Structural characterization of PaaX, the main repressor of the phenylacetate degradation pathway in Escherichia coli W: A novel fold of transcription regulator proteins.

PaaX is a transcriptional repressor of the phenylacetic acid (PAA) catabolic pathway, a central route for bacterial aerobic degradation of aromatic compounds. Induction of the route is achieved through the release of PaaX from its promoter sequences by the first compound of the pathway, phenylacetyl-coenzyme A (PA-CoA). We report the crystal structure of PaaX from Escherichia coli W. PaaX displays a novel type of fold for transcription regulators, showing a dimeric conformation where the monomers present a three-domain structure: an N-terminal winged helix-turn-helix domain, a dimerization domain similar to the Cas2 protein and a C-terminal domain without structural homologs. The domains are separated by a crevice amenable to harbour a PA-CoA molecule. The biophysical characterization of the protein in solution confirmed several hints predicted from the structure, i.e. its dimeric conformation, a modest importance of cysteines and a high dependence of solubility and thermostability on ionic strength. At a moderately acidic pH, the protein formed a stable folding intermediate with remaining α-helical structure, a disrupted tertiary structure and exposed hydrophobic patches. Our results provide valuable information to understand the stability and mechanism of PaaX and pave the way for further analysis of other regulators with similar structural configurations.

Multi-omic analyses reveal the unique properties of chia (Salvia hispanica) seed metabolism.

Chia (Salvia hispanica) is an emerging crop considered a functional food containing important substances with multiple potential applications. However, the molecular basis of some relevant chia traits, such as seed mucilage and polyphenol content, remains to be discovered. This study generates an improved chromosome-level reference of the chia genome, resolving some highly repetitive regions, describing methylation patterns, and refining genome annotation. Transcriptomic analysis shows that seeds exhibit a unique expression pattern compared to other organs and tissues. Thus, a metabolic and proteomic approach is implemented to study seed composition and seed-produced mucilage. The chia genome exhibits a significant expansion in mucilage synthesis genes (compared to Arabidopsis), and gene network analysis reveals potential regulators controlling seed mucilage production. Rosmarinic acid, a compound with enormous therapeutic potential, was classified as the most abundant polyphenol in seeds, and candidate genes for its complex pathway are described. Overall, this study provides important insights into the molecular basis for the unique characteristics of chia seeds.

Prevalence and Prognostic Implications of Amyloidosis in Valvular Heart Disease.

There has been less emphasis on the prognostic impact of amyloidosis in patients with valvular heart disease (VHD). We aimed to determine the prevalence of amyloidosis in VHD and its clinical implications in terms of mortality. Patients hospitalized for VHD were identified using National Inpatient Sample 2016-2020 which were divided into 2 cohorts: with and without amyloidosis. Among 5,728,873 patients hospitalized with VHD, 11,715 patients had amyloidosis in which mitral valve disease has the highest prevalence (7.6%) followed by aortic (3.6%), and tricuspid valve disease (1%). Underlying amyloidosis is associated with higher mortality in VHD (OR 1.45, CI 1.2-1.7, P<0.001), mainly mitral valve disease (OR 1.44, CI 1.1-1.9, P<0.01). Patients with amyloidosis have higher adjusted mortality rates (5-6% vs 2.6%, P<0.01), longer mean length of stay (7.1 vs 5.7 days, P<0.001), but they have lower valvular intervention rates. In hospitalized VHD patients, underlying amyloidosis is associated with higher in-hospital mortality.

Crk proteins activate the Rap1 guanine nucleotide exchange factor C3G by segregated adaptor-dependent and -independent mechanisms.

BACKGROUND: C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood. METHODS: We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors. RESULTS: CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G. CONCLUSION: Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases. Video abstract.

Transcatheter Aortic Valve Replacement for Severe Symptomatic Aortic Stenosis in Rheumatic Heart Disease: A Systematic Review.

