Inhibition Of Protein Synthesis Research Articles

Suppression of eEF2 phosphorylation alleviates synaptic failure and cognitive deficits in mouse models of Down syndrome.

Cognitive impairment is a core feature of Down syndrome (DS), and the underlying neurobiological mechanisms remain unclear. Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. We used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology. We found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS-associated pathophysiology including de novo protein synthesis deficiency, synaptic morphological defects, long-term synaptic plasticity failure, and cognitive impairments. Our data suggested that eEF2K signaling dysregulation mediates DS-associated synaptic and cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain. Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models. Suppression of eEF2K improves synaptic dysregulation in DS models. Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.

Are Infants and Children at Risk of Adverse Health Effects from Dietary Deoxynivalenol Exposure? An Integrative Review.

Deoxynivalenol (DON) is a foodborne mycotoxin produced by Fusarium molds that commonly infect cereal grains. It is a potent protein synthesis inhibitor that can significantly impact humans' gastrointestinal, immune, and nervous systems and can alter the microbiome landscape. Low-dose, chronic exposure to DON has been found to stimulate the immune system, inhibit protein synthesis, and cause appetite suppression, potentially leading to growth failure in children. At higher doses, DON has been shown to cause immune suppression, nausea, vomiting, abdominal pain, headache, diarrhea, gastroenteritis, the malabsorption of nutrients, intestinal hemorrhaging, dizziness, and fever. A provisional maximum tolerable daily intake (PMTDI) limit of 1 µg/kg/body weight has been established to protect humans, underscoring the potential health risks associated with DON intake. While the adverse effects of dietary DON exposure have been established, healthcare communities have not adequately investigated or addressed this threat to child health, possibly due to the assumption that current regulatory exposure limits protect the public appropriately. This integrative review investigated whether current dietary DON exposure rates in infants and children regularly exceed PMTDI limits, placing them at risk of negative health effects. On a global scale, the routine contamination of cereal grains, bakery products, pasta, and human milk with DON could lead to intake levels above PMTDI limits. Furthermore, evidence suggests that other food commodities, such as soy, coffee, tea, dried spices, nuts, certain seed oils, animal milk, and various water reservoirs, can be intermittently contaminated, further amplifying the scope of the issue. Better mitigation strategies and global measures are needed to safeguard vulnerable youth from this harmful toxicant.

Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane

The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 Å resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 Å resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.

Actinomycin D and bortezomib disrupt protein homeostasis in Wilms tumor.

Wilms tumor is the most common kidney cancer in children, and diffusely anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell cycle progression. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Furthermore, the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment by inducing apoptosis both in vitro and in vivo. Lastly, we show that increased levels of proteasome components are associated with anaplastic histology and with worse prognosis in non-anaplastic Wilms tumor. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.

Phytochemistry and Biological Activities of Agrostemma Genus-A Review.

The family Caryophyllaceae comprises more than 2600 species spread widely across all the continents. Their economic importance is mainly as ornamentals (carnation) and as weeds in agriculture. Some species have been used traditionally (and some are still) in herbal medicine or as emulsifiers in food processing. These applications are based on the high content of triterpenoid saponins. Typical for this family are also ribosome-inactivating proteins (RIPs), which are potentially highly toxic. Agrostemma githago L. (common corncockle) was historically considered a serious toxicological hazard owing to cereal grain contamination by its seeds. Notwithstanding, it was also recommended as a drug by various herbalists. In this review, the literature was searched in the PubMed, Google Scholar, and Scopus databases for papers focused on the chemical composition and bioactivity of the two accepted species of the Agrostemma genus. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and MetaAnalysis (PRISMA) guidelines. Current research reports the cytotoxicity against neoplastic cells; the protection against oxidative stress; the suppression of Leishmania major culture growth; the inhibition of protein synthesis; and the antiviral, anti-angiogenic, and antihypercholesterolemic activities of common corncockle. The future prospects of using A. githago saponins as adjuvants in drug formulations and enhancing the cytotoxicity of RIPs are also discussed.

