure and proximal descending colon who underwent a laparoscopic left extended hemicolectomy (LELC) with derotation of the right colon and primary colorectal anastomosis. BACKGROUND: While laparoscopic extended right colectomy is a well-established procedure, LELC is rarely used (mainly for distal transverse or proximal descending colon carcinomas extending to the area of the splenic flexure). LELC presents several technical challenges which are demonstrated in this How-I-Do-It article. TECHNIQUE AND METHODS: Firstly, the steps needed to mobilize the left colon and procure a safe approach to the splenic flexure are described, especially when a tumor is closely related to it. This is achieved by mobilization and resection of the descending colon, while maintaining a complete mesocolic excision to the level of the duodenojejunal ligament for the inferior mesenteric vein and flush to the aorta for the inferior mesenteric artery. Subsequently, we depict the adjuvant steps required to enable a primary anastomosis by trying to mobilize the transverse colon and release as much of the mesocolic attachments at the splenic flexure area. Finally, we present the rare instance when a laparoscopic derotation of the ascending colon is required to provide a tension-free anastomosis. The resection is completed by delivery of the fully derotated ascending colon and hepatic flexure through a suprapubic mini-Pfannenstiel incision. The primary colorectal anastomosis is subsequently fashioned in a tension-free way and provides for a quick postoperative recovery of the patient. RESULTS: This modified Deloyers procedure preserves the middle colic since the fully mobilized mesocolon allows for a tension-free anastomosis while maintaining better blood supply to the mobilized stump. Also, by eliminating the need for a mesenteric window and the transposition of the caecum, we allow the small bowel to rest over the anastomosis and the mobilized transverse colon and reduce the possibility of an internal herniation of the small bowel into the mesentery. CONCLUSIONS: Laparoscopic derotation of the right colon and a partial, modified Deloyers procedure preserving the middle colic vessels are feasible techniques in experienced hands to provide primary anastomosis after LELC with improved functional outcome. Nevertheless, it is important to consider anatomical aspects of the left hemicolectomy along with oncological considerations, to provide both a safe oncological resection along with good postoperative bowel function
Metabolic Regulation of Invadopodia and Invasion by Acetyl-CoA Carboxylase 1 and De novo Lipogenesis
Invadopodia are membrane protrusions that facilitate matrix degradation and cellular invasion. Although lipids have been implicated in several aspects of invadopodia formation, the contributions of de novo fatty acid synthesis and lipogenesis have not been defined. Inhibition of acetyl-CoA carboxylase 1 (ACC1), the committed step of fatty acid synthesis, reduced invadopodia formation in Src-transformed 3T3 (3T3-Src) cells, and also decreased the ability to degrade gelatin. Inhibition of fatty acid synthesis through AMP-activated kinase (AMPK) activation and ACC phosphorylation also decreased invadopodia incidence. The addition of exogenous 16∶0 and 18∶1 fatty acid, products of de novo fatty acid synthesis, restored invadopodia and gelatin degradation to cells with decreased ACC1 activity. Pharmacological inhibition of ACC also altered the phospholipid profile of 3T3-Src cells, with the majority of changes occurring in the phosphatidylcholine (PC) species. Exogenous supplementation with the most abundant PC species, 34∶1 PC, restored invadopodia incidence, the ability to degrade gelatin and the ability to invade through matrigel to cells deficient in ACC1 activity. On the other hand, 30∶0 PC did not restore invadopodia and 36∶2 PC only restored invadopodia incidence and gelatin degradation, but not cellular invasion through matrigel. Pharmacological inhibition of ACC also reduced the ability of MDA-MB-231 breast, Snb19 glioblastoma, and PC-3 prostate cancer cells to invade through matrigel. Invasion of PC-3 cells through matrigel was also restored by 34∶1 PC supplementation. Collectively, the data elucidate the novel metabolic regulation of invadopodia and the invasive process by de novo fatty acid synthesis and lipogenesis
The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): illuminating the functional diversity of eukaryotic life in the oceans through transcriptome sequencing.
Microbial ecology is plagued by problems
of an abstract nature. Cell sizes are so
small and population sizes so large that
both are virtually incomprehensible. Niches
are so far from our everyday experience
as to make their very definition elusive.
Organisms that may be abundant and
critical to our survival are little understood,
seldom described and/or cultured,
and sometimes yet to be even seen. One
way to confront these problems is to use
data of an even more abstract nature:
molecular sequence data. Massive environmental
nucleic acid sequencing, such
as metagenomics or metatranscriptomics,
promises functional analysis of microbial
communities as a whole, without prior
knowledge of which organisms are in the
environment or exactly how they are
interacting. But sequence-based ecological
studies nearly always use a comparative
approach, and that requires relevant
reference sequences, which are an extremely
limited resource when it comes to
microbial eukaryotes.