Transcatheter aortic valve replacement (TAVR) is well-established for severe symptomatic aortic stenosis (AS), but its use in rheumatic heart disease (RHD) has been limited. We systematically review the use of TAVR for severe symptomatic AS in RHD. Pubmed, Embase, and Scopus were searched for TAVR for symptomatic severe AS and proven or suspected RHD. Procedure characteristics, efficacy, and safety endpoints were collected and all definitions were based on the Valve Academic Research Consortium-2 (VARC-2) criteria. We included 3 case series and 12 case reports, with a total of 43 patients. Mean age was 76 years, 75% were female, and 85% had NYHA class III-IV symptoms. Follow up ranged from 1 to 29 months. Patients were moderate to high risk, with Society of Thoracic Surgery score ranging from 6.1% to 17.6%. The approach was transfemoral in 30 (83%) cases. Procedural success occurred in 37 (86%) patients. Of the 7 patients with periprocedural complications, 4 had valve dislodgement, 1 deployment failure, 1 unplanned cardiopulmonary bypass, and 1 moderate aortic regurgitation. Paravalvular leak was reported in 5 (11.6%) patients. Only 1 patient had heart block requiring pacemaker. Among 13 studies (23 patients), 30-day mortality was 0%. One case series with 19 patients had a 30-day, 1-year, 2-year, and 5-year mortality of 5%, 11%, 31%, and 48%, respectively. TAVR appears feasible for selected patients with rheumatic severe AS, albeit our results indicate a 14% incidence of device failure. Future randomized clinical trials may clarify the role of TAVR in this group.

Genome-wide chromatin accessibility analysis unveils open chromatin convergent evolution during polyploidization in cotton.

Allopolyploidization, resulting in divergent genomes in the same cell, is believed to trigger a "genome shock", leading to broad genetic and epigenetic changes. However, little is understood about chromatin and gene-expression dynamics as underlying driving forces during allopolyploidization. Here, we examined the genome-wide DNase I-hypersensitive site (DHS) and its variations in domesticated allotetraploid cotton (Gossypium hirsutum and Gossypium barbadense, AADD) and its extant AA (Gossypium arboreum) and DD (Gossypium raimondii) progenitors. We observed distinct DHS distributions between G. arboreum and G. raimondii. In contrast, the DHSs of the two subgenomes of G. hirsutum and G. barbadense showed a convergent distribution. This convergent distribution of DHS was also present in the wild allotetraploids Gossypium darwinii and G. hirsutum var. yucatanense, but absent from a resynthesized hybrid of G. arboreum and G. raimondii, suggesting that it may be a common feature in polyploids, and not a consequence of domestication after polyploidization. We revealed that putative cis-regulatory elements (CREs) derived from polyploidization-related DHSs were dominated by several families, including Dof, ERF48, and BPC1. Strikingly, 56.6% of polyploidization-related DHSs were derived from transposable elements (TEs). Moreover, we observed positive correlations between DHS accessibility and the histone marks H3K4me3, H3K27me3, H3K36me3, H3K27ac, and H3K9ac, indicating that coordinated interplay among histone modifications, TEs, and CREs drives the DHS landscape dynamics under polyploidization. Collectively, these findings advance our understanding of the regulatory architecture in plants and underscore the complexity of regulome evolution during polyploidization.

Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity.

Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies (mAbs) has shown anti-tumor activity in human trials, but can be associated with significant off-tumor toxicities involving FcγR interactions. Here, we introduce albumin-fused mouse and human bispecific antibodies with clinically favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. These Fc-free 4-1BB agonists consist of an EGFR-specific VHH antibody, a 4-1BB-specific scFv, and a human albumin sequence engineered for high FcRn binding connected in tandem (LiTCo-Albu). We demonstrate in vitro cognate target engagement, EGFR-specific costimulatory activity, and FcRn-driven cellular recycling similar to non-fused FcRn high-binding albumin. The mouse LiTCo-Albu exhibited a prolonged circulatory half-life and in vivo tumor inhibition, with no indication of 4-1BB mAb-associated toxicity. Furthermore, we show a greater therapeutic effect when used in combination with PD-1-blocking mAbs. These findings demonstrate the feasibility of tumor-specific LiTCo-Albu antibodies for safe and effective costimulatory strategies in cancer immunotherapy.

A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation.

The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs.

The Role of Neuregulin-1 in Steatotic and Non-Steatotic Liver Transplantation from Brain-Dead Donors.

BACKGROUND: Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). METHODS: NRG1 pathways were characterized after surgery. RESULTS: NRG1 and p21-activated kinase 1 (PAK1) levels increased in steatotic and non-steatotic grafts from DBDs. The abolishment of NRG1 effects reduced PAK1. When the effect of either NRG1 nor PAK1 was inhibited, injury and regenerative failure were exacerbated. The benefits of the NRG-1-PAK1 axis in liver grafts from DBDs were associated with increased vascular endothelial growth factor-A (VEGFA) and insulin growth factor-1 (IGF1) levels, respectively. Indeed, VEGFA administration in non-steatotic livers and IGF1 treatment in steatotic grafts prevented damage and regenerative failure resulting from the inhibition of either NRG1 or PAK-1 activity in each type of liver. Exogenous NRG1 induced greater injury than BD induction. CONCLUSIONS: This study indicates the benefits of endogenous NRG1 in liver grafts from DBDs and underscores the specificity of the NRG1 signaling pathway depending on the type of liver: NRG1-PAK1-VEGFA in non-steatotic livers and NRG1-PAK1-IGF1 in steatotic livers. Exogenous NRG1 is not an appropriate strategy to apply to liver grafts from DBD.

Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection.

Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.

Role of Dietary Nutritional Treatment on Hepatic and Intestinal Damage in Transplantation with Steatotic and Non-Steatotic Liver Grafts from Brain Dead Donors.

Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs); and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs; the benefits were independent of alterations in the recipient intestine.

Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation.

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by the extracellular deposition of the transport protein transthyretin (TTR) as amyloid fibrils. Despite the progress achieved in recent years, understanding why different TTR residue substitutions lead to different clinical manifestations remains elusive. Here, we studied the molecular basis of disease-causing missense mutations affecting residues R34 and K35. R34G and K35T variants cause vitreous amyloidosis, whereas R34T and K35N mutations result in amyloid polyneuropathy and restrictive cardiomyopathy. All variants are more sensitive to pH-induced dissociation and amyloid formation than the wild-type (WT)-TTR counterpart, specifically in the variants deposited in the eyes amyloid formation occurs close to physiological pHs. Chemical denaturation experiments indicate that all the mutants are less stable than WT-TTR, with the vitreous amyloidosis variants, R34G and K35T, being highly destabilized. Sequence-induced stabilization of the dimer-dimer interface with T119M rendered tetramers containing R34G or K35T mutations resistant to pH-induced aggregation. Because R34 and K35 are among the residues more distant to the TTR interface, their impact in this region is therefore theorized to occur at long range. The crystal structures of double mutants, R34G/T119M and K35T/T119M, together with molecular dynamics simulations indicate that their strong destabilizing effect is initiated locally at the BC loop, increasing its flexibility in a mutation-dependent manner. Overall, the present findings help us to understand the sequence-dynamic-structural mechanistic details of TTR amyloid aggregation triggered by R34 and K35 variants and to link the degree of mutation-induced conformational flexibility to protein aggregation propensity.

Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.

A new layer of phosphoinositide-mediated allosteric regulation uncovered for SHIP2.

The Src homology 2 containing inositol 5-phosphatase 2 (SHIP2) is a large multidomain enzyme that catalyzes the dephosphorylation of the phospholipid phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3 ) to form PI(3,4)P2 . PI(3,4,5)P3 is a key lipid second messenger controlling the recruitment of signaling proteins to the plasma membrane, thereby regulating a plethora of cellular events, including proliferation, growth, apoptosis, and cytoskeletal rearrangements. SHIP2, alongside PI3K and PTEN, regulates PI(3,4,5)P3 levels at the plasma membrane and has been heavily implicated in serious diseases such as cancer and type 2 diabetes; however, many aspects of its regulation mechanism remain elusive. We recently reported an activating effect of the SHIP2 C2 domain and here we describe an additional layer of regulation via the pleckstrin homology-related (PHR) domain. We show a phosphoinositide-induced transition to a high activity state of the enzyme that increases phosphatase activity up to 10-15 fold. We further show that PI(3,4)P2 directly interacts with the PHR domain to trigger this allosteric activation. Modeling of the PHR-phosphatase-C2 region of SHIP2 on the membrane suggests no major inter-domain interactions with the PHR domain, but close contacts between the two linkers offer a possible path of allosteric communication. Together, our data show that the PHR domain acts as an allosteric module regulating the catalytic activity of SHIP2 in response to specific phosphoinositide levels in the cell membrane.

New Insights Into the Role of Autophagy in Liver Surgery in the Setting of Metabolic Syndrome and Related Diseases.