Analytical Profile of Antiviral Drugs-Remdesivir, Simeprevir, and Sofosbuvir: A Review

Remdesivir (RDV) is an antiviral drug and a phosphonamidite prodrug designed to have activity against a broad spectrum of viruses, act as a nucleoside analogue, and inhibit the RNA-dependent RNA polymerase [RDRP] of coronaviruses, including SARS-CoV-2, whereas Simeprevir (SMV) and Sofosbuvir (SFS) are direct-acting antiviral drugs approved for the treatment of chronic Hepatitis C virus (HCV) infection. Reports show that the structure and replication mechanism of HCV and SARS-COV-2 are comparable. Hepatitis C virus protease inhibitors include Simeprevir. Because it is an NS3/4A protease inhibitor, it inhibits protein synthesis, which stops viruses from maturing. A nucleotide analogue inhibitor called sofosbuvir selectively blocks the RNA-dependent RNA polymerase of HCV NS5B (non-structural protein 5B). This review article gathers and discusses the range of analytical techniques—UV, HPLC, and hyphenated procedures like LC-MS—that are available in the literature for the determination of RDV, SMV, and SFS. This review article can be effectively explored to conduct future analytical investigation for the estimation of the selected drugs in pharmaceutical and biological samples.

Exploring mechanisms of mupirocin resistance and hyper-resistance.

Mupirocin is a broad-spectrum antibiotic that acts predominantly against Gram-positive bacteria. It is produced by Pseudomonas fluorescens NCIMB 10586 and has been clinically used to treat primary and secondary skin infections and to eradicate nasal colonisation of methicillin-resistant Staphylococcus aureus strains. Mupirocin inhibits protein synthesis by blocking the active site of isoleucyl-tRNA synthetase (IleRS), which prevents the enzyme from binding isoleucine and ATP for Ile-tRNAIle synthesis. Two types of IleRS are found in bacteria - while IleRS1 is susceptible to mupirocin inhibition, IleRS2 provides resistance to cells. These two types belong to distinct evolutionary clades which likely emerged from an early gene duplication in bacteria. Resistance in IleRS2 is based on the loss of interactions that govern mupirocin binding to IleRS1, such as hydrogen bonding to the carboxylate moiety of mupirocin. IleRS2 enzymes with Ki in the millimolar range have recently been discovered. These hyper-resistant IleRS2 variants surprisingly have a non-canonical version of the catalytic motif, which serves as a signature motif of class I aminoacyl-tRNA synthetases to which IleRS belongs. The non-canonical motif, in which the 1st and 3rd positions are swapped, is key for hyper-resistance and can be accommodated without abolishing enzyme activity in IleRS2 but not in IleRS1. Clinical use of mupirocin led to the emergence of resistance in S. aureus. Low-level resistance arises by mutations of the housekeeping IleRS1, while high-level resistance develops by the acquisition of the resistant IleRS2 on a plasmid. There is no evidence that hyper-resistant variants have been found in clinical isolates.

Inhibition of Protein Synthesis Attenuates Formation of Traumatic Memory and Normalizes Fear-Induced c-Fos Expression in a Mouse Model of Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a debilitating psychosomatic condition characterized by impairment of brain fear circuits and persistence of exceptionally strong associative memories resistant to extinction. In this study, we investigated the neural and behavioral consequences of inhibiting protein synthesis, a process known to suppress the formation of conventional aversive memories, in an established PTSD animal model based on contextual fear conditioning in mice. Control animals were subjected to the conventional fear conditioning task. Utilizing c-Fos neural activity mapping, we found that the retrieval of PTSD and normal aversive memories produced activation of an overlapping set of brain structures. However, several specific areas, such as the infralimbic cortex and the paraventricular thalamic nucleus, showed an increase in the PTSD group compared to the normal aversive memory group. Administration of protein synthesis inhibitor before PTSD induction disrupted the formation of traumatic memories, resulting in behavior that matched the behavior of mice with usual aversive memory. Concomitant with this behavioral shift was a normalization of brain c-Fos activation pattern matching the one observed in usual fear memory. Our findings demonstrate that inhibiting protein synthesis during traumatic experiences significantly impairs the development of PTSD in a mouse model. These data provide insights into the neural underpinnings of protein synthesis-dependent traumatic memory formation and open prospects for the development of new therapeutic strategies for PTSD prevention.

Auranofin and reactive oxygen species inhibit protein synthesis and regulate the level of the PLK1 protein in Ewing sarcoma cells.

