El doctor Mauricio Castaño Ramírez, presidente Junta Directiva de la Asociación Colombiana de Psiquiatría, reiteró que es un problema que se viene presentando desde el 2023, y podría afectar a niños, adolescentes y otros pacientes con conductas agresivas

El doctor Jorge Ramírez Molina, miembro de La Fundación Liga Central Contra la Epilepsia, explicó la problemática y la respuesta del gobierno

En 6AM de Caracol Radio estuvo el gobernador de Cundinamarca, Jorge Emilio Rey, para hablar sobre el lamentable caso de Alexis Delgado, el niño de 2 años que fue encontrado con signos de tortura en Cundinamarca.

It’s the premiere of The Debaters’ 19th season and this is one for the bever-ages! Dave Hemstad and Lisa Baker are in Newfoundland trying to burst each other’s bubble when they decide if Coke is superior to Pepsi. Then, are family doctors overrated? Clifton Cremo and Martha Chaves checkup on these medical professionals.

Your best bets also include the relaunch of the ARTcade arcade.

From holes on Mars to a spun-around moon and a flipped reflection, space science involves looking at things from all different angles.

O Censo da Educação Superior aponta que a procura por cursos de psicologia disparou no Brasil. Entre 2010 e 2021, o aumento de matrículas nessa graduação foi de 112,4%.

Numerous iron-sulfur (Fe-S) proteins with diverse functions are present in the matrix and respiratory chain complexes of mitochondria. Although [4Fe-4S] clusters are the most common type of Fe-S cluster in mitochondria, the molecular mechanism of [4Fe-4S] cluster assembly and insertion into target proteins by the mitochondrial iron-sulfur cluster (ISC) maturation system is not well-understood. Here we report a detailed characterization of two late-acting Fe-S cluster-carrier proteins from Arabidopsis thaliana, NFU4 and NFU5. Yeast two-hybrid and bimolecular fluorescence complementation studies demonstrated interaction of both the NFU4 and NFU5 proteins with the ISCA class of Fe-S carrier proteins. Recombinant NFU4 and NFU5 were purified as apo-proteins after expression in Escherichia coli. In vitro Fe-S cluster reconstitution led to the insertion of one [4Fe-4S]2+ cluster per homodimer as determined by UV-visible absorption/CD, resonance Raman and EPR spectroscopy, and analytical studies. Cluster transfer reactions, monitored by UV-visible absorption and CD spectroscopy, showed that a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer is effective in transferring [4Fe-4S]2+ clusters to both NFU4 and NFU5 with negligible back reaction. In addition, [4Fe-4S]2+ cluster-bound ISCA1a/2, NFU4, and NFU5 were all found to be effective [4Fe-4S]2+ cluster donors for maturation of the mitochondrial apo-aconitase 2 as assessed by enzyme activity measurements. The results demonstrate rapid, unidirectional, and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

Joris J. Benschop
Jul 1, 2007; 6:1198-1214
Research

Jesper V. Olsen
Jun 1, 2004; 3:608-614
Technology

Phospholipase Cε (PLCε) is activated downstream of G protein–coupled receptors and receptor tyrosine kinases through direct interactions with small GTPases, including Rap1A and Ras. Although Ras has been reported to allosterically activate the lipase, it is not known whether Rap1A has the same ability or what its molecular mechanism might be. Rap1A activates PLCε in response to the stimulation of β-adrenergic receptors, translocating the complex to the perinuclear membrane. Because the C-terminal Ras association (RA2) domain of PLCε was proposed to the primary binding site for Rap1A, we first confirmed using purified proteins that the RA2 domain is indeed essential for activation by Rap1A. However, we also showed that the PLCε pleckstrin homology (PH) domain and first two EF hands (EF1/2) are required for Rap1A activation and identified hydrophobic residues on the surface of the RA2 domain that are also necessary. Small-angle X-ray scattering showed that Rap1A binding induces and stabilizes discrete conformational states in PLCε variants that can be activated by the GTPase. These data, together with the recent structure of a catalytically active fragment of PLCε, provide the first evidence that Rap1A, and by extension Ras, allosterically activate the lipase by promoting and stabilizing interactions between the RA2 domain and the PLCε core.

Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization.

α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.