Visceral obesity is an important component of metabolic syndrome, a cluster of diseases that also includes diabetes and insulin resistance. A combination of these metabolic disorders damages liver function, which manifests as non-alcoholic fatty liver disease (NAFLD). NAFLD is a common cause of abnormal liver function, and numerous studies have established the enormously deleterious role of hepatic steatosis in ischemia-reperfusion (I/R) injury that inevitably occurs in both liver resection and transplantation. Thus, steatotic livers exhibit a higher frequency of post-surgical complications after hepatectomy, and using liver grafts from donors with NAFLD is associated with an increased risk of post-surgical morbidity and mortality in the recipient. Diabetes, another MetS-related metabolic disorder, also worsens hepatic I/R injury, and similar to NAFLD, diabetes is associated with a poor prognosis after liver surgery. Due to the large increase in the prevalence of MetS, NAFLD, and diabetes, their association is frequent in the population and therefore, in patients requiring liver resection and in potential liver graft donors. This scenario requires advancement in therapies to improve postoperative results in patients suffering from metabolic diseases and undergoing liver surgery; and in this sense, the bases for designing therapeutic strategies are in-depth knowledge about the molecular signaling pathways underlying the effects of MetS-related diseases and I/R injury on liver tissue. A common denominator in all these diseases is autophagy. In fact, in the context of obesity, autophagy is profoundly diminished in hepatocytes and alters mitochondrial functions in the liver. In insulin resistance conditions, there is a suppression of autophagy in the liver, which is associated with the accumulation of lipids, being this is a risk factor for NAFLD. Also, oxidative stress occurring in hepatic I/R injury promotes autophagy. The present review aims to shed some light on the role of autophagy in livers undergoing surgery and also suffering from metabolic diseases, which may lead to the discovery of effective therapeutic targets that could be translated from laboratory to clinical practice, to improve postoperative results of liver surgeries when performed in the presence of one or more metabolic diseases.

Initial Findings From the North American COVID-19 Myocardial Infarction Registry.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of ST-segment elevation myocardial infarction (STEMI) care, including timely access to primary percutaneous coronary intervention (PPCI). OBJECTIVES: The goal of the NACMI (North American COVID-19 and STEMI) registry is to describe demographic characteristics, management strategies, and outcomes of COVID-19 patients with STEMI. METHODS: A prospective, ongoing observational registry was created under the guidance of 3 cardiology societies. STEMI patients with confirmed COVID+ (group 1) or suspected (person under investigation [PUI]) (group 2) COVID-19 infection were included. A group of age- and sex-matched STEMI patients (matched to COVID+ patients in a 2:1 ratio) treated in the pre-COVID era (2015 to 2019) serves as the control group for comparison of treatment strategies and outcomes (group 3). The primary outcome was a composite of in-hospital death, stroke, recurrent myocardial infarction, or repeat unplanned revascularization. RESULTS: As of December 6, 2020, 1,185 patients were included in the NACMI registry (230 COVID+ patients, 495 PUIs, and 460 control patients). COVID+ patients were more likely to have minority ethnicity (Hispanic 23%, Black 24%) and had a higher prevalence of diabetes mellitus (46%) (all p < 0.001 relative to PUIs). COVID+ patients were more likely to present with cardiogenic shock (18%) but were less likely to receive invasive angiography (78%) (all p < 0.001 relative to control patients). Among COVID+ patients who received angiography, 71% received PPCI and 20% received medical therapy (both p < 0.001 relative to control patients). The primary outcome occurred in 36% of COVID+ patients, 13% of PUIs, and 5% of control patients (p < 0.001 relative to control patients). CONCLUSIONS: COVID+ patients with STEMI represent a high-risk group of patients with unique demographic and clinical characteristics. PPCI is feasible and remains the predominant reperfusion strategy, supporting current recommendations.

Psychosis induced by abuse of ayahuasca: a case report / Psicosis inducida por el abuso de la ayahuasca: un caso clínico

A B S T R A C T Ayahuasca is a psychotropic infusion prepared by boiling the bark of Amazonian plants and has many psychopharmacological effects not fully understood. Some of those effects are used as treatment for different diseases. However, the side effects of ayahuasca, including ayahuasca-induced psychosis, are an important issue. Here we report the case of a patient who had a psychotic episode after taking ayahuasca and who was successfully treated with antipsychotic medication. Given the current spread of ayahuasca consumption in developed societies, the present case highlights the need for better understanding and regulation of the social-legal condition of ayahuasca and the need for further research. Additionally, psycho-education seems advisable in order to create awareness of the potential risks of the use of ayahuasca.

RESUMEN La ayahuasca es una bebida psicotrópica preparada a través de la cocción de plantas de la cuenca amazónica que tiene muchos efectos psicofarmacológicos no del todo estudiados. Algunos de esos efectos son usados como tratamiento de diversas patologías. Sin embargo, existen efectos secundarios de la ayahuasca que deben ser tenidos en cuenta, entre ellos psicosis inducida por ayahuasca. Reportamos un caso de un paciente que, tras autoadministración de ayahuasca, presentó un episodio psicótico y que fue satisfactoriamente tratado con antipsicóticos. Dada el uso cada vez más frecuente de ayahuasca en las sociedades desarrolladas, el caso actual resalta las necesidades de entender, regular e investigar el uso de la ayahuasca. Además, crear conciencia de los potenciales riesgos del uso de ayahuasca a través de la psicoeducación debería ser implementado.