Novel therapeutic approaches are needed for the treatment of Ewing sarcoma tumors. We previously identified that Ewing sarcoma cell lines are sensitive to drugs that inhibit protein translation. However, translational and therapeutic approaches to inhibit protein synthesis in tumors are limited. In this work, we identified that reactive oxygen species, which are generated by a wide range of chemotherapy and other drugs, inhibit protein synthesis and reduce the level of critical proteins that support tumorigenesis in Ewing sarcoma cells. In particular, we identified that both hydrogen peroxide and auranofin, an inhibitor of thioredoxin reductase and regulator of oxidative stress and reactive oxygen species, activate the repressor of protein translation 4E-BP1 and reduce the levels of the oncogenic proteins RRM2 and PLK1 in Ewing and other sarcoma cell lines. These results provide novel insight into the mechanism of how ROS-inducing drugs target cancer cells via inhibition of protein translation and identify a mechanistic link between ROS and the DNA replication (RRM2) and cell cycle regulatory (PLK1) pathways.

In Vitro Antibiofilm Activity of Fosfomycin Alone and in Combination with Other Antibiotics against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa.

Due to its rapid resistance development and ability to form biofilms, treatment of Pseudomonas aeruginosa infections is becoming more complicated by the day. Drug combinations may help reduce both resistance and biofilm formation. Using the microtiter plate assay, we investigated the in vitro inhibition of biofilm formation and the disruption of preformed biofilms in multidrug-resistant and extensively drug-resistant clinical isolates of P. aeruginosa in the presence of peak plasma levels of eight antipseudomonal antibiotics alone and in combination with fosfomycin: ceftazidime, piperacillin/tazobactam, cefepime, imipenem, gentamicin, amikacin, ciprofloxacin and colistin. Combination therapy was significantly superior to monotherapy in its inhibition of biofilm formation. The highest inhibition rates were observed for combinations with colistin, cefepime and ceftazidime. Our results support fosfomycin combination therapy as an enhanced prophylactic option. Moreover, combinations with β-lactam antibiotics and colistin demonstrated a more potent inhibition effect on biofilm formation than protein synthesis inhibitors.

Increased PHLPP1 expression through ERK-4E-BP1 signaling axis drives nicotine induced oxidative stress related damage of cardiomyocytes

Nicotine, a key constituent of tobacco/electronic cigarettes causes cardiovascular injury and mortality. Nicotine is known to induce oxidative stress and mitochondrial dysfunction in cardiomyocytes leading to cell death. However, the underlying mechanisms remain unclear. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) is a member of metal-dependent protein phosphatase (PPM) family and is known to dephosphorylate several AGC family kinases and thereby regulate a diverse set of cellular functions including cell growth, survival, and death. Our lab has previously demonstrated that PHLPP1 removal reduced cardiomyocyte death and cardiac dysfunction following injury. Here, we present a novel finding that nicotine exposure significantly increased PHLPP1 protein expression in the adolescent rodent heart. Building upon our in vivo finding, we determined the mechanism of PHLPP1 expression in cardiomyocytes. Nicotine significantly increased PHLPP1 protein expression without altering PHLPP2 in cardiomyocytes. In cardiomyocytes, nicotine significantly increased NADPH oxidase 4 (NOX4), which coincided with increased reactive oxygen species (ROS) and increased cardiomyocyte apoptosis which were dependent on PHLPP1 expression. PHLPP1 expression was both necessary and sufficient for nicotine induced mitochondrial dysfunction. Mechanistically, nicotine activated extracellular signal-regulated protein kinases (ERK1/2) and subsequent eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) to increase PHLPP1 protein expression. Inhibition of protein synthesis with cycloheximide (CHX) and 4EGI-1 abolished nicotine induced PHLPP1 protein expression. Moreover, inhibition of ERK1/2 activity by U0126 significantly blocked nicotine induced PHLPP1 expression. Overall, this study reveals a novel mechanism by which nicotine regulates PHLPP1 expression through ERK-4E-BP1 signaling axis to drive cardiomyocyte injury.

Potential applications of antofine and its synthetic derivatives in cancer therapy: structural and molecular insights.