In practice, this means sequence databases
need to be populated with enormous
quantities of data for which we have
some certainties about the source. Most
important is the taxonomic identity of
the organism from which a sequence is
derived and as much functional identification
of the encoded proteins as possible. In
an ideal world, such information would be
available as a large set of complete, well curated,
and annotated genomes for all the
major organisms from the environment
in question. Reality substantially diverges
from this ideal, but at least for bacterial
molecular ecology, there is a database
consisting of thousands of complete genomes
from a wide range of taxa,
supplemented by a phylogeny-driven approach
to diversifying genomics [2]. For
eukaryotes, the number of available genomes
is far, far fewer, and we have relied
much more heavily on random growth of
sequence databases, raising the
question as to whether this is fit for
purpose
Evolutionary genomics of a cold-adapted diatom: Fragilariopsis cylindrus
The Southern Ocean houses a diverse and productive community of organisms1, 2. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice3, 4, 5, 6, 7. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus8, 9, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean
Pervasive Hitchhiking at Coding and Regulatory Sites in Humans
Much effort and interest have focused on assessing the importance of natural
selection, particularly positive natural selection, in shaping the human genome.
Although scans for positive selection have identified candidate loci that may be
associated with positive selection in humans, such scans do not indicate whether
adaptation is frequent in general in humans. Studies based on the reasoning of
the MacDonald–Kreitman test, which, in principle, can be used to
evaluate the extent of positive selection, suggested that adaptation is
detectable in the human genome but that it is less common than in Drosophila or
Escherichia coli. Both positive and purifying natural
selection at functional sites should affect levels and patterns of polymorphism
at linked nonfunctional sites. Here, we search for these effects by analyzing
patterns of neutral polymorphism in humans in relation to the rates of
recombination, functional density, and functional divergence with chimpanzees.
We find that the levels of neutral polymorphism are lower in the regions of
lower recombination and in the regions of higher functional density or
divergence. These correlations persist after controlling for the variation in GC
content, density of simple repeats, selective constraint, mutation rate, and
depth of sequencing coverage. We argue that these results are most plausibly
explained by the effects of natural selection at functional
sites—either recurrent selective sweeps or background
selection—on the levels of linked neutral polymorphism. Natural
selection at both coding and regulatory sites appears to affect linked neutral
polymorphism, reducing neutral polymorphism by 6% genome-wide and by
11% in the gene-rich half of the human genome. These findings suggest
that the effects of natural selection at linked sites cannot be ignored in the
study of neutral human polymorphism
The Vein Patterning 1 (VEP1) Gene Family Laterally Spread through an Ecological Network
Lateral gene transfer (LGT) is a major evolutionary mechanism in prokaryotes. Knowledge about LGT— particularly, multicellular— eukaryotes has only recently started to accumulate. A widespread assumption sees the gene as the unit of LGT, largely because little is yet known about how LGT chances are affected by structural/functional features at the subgenic level. Here we trace the evolutionary trajectory of VEin Patterning 1, a novel gene family known to be essential for plant development and defense. At the subgenic level VEP1 encodes a dinucleotide-binding Rossmann-fold domain, in common with members of the short-chain dehydrogenase/reductase (SDR) protein family. We found: i) VEP1 likely originated in an aerobic, mesophilic and chemoorganotrophic α-proteobacterium, and was laterally propagated through nets of ecological interactions, including multiple LGTs between phylogenetically distant green plant/fungi-associated bacteria, and five independent LGTs to eukaryotes. Of these latest five transfers, three are ancient LGTs, implicating an ancestral fungus, the last common ancestor of land plants and an ancestral trebouxiophyte green alga, and two are recent LGTs to modern embryophytes. ii) VEP1's rampant LGT behavior was enabled by the robustness and broad utility of the dinucleotide-binding Rossmann-fold, which provided a platform for the evolution of two unprecedented departures from the canonical SDR catalytic triad. iii) The fate of VEP1 in eukaryotes has been different in different lineages, being ubiquitous and highly conserved in land plants, whereas fungi underwent multiple losses. And iv) VEP1-harboring bacteria include non-phytopathogenic and phytopathogenic symbionts which are non-randomly distributed with respect to the type of harbored VEP1 gene. Our findings suggest that VEP1 may have been instrumental for the evolutionary transition of green plants to land, and point to a LGT-mediated ‘Trojan Horse’ mechanism for the evolution of bacterial pathogenesis against plants. VEP1 may serve as tool for revealing microbial interactions in plant/fungi-associated environments
Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p
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