Translational impacts of enzymes that modify ribosomal RNA around the peptidyl transferase centre.

Large ribosomal RNAs (rRNAs) are modified heavily post-transcriptionally in functionally important regions but, paradoxically, individual knockouts (KOs) of the modification enzymes have minimal impact on Escherichia coli growth. Furthermore, we recently constructed a strain with combined KOs of five modification enzymes (RluC, RlmKL, RlmN, RlmM and RluE) of the 'critical region' of the peptidyl transferase centre (PTC) in 23S rRNA that exhibited only a minor growth defect at 37°C (although major at 20°C). However, our combined KO of modification enzymes RluC and RlmE (not RluE) resulted in conditional lethality (at 20°C). Although the growth rates for both multiple-KO strains were characterized, the molecular explanations for such deficits remain unclear. Here, we pinpoint biochemical defects in these strains. In vitro fast kinetics at 20°C and 37°C with ribosomes purified from both strains revealed, counterintuitively, the slowing of translocation, not peptide bond formation or peptidyl release. Elongation rates of protein synthesis in vivo, as judged by the kinetics of ß-galactosidase induction, were also slowed. For the five-KO strain, the biggest deficit at 37°C was in 70S ribosome assembly, as judged by a dominant 50S peak in ribosome sucrose gradient profiles at 5 mM Mg2+. Reconstitution of this 50S subunit from purified five-KO rRNA and ribosomal proteins supported a direct role in ribosome biogenesis of the PTC region modifications per se, rather than of the modification enzymes. These results clarify the importance and roles of the enigmatic rRNA modifications.

Plasticity and conditional essentiality of modification enzymes for domain V of Escherichia coli 23S ribosomal RNA.

Escherichia coli rRNAs are post-transcriptionally modified at 36 positions but their modification enzymes are dispensable individually for growth, bringing into question their significance. However, a major growth defect was reported for deletion of the RlmE enzyme, which abolished a 2'O methylation near the peptidyl transferase center (PTC) of the 23S rRNA. Additionally, an adjacent 80-nt "critical region" around the PTC had to be modified to yield significant peptidyl transferase activity in vitro. Surprisingly, we discovered that an absence of just two rRNA modification enzymes is conditionally lethal (at 20°C): RlmE and RluC. At a permissive temperature (37°C), this double knockout was shown to abolish four modifications and be defective in ribosome assembly, though not more so than the RlmE single knockout. However, the double knockout exhibited an even lower rate of tripeptide synthesis than did the single knockout, suggesting an even more defective ribosomal translocation. A combination knockout of the five critical-region-modifying enzymes RluC, RlmKL, RlmN, RlmM, and RluE (not RlmE), which synthesize five of the seven critical-region modifications and 14 rRNA and tRNA modifications altogether, was viable (minor growth defect at 37°C, major at 20°C). This was surprising based on prior in vitro studies. This five-knockout combination had minimal effects on ribosome assembly and frameshifting at 37°C, but greater effects on ribosome assembly and in vitro peptidyl transferase activity at cooler temperatures. These results establish the conditional essentiality of bacterial rRNA modification enzymes and also reveal unexpected plasticity of modification of the PTC region in vivo.

Lumbar radiculopathy associated radicular schwannoma: A case report and literature review.

Lumbar radiculopathy is a clinical condition defined by symptoms of pain, weakness, numbness, or tingling due to lumbar nerve root compression in levels L1-L4. Typically, it is characterized by a narrowing near the nerve root possibly caused by stenosis, bone osteophytes, disc herniation, and similar conditions. Reports of lumbar radiculopathy brought about by the presence of a radicular schwannoma are exceedingly rare. In this paper, we discuss the case of a 67-year-old female patient, presenting with complaints of low back pain, numbness, and antalgic gait for the past eight months. Her physical examination revealed motor and sensor neurological deficits affecting the left lower limb. The electromyoneurography evaluation showed neurogenic atrophy of the left radicular area, while the MRI revealed the presence of a giant, radicular schwannoma at L4-L5 level. This case report aims to underscore the clinical course and management of lumbar radiculopathy caused by a rare L4-L5 radicular schwannoma. Our patient had no significant risk factors or previous spinal pathology.

Corrigendum to 'Anterior interosseous nerve lesion and distal myoclonus revealing a Parsonage Turner Syndrome associated with Hashimoto's thyroiditis' [Radiology Case Reports 16 (2021) 3176-3181].

[This corrects the article DOI: 10.1016/j.radcr.2021.07.067.].

Anterior interosseous nerve lession and distal myoclonus revealing a parsonage turner syndrome associated with hashimoto thyroiditys.

Parsonage-Turner Syndrome (PTS), also known as brachial neuritis or neuralgic amyotrophy, is a rare disorder affecting 2 to 3 individuals per 100,000 each year. Abrupt onset shoulder pain, followed by motor weakness, paresthesia and hypoesthesia, is usually reported, lasting several months with variable recovery. The etiology of the disease may be idiopathic or triggered by an underlying autoimmune disease in genetically susceptible individuals. Our report addresses a unique case of Parsonage-Turner Syndrome in a patient suffering from concurrent Hashimoto Thyroiditis. A previously healthy A 22 year-old female was referred to the Department of Neurology after complaints of sudden-onset motor weakness in her left upper limb. On physical examination, the patient could not make an "Ok sign" with her thumb and distal phalanx or form a complete fist, revealing weakness within the anterior interosseous branch of the median nerve. Further testing with electromyography demonstrated muscular atrophy within the arm's anterior compartment, forearm, and triceps brachii of the posterior compartment. Additional imaging and physical examination were unremarkable, confirming our diagnosis of PTS. Furthermore, lab reports revealed elevated levels of anti-thyroglobulin and anti-thyroid peroxidase antibodies and our patient was concurrently diagnosed with Hashimoto's thyroiditis. This case aims to highlight the rare co-occurrence of Hashimoto's thyroiditis with Parsonage-Turner Syndrome in an otherwise healthy patient. A 2014 study published by Nugent et al. had also shed light on brachial neuritis in a patient suffering from autoimmune connective tissue disease, and through this case study, we hope to add to the growing literature regarding the correlation between PTS and autoimmune diseases. Symptoms of PTS can easily be misdiagnosed given its similarity to other peripheral neuropathies, and careful assessment and thorough understanding of the disease is required to successfully distinguish it from other neurological pathologies.