Yi-Han Lin
Dec 1, 2020; 19:2030-2046
Research

Sylwia Struk
Dec 28, 2020; 0:RA119.001766v1-mcp.RA119.001766
Research

Diana Samodova
Dec 1, 2020; 19:2139-2156
Technological Innovation and Resources

Aloïs Dusuel
Dec 9, 2020; 0:jlr.RA120000704v1-jlr.RA120000704
Research Articles

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.

Trypsin is the protease of choice in bottom-up proteomics. However, its application can be limited by the amino acid composition of target proteins and the pH of the digestion solution. In this study we characterize ProAlanase, a protease from the fungus Aspergillus niger that cleaves primarily on the C-terminal side of proline and alanine residues. ProAlanase achieves high proteolytic activity and specificity when digestion is carried out at acidic pH (1.5) for relatively short (2 h) time periods. To elucidate the potential of ProAlanase in proteomics applications, we conducted a series of investigations comprising comparative multi-enzymatic profiling of a human cell line proteome, histone PTM analysis, ancient bone protein identification, phosphosite mapping and de novo sequencing of a proline-rich protein and disulfide bond mapping in mAb. The results demonstrate that ProAlanase is highly suitable for proteomics analysis of the arginine- and lysine-rich histones, enabling high sequence coverage of multiple histone family members. It also facilitates an efficient digestion of bone collagen thanks to the cleavage at the C terminus of hydroxyproline which is highly prevalent in collagen. This allows to identify complementary proteins in ProAlanase- and trypsin-digested ancient bone samples, as well as to increase sequence coverage of noncollagenous proteins. Moreover, digestion with ProAlanase improves protein sequence coverage and phosphosite localization for the proline-rich protein Notch3 intracellular domain (N3ICD). Furthermore, we achieve a nearly complete coverage of N3ICD protein by de novo sequencing using the combination of ProAlanase and tryptic peptides. Finally, we demonstrate that ProAlanase is efficient in disulfide bond mapping, showing high coverage of disulfide-containing regions in a nonreduced mAb.

Sepsis-induced acute kidney injury (S-AKI) is the most common complication in hospitalized and critically ill patients, highlighted by a rapid decline of kidney function occurring a few hours or days after sepsis onset. Systemic inflammation elicited by microbial infections is believed to lead to kidney damage under immunocompromised conditions. However, although AKI has been recognized as a disease with long-term sequelae, partly because of the associated higher risk of chronic kidney disease (CKD), the understanding of kidney pathophysiology at the molecular level and the global view of dynamic regulations in situ after S-AKI, including the transition to CKD, remains limited. Existing studies of S-AKI mainly focus on deriving sepsis biomarkers from body fluids. In the present study, we constructed a mid-severity septic murine model using cecal ligation and puncture (CLP), and examined the temporal changes to the kidney proteome and phosphoproteome at day 2 and day 7 after CLP surgery, corresponding to S-AKI and the transition to CKD, respectively, by employing an ultrafast and economical filter-based sample processing method combined with the label-free quantitation approach. Collectively, we identified 2,119 proteins and 2950 phosphosites through multi-proteomics analyses. Among them, we identified an array of highly promising candidate marker proteins indicative of disease onset and progression accompanied by immunoblot validations, and further denoted the pathways that are specifically responsive to S-AKI and its transition to CKD, which include regulation of cell metabolism regulation, oxidative stress, and energy consumption in the diseased kidneys. Our data can serve as an enriched resource for the identification of mechanisms and biomarkers for sepsis-induced kidney diseases.