Effects of Gut Metabolites and Microbiota in Healthy and Marginal Livers Submitted to Surgery.

Microbiota is defined as the collection of microorganisms within the gastrointestinal ecosystem. These microbes are strongly implicated in the stimulation of immune responses. An unbalanced microbiota, termed dysbiosis, is related to the development of several liver diseases. The bidirectional relationship between the gut, its microbiota and the liver is referred to as the gut-liver axis. The translocation of bacterial products from the intestine to the liver induces inflammation in different cell types such as Kupffer cells, and a fibrotic response in hepatic stellate cells, resulting in deleterious effects on hepatocytes. Moreover, ischemia-reperfusion injury, a consequence of liver surgery, alters the microbiota profile, affecting inflammation, the immune response and even liver regeneration. Microbiota also seems to play an important role in post-operative outcomes (i.e., liver transplantation or liver resection). Nonetheless, studies to determine changes in the gut microbial populations produced during and after surgery, and affecting liver function and regeneration are scarce. In the present review we analyze and discuss the preclinical and clinical studies reported in the literature focused on the evaluation of alterations in microbiota and its products as well as their effects on post-operative outcomes in hepatic surgery.

Inactivation of the dimeric RappLS20 anti-repressor of the conjugation operon is mediated by peptide-induced tetramerization.

Quorum sensing allows bacterial cells to communicate through the release of soluble signaling molecules into the surrounding medium. It plays a pivotal role in controlling bacterial conjugation in Gram-positive cells, a process that has tremendous impact on health. Intracellular regulatory proteins of the RRNPP family are common targets of these signaling molecules. The RRNPP family of gene regulators bind signaling molecules at their C-terminal domain (CTD), but have highly divergent functionalities at their N-terminal effector domains (NTD). This divergence is also reflected in the functional states of the proteins, and is highly interesting from an evolutionary perspective. RappLS20 is an RRNPP encoded on the Bacillus subtilis plasmid pLS20. It relieves the gene repression effectuated by RcopLS20 in the absence of the mature pLS20 signaling peptide Phr*pLS20. We report here an in-depth structural study of apo and Phr*pLS20-bound states of RappLS20 at various levels of atomic detail. We show that apo-RappLS20 is dimeric and that Phr*pLS20-bound Rap forms NTD-mediated tetramers. In addition, we show that RappLS20 binds RcopLS20 directly in the absence of Phr*pLS20 and that addition of Phr*pLS20 releases RcopLS20 from RappLS20. This allows RcopLS20 to bind the promotor region of crucial conjugation genes blocking their expression.

Predictors and etiologies of 30-day readmissions in patients with non-ST-elevation acute coronary syndrome.

BACKGROUND: Despite improvements in acute care and survival after non-ST-elevation acute coronary syndrome (NSTE-ACS) hospitalization, early readmissions remain common, and have significant clinical and financial impact. OBJECTIVES: Determine the predictors and etiologies of 30-day readmissions in NSTE-ACS. METHOD: The study cohort was derived from the National Readmission Database 2014 identifying patients with a primary diagnosis of NSTE-ACS using ICD9 code. RESULTS: We identified a total of 300,269 patients admitted with NSTE-ACS; 13.4% were readmitted within 30-day. The most common cause of readmission was heart failure (HF) (15.6%), followed by a recurrent myocardial infarction (MI) (10%). Predictors of increased readmissions were age ≥ 75 years (OR: 1.34, 95% CI: 1.30-1.39), female gender (OR 1.12, 95% CI 1.09-1.16), a Charlson Comorbidity Index (CCI) >3 (OR 2.11, 95% CI: 2.04-2.18), ESRD (OR 2.01, 95% CI 1.89-2.14), CKD (OR: 1.58, 95% CI: 1.51-1.64), length of stay ≥5 days (OR: 1.51, 95% CI 1.46-1.56) and adverse events during the index admission such as AKI (OR:1.31, 95% CI: 1.25-1.36), major bleeding (OR:1.20, 95% CI: 1.12-1.24); whereas admission to a teaching hospital (OR 0.92, 95% CI 0.89-0.95) and PCI (OR 0.70, 95% CI 0.67-0.72) were associated with less likelihood of 30-day readmission. CONCLUSION: Readmission rate at 30-days is high among NSTE-ACS patients and the most common readmission etiologies are HF and recurrent MI. A CCI more than 3 and ESRD were the most significant predictors for readmission; patients undergoing PCI had less odds of readmission.