Cancer is a major global health challenge, being the second leading cause of morbidity and mortality after cardiovascular disease. The growing economic burden and profound psychosocial impact on patients and their families make it urgent to find innovative and effective anticancer solutions. For this reason, interest in using natural compounds to develop new cancer treatments has grown. In this respect, antofine, an alkaloid class found in Apocynaceae, Lauraceae, and Moraceae family plants, exhibits promising biological properties, including anti-inflammatory, anticancer, antiviral, and antifungal activities. Several molecular mechanisms have been identified underlying antofine anti-cancerous effects, including the inhibition of nuclear factor κB (NF-κB) and AKT/mTOR signaling pathways, epigenetic inhibition of protein synthesis, ribosomal targeting, induction of apoptosis, inhibition of DNA synthesis, and cell cycle arrest. This study discusses the molecular structure, sources, photochemistry, and anticancer properties of antofine in relation to its structure-activity relationship and molecular targets. Then, examine in vitro and in vivo studies and analyze the mechanisms of action underpinning antofine efficacy against cancer cells. This review also discusses multidrug resistance in human cancer and the potential of antofine in this context. Safety and toxicity concerns are also addressed as well as current challenges in antofine research, including the need for clinical trials and bioavailability optimization. This review aims to provide comprehensive information for more effective natural compound-based cancer treatments.

Direct and acute effects of advanced glycation end products on proteostasis in isolated mouse skeletal muscle.

Advanced glycation end products (AGEs) have been implicated in several skeletal muscle dysfunctions. However, whether the adverse effects of AGEs on skeletal muscle are because of their direct action on the skeletal muscle tissue is unclear. Therefore, this study aimed to investigate the direct and acute effects of AGEs on skeletal muscle using an isolated mouse skeletal muscle to eliminate several confounders derived from other organs. The results showed that the incubation of isolated mouse skeletal muscle with AGEs (1 mg/mL) for 2-6 h suppressed protein synthesis and the mechanistic target of rapamycin signaling pathway. Furthermore, AGEs showed potential inhibitory effects on protein degradation pathways, including autophagy and the ubiquitin-proteasome system. Additionally, AGEs stimulated endoplasmic reticulum (ER) stress by modulating the activating transcription factor 6, PKR-like ER kinase, C/EBP homologous protein, and altered inflammatory cytokine expression. AGEs also stimulated receptor for AGEs (RAGE)-associated signaling molecules, including mitogen-activated protein kinases. These findings suggest that AGEs have direct and acute effect on skeletal muscle and disturb proteostasis by modulating intracellular pathways such as RAGE signaling, protein synthesis, proteolysis, ER stress, and inflammatory cytokines.

A Review on Toxicity and Degradation of Ethidium Bromide (EtBr)

Ethidium bromide (EtBr) serves as an interpolating agent utilized for its fluorescent properties in gel electrophoresis, aiding in the detection of various DNA fragments. However, its usage has been associated with DNA mutations, inhibition of mitochondrial protein synthesis and other alterations, particularly at high concentrations. Due to its remarkable stability in the environment and propensity to degrade into mutagenic compounds, especially when exposed to bleaching agents, there are significant concerns regarding its widespread use. Given the potential toxic and mutagenic effects of EtBr and the possibility of its entry into the food chain, it becomes crucial to monitor its concentration at emission sources across different ecosystems, including aquatic, terrestrial, and plant environments. Improper disposal of EtBr poses substantial risks, including the induction of mutations and cancer. Various disposal methods have been explored, such as phytoremediation and employing bacteria capable of degrading this chemical. Proper management of EtBr disposal is paramount to mitigate its harmful impact on the environment and living organisms.

One-Trial Appetitive Learning Tasks for Drug Targeting.

One-trial appetitive learning developed from one-trial passive avoidance learning as a standard test of retrograde amnesia. It consists of one learning trial followed by a retention test, in which physiological manipulations are presented. As in passive avoidance learning, food- or waterdeprived rats or mice finding food or water inside an enclosure are vulnerable to the retrograde amnesia produced by electroconvulsive shock treatment or the injection of various drugs. In one-trial taste or odor learning conducted in rats, birds, snails, bees, and fruit flies, there is an association between a food item or odorant and contextual stimuli or the unconditioned stimulus of Pavlovian conditioning. The odor-related task in bees was sensitive to protein synthesis inhibition as well as cholinergic receptor blockade, both analogous to results found on the passive avoidance response in rodents, while the task in fruit flies was sensitive to genetic modifications and aging, as seen in the passive avoidance response of genetically modified and aged rodents. These results provide converging evidence of interspecies similarities underlying the neurochemical basis of learning.