The F-box protein MORE AXILLARY GROWTH 2 (MAX2) is a central component in the signaling cascade of strigolactones (SLs) as well as of the smoke derived karrikins (KARs) and the so far unknown endogenous KAI2 ligand (KL). The two groups of molecules are involved in overlapping and unique developmental processes, and signal-specific outcomes are attributed to perception by the paralogous α/β-hydrolases DWARF14 (D14) for SL and KARRIKIN INSENSITIVE 2/ HYPOSENSITIVE TO LIGHT (KAI2/HTL) for KAR/KL. Additionally, depending on which receptor is activated, specific members of the SUPPRESSOR OF MAX2 1 (SMAX1) – LIKE (SMXL) family control KAR/KL and SL responses. As proteins that function in the same signal transduction pathway often occur in large protein complexes, we aimed at discovering new players of the MAX2, D14 and KAI2 protein network by tandem affinity purification using Arabidopsis cell cultures. When using MAX2 as a bait, various proteins were co-purified among which general components of the Skp1-Cullin-F-box complex and members of the CONSTITUTIVE PHOTOMORPHOGENIC 9 signalosome. Here, we report the identification of a novel interactor of MAX2, a type 5 serine/threonine protein phosphatase, designated PHYTOCHROME-ASSOCIATED PROTEIN PHOSPHATASE 5 (PAPP5). Quantitative affinity purification pointed at PAPP5 as being more present in KAI2 rather than D14 protein complexes. In agreement, mutant analysis suggests that PAPP5 modulates KAR/KL-dependent seed germination in suboptimal conditions and seedling development. Additionally, a phosphopeptide enrichment experiment revealed that PAPP5 might dephosphorylate MAX2 in vivo independently of the synthetic strigolactone analog, rac-GR24. Together, by analyzing the protein complexes to which MAX2, D14 and KAI2 belong, we revealed a new MAX2 interactor, PAPP5, that might act through dephosphorylation of MAX2 to control mainly KAR/KL- related phenotypes and, hence, provide another link with the light pathway.

In eukaryotic DNA replication, DNA polymerase ε (Polε) is responsible for leading strand synthesis, whereas DNA polymerases α and δ synthesize the lagging strand. The human Polε (hPolε) holoenzyme is comprised of the catalytic p261 subunit and the noncatalytic p59, p17, and p12 small subunits. So far, the contribution of the noncatalytic subunits to hPolε function is not well understood. Using pre-steady-state kinetic methods, we established a minimal kinetic mechanism for DNA polymerization and editing catalyzed by the hPolε holoenzyme. Compared with the 140-kDa N-terminal catalytic fragment of p261 (p261N), which we kinetically characterized in our earlier studies, the presence of the p261 C-terminal domain (p261C) and the three small subunits increased the DNA binding affinity and the base substitution fidelity. Although the small subunits enhanced correct nucleotide incorporation efficiency, there was a wide range of rate constants when incorporating a correct nucleotide over a single-base mismatch. Surprisingly, the 3'→5' exonuclease activity of the hPolε holoenzyme was significantly slower than that of p261N when editing both matched and mismatched DNA substrates. This suggests that the presence of p261C and the three small subunits regulates the 3'→5' exonuclease activity of the hPolε holoenzyme. Together, the 3'→5' exonuclease activity and the variable mismatch extension activity modulate the overall fidelity of the hPolε holoenzyme by up to 3 orders of magnitude. Thus, the presence of p261C and the three noncatalytic subunits optimizes the dual enzymatic activities of the catalytic p261 subunit and makes the hPolε holoenzyme an efficient and faithful replicative DNA polymerase.

Unpleasant emotions like sadness and anger can feel overwhelming, but recent research suggests they can trigger behaviors that lead to something better

Danilo De Gregorio
Feb 3, 2021; 41:891-900
Symposium and Mini-Symposium

This is video of the new hermit crab species Pylopaguropsis mollymullerae taken by Ellen Muller at dive site 'Something Special', southern Caribbean. Credit: Rafael Lemaitre and Ellen Muller

Finding antivirals to reduce coronavirus disease 2019 (COVID-19) morbidity and mortality has been challenging. Large randomized clinical trials that aimed to test four repurposed drugs, hydroxychloroquine, lopinavir-ritonavir, interferon beta 1a, and remdesivir, have shown that these compounds lack an impact on the COVID-19 course. Although the phase III COVID-19 vaccine trial results are encouraging, the search for effective COVID-19 therapeutics should not stop. Recently, plitidepsin (aplidin) demonstrated highly effective preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its antiviral activity was 27.5-fold more potent than that of remdesivir (K. M. White, R. Rosales, S. Yildiz, T. Kehrer, et al., Science, 2021, https://science.sciencemag.org/content/early/2021/01/22/science.abf4058). Plitidepsin, a repurposed drug developed for the treatment of multiple myeloma, targets the host translation cofactor eEF1A. Plitidepsin has shown efficacy in animal models and phase I/II human trials. Although plitidepsin is administered intravenously and its toxicity profile remains to be fully characterized, this compound may be a promising alternative COVID-19 therapeutic.

Effective June 1, outdoor gatherings of more than 25 people will be permitted at Delaware’s state forests, subject to compliance with the Division of Public Health's "Guidance on Outdoor Gatherings." While the state's ban on short-term rentals will be lifted on June 1, camping at Blackbird State Forest and Redden State Forest, as well as the Redden Lodge, will be closed to the public until further notice. Plans are underway to implement a new online, fee-based reservation system expected to be operational later this summer. There is no fixed date on the launch of the new system, which will include the addition of two new camp sites each at both Blackbird and Redden. The new system will also handle advance bookings for the popular and historic Redden Lodge. Users can make camping and lodge reservations for future dates, receive electronic confirmations, and make payments and receive refunds via credit card.

Redden State Forest has closed its campsites and many trails still remain inaccessible following the heavy snowstorm on January 3 that dumped up to 14.5 inches in nearby Ellendale. With a potential for additional snowfall of 3 inches or more and wind gusts to 35 m.p.h., Delaware Forest Service staff are currently assessing impacts from the storm and working to mitigate hazardous trees in and around high-use areas and clear trails and access roads. The Redden Education Trail (photo) on the Headquarters Tract is littered with downed trees and covered with heavy snow. Visitors should be aware of the potential for falling tree limbs on all areas of the state forest. The historic Redden Lodge, also on the Headquarters Tract, remains accessible for now and is open for previously scheduled events and bookings.

The Delaware Forest Service has launched a new online portal for reserving campsites and other venues on state forestland. Applicants can make reservations for primitive tent camping, rent the Lodge at Redden State Forest and reserve the pavilions. Additional campsites at Blackbird State Forest and Redden State Forest are also now open to the public.

1. Battered Reliance Shares To Make A Comeback? This Analyst Sees 29% Upside Ahead  Benzinga India
2. Reliance Industries shares may see 30% upside according to CLSA, who cites this key trigger  CNBCTV18
3. RIL shares are down 20% from record high, oversold on charts; here's what analysts say  Business Today
4. Six of India’s top 10 most valuable firms shed Rs 1.55 lakh crore in market value  Moneycontrol
5. Reliance Industries Share Price Today on 13-11-2024: Reliance Industries share price are down by -0.63%, Nifty down by -0.8%  Mint

[DA] It is a national embarrassment that the inability of the City of Johannesburg to supply water to its residents, business and public sector offices, has now led to the shutdown of operations at the Constitutional Court, on Constitution Hill in Braamfontein.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

Turning around and backing up out of pools found in tree hollows may help mating Charles Darwin’s frogs find a safe place to lay their eggs while fending off competitive males

Evidence from an archaeological site in Ethiopia suggests ancient humans adapted their diet during a dry spell after the Toba volcano eruption 74,000 years ago

Title: Too Many Unnecessary Thyroid Biopsies Performed, Experts Say
Category: Health News
Created: 8/26/2013 4:36:00 PM
Last Editorial Review: 8/27/2013 12:00:00 AM

Title: Fast Action Can Prevent Sepsis Death: CDC
Category: Health News
Created: 8/23/2016 12:00:00 AM
Last Editorial Review: 8/24/2016 12:00:00 AM

Title: AHA News: Preeclampsia May Double a Woman's Chances for Later Heart Failure
Category: Health News
Created: 8/24/2020 12:00:00 AM
Last Editorial Review: 8/25/2020 12:00:00 AM

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Pepsi at Dubai Fashion Forward 2016

Let's say you have a PlayStation, either because it was already in your closet or because you decided to spend ten thousand dollars for one after the virus arrived. How can you get the most out of the console in 2020?

Routine blood tests may identify laboring women at risk for preeclampsia, a leading cause of maternal death as per research presented at the ANESTHESIOLOGY (Regd) 2024 annual meeting.

Autologous hematopoietic stem cell transplantation or aHSCT, often used to treat medlinkblood cancers/medlink, was also demonstrated to be safe and

Sepsis is a life-threatening condition that happens when the body's response to infections causes adverse effects on the tissues and organs. Dr. Finn E.