Bacterial ubiquitin ligases hijack the host deubiquitinase OTUB1 to inhibit MTORC1 signaling and promote autophagy

ABSTRACT Many bacterial pathogens have evolved effective strategies to interfere with the ubiquitination network to evade clearance by the innate immune system. Here, we report that OTUB1, one of the most abundant deubiquitinases (DUBs) in mammalian cells, is subjected to both canonical and noncanonical ubiquitination during Legionella pneumophila infection. The effectors SidC and SdcA catalyze OTUB1 ubiquitination at multiple lysine residues, resulting in its association with a Legionella-containing vacuole. Lysine ubiquitination by SidC and SdcA promotes interactions between OTUB1 and DEPTOR, an inhibitor of the MTORC1 pathway, thus suppressing MTORC1 signaling. The inhibition of MTORC1 leads to suppression of host protein synthesis and promotion of host macroautophagy/autophagy during L. pneumophila infection. In addition, members of the SidE family effectors (SidEs) induce phosphoribosyl (PR)-linked ubiquitination of OTUB1 at Ser16 and Ser18 and block its DUB activity. The levels of the lysine and serine ubiquitination of OTUB1 are further regulated by effectors that function to antagonize the activities of SidC, SdcA and SidEs, including Lem27, DupA, DupB, SidJ and SdjA. Our study reveals an effectors-mediated complicated mechanism in regulating the activity of a host DUB. Abbreviations: BafA1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; DUB: deubiquitinase; Dot/Icm: defective for organelle trafficking/intracellular multiplication; DEPTOR: DEP domain containing MTOR interacting protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; L. pneumophila: Legionella pneumophila; LCV: L egionella-containing vacuole; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MTORC1: mechanistic target of rapamycin kinase complex 1; OTUB1: OTU deubiquitinase, ubiquitin aldehyde binding 1; PR-Ub: phosphoribosyl (PR)-linked ubiquitin; PTM: posttranslational modification; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SidEs: SidE family effectors; Ub: ubiquitin.

A high content imaging assay for identification of specific inhibitors of native Plasmodium liver stage protein synthesis.

Plasmodium parasite resistance to antimalarial drugs is a serious threat to public health in malaria-endemic areas. Compounds that target core cellular processes like translation are highly desirable, as they should be multistage actives, capable of killing parasites in the liver and blood, regardless of molecular target or mechanism. Assays that can identify these compounds are thus needed. Recently, specific quantification of native Plasmodium berghei liver stage protein synthesis as well as that of the hepatoma cells supporting parasite growth, was achieved via automated confocal feedback microscopy of the o-propargyl puromycin (OPP)-labeled nascent proteome, but this imaging modality is limited in throughput. Here, we developed and validated a miniaturized high content imaging (HCI) version of the OPP assay that increases throughput, before deploying this approach to screen the Pathogen Box. We identified only two hits, both of which are parasite-specific quinoline-4-carboxamides, and analogues of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of the P. berghei liver stage OPP HCI assay for specific, single-well quantification of Plasmodium and human protein synthesis in the native cellular context, allowing identification of selective Plasmodium translation inhibitors with the highest potential for multistage activity.

Does Adjunctive Clindamycin Have a Role in Staphylococcus aureus Bacteremia? A Protocol for the Adjunctive Treatment Domain of the Staphylococcus aureus Network Adaptive Platform (SNAP) Randomized Controlled Trial.

The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and it is recommended in many guidelines, but this is based on limited evidence. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leukocidins (eg, Panton-Valentine leukocidin, toxic shock syndrome toxin 1, exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multicenter adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality rates. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either 5 days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard-of-care antibiotics. Most participants with SAB (within 72 hours of index blood culture and with no contraindications) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol, and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and Panton-Valentine leukocidin-positive isolate.

The translational inhibitor and amnestic agent emetine also suppresses ongoing hippocampal neural activity similarly to other blockers of protein synthesis.

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long-term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra-hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression.

Paraproteinemic neuropathies

Paraproteinemic polyneuropathies (PPN) occur generally infrequently and arise from diseases, associated with formation and accumulation of a pathological protein, commonly known as paraprotein, which is typically an immunoglobulin or its free light chain. Such diseases include the following: monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenström’s macroglobulinemia, AL amyloidosis, POEMS syndrome, etc. Diagnosis of PPN is challenging due to nonspecific, indistinct or atypical clinical manifestation, and it is necessary to apply specialized laboratory methods, including immunochemical analysis of blood and urine. Moreover, medications can cause symptoms of polyneuropathy themselves. Thus, it is important to suspect the first symptoms of the disease in time, determine the mechanism of damage to nerve fibers, carry out differential diagnosis and initiate therapy targeting the suppression of pathological protein synthesis.