A Rare Case of Amyotrophic Lateral Sclerosis With Asymmetrical Phrenic Nerve Lesion Presenting With Acute Respiratory Failure as an Initial Manifestation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually, death. Respiratory failure is the leading cause of death in ALS. It is common in the advanced stages of the disease. However, acute respiratory failure is a presenting symptom in only a small number of patients, such as in our case. Here, we present the case of a 54-year-old woman with ALS presenting with respiratory failure due to unilateral diaphragm paralysis as the first manifestation. Although rare, respiratory muscle function failure can be the first symptom of motor neuron disease. Therefore, a motor neuron disease such as ALS, which leads to respiratory muscle weakness and diaphragm paralysis, should be considered in cases of unexplained acute respiratory failure.

Generalized Hypotonia Revealing Spinal Muscular Atrophy Type 2: The First Case Reported From the Dominican Republic and a Review of the Literature.

Spinal muscular atrophy (SMA) is a rare, inherited autosomal recessive disease. Histopathological shreds of evidence related to the condition have suggested degenerative changes at the level of the spinal cord and brain stem. Deletions or mutations in the survival motor neuron 1 (SMN1) gene are the underlying cause of this disease. It is characterized by hypotonia, muscular atrophy, areflexia, fasciculations, and flaccid paralysis. It is further classified into five variants, depending upon the patient's age and clinical features. In this report, we present a rare case of SMA type 2 in a one-year-old female infant who presented with generalized hypotonia and axial body weakness. Besides clinical evaluation, her genetic analysis confirmed that she had a deletion of one of the SMN1 genes. Hence, the diagnosis of SMA type 2 was confirmed. Our study aims to emphasize that clinicians must consider this rare entity whenever a patient presents with the signs and symptoms mentioned above. As the most common cause of death in this disease is respiratory depression, an early diagnosis would prevent complications and help in the parents' genetic counseling.

The Importance of Imaging Studies in the Assessment of Response to Immunotherapy in Lung Cancer. / Importancia de la imagen en la valoración de la respuesta al tratamiento con inmunoterapia del cáncer de pulmón.

Immunotherapy (particularly immune checkpoint inhibitors) in the treatment of patients with lung cancer has aroused great interest in recent years, revolutionized the management of patients with locally advanced/metastatic disease, and given hope to both patients and treating physicians. These drugs, in combination or in monotherapy, have become the standard treatment for many patients with lung cancer, and their use is expected to increase significantly in the near future. In this article, we will review the growing importance of imaging techniques in the evaluation of therapeutic response to immunotherapy in lung cancer patients, with emphasis on the new specific radiological criteria on response to immunotherapy, atypical radiological responses (pseudoprogresion, dissociative responses, hyperprogresion), and the main radiological manifestations of adverse events associated with immunotherapy (sarcoid reactions, pulmonary toxicities, etc.). Pulmonologists must be familiar not only with atypical radiological responses to immunotherapy and their prognostic implications, but also with their effects and the new radiological criteria of response to assess treatment response. In this study, we will address key concepts such as "pseudoprogresion", "paradoxical response", "hyperprogresion", or "unconfirmed progression", and their significance in the management of patients with lung cancer treated with immunotherapy.

Social (dis)order and psychosocial trauma: Look earlier, look outside, and look beyond the persons.

The most common and extreme suffering humankind has ever experienced comes from interpersonal and collective intentional violence. In dealing with traumatic outcomes psychology must overcome the mutually constitutive interaction between the (dis)order of a given macro or microsocial context and the mental health of the persons living in it. Social psychologist Ignacio Martín-Baró addressed in a preferential way the study of civil war in El Salvador in terms of intergroup hostility and polarization. He also approached the aftereffects of war by means of a theoretical core assumption: that traumatic experience rooted in collective violence (a human-made stressor) should be understood bearing in mind its social roots (pretraumatic situation), its personal and collective harm (collective injury), and the destruction of the social fabric. These are the arguments for his conceptualization of psychosocial trauma. Twenty-six years after the violent murder of Martín-Baró, along with 5 Jesuit priests, a housekeeper, and his teenage daughter, the current authors have adopted his general framework. Based on new theoretical insights and supporting data, the authors propose an expanded 4-dimension theoretical argument on psychosocial trauma: (a) pretrauma conditions based on social distress, (b) shared network of fear leading to breakdown of core social assumptions, (c) the outgroup as a target of negative emotions, and (d) destruction of family ties and community networks.

Survival of human circulating antigen-induced plasma cells is supported by plasma cell-niche cytokines and T follicular helper lymphocytes.

Human circulating Ag-induced plasma cells (PCs) contain a high proportion of cycling cells. This study reveals that these PCs spontaneously proliferate in culture during 72 h, as determined by BrdU-uptake detection. Transcriptome analysis indicates that, in comparison with tonsil and bone marrow (BM) PCs, these PCs distinctively upregulate genes involved in cell division. Blood PC proliferation occurs simultaneously with increasing apoptosis rates, and is associated with PC survival. In addition, the proliferating activity of these PCs is enhanced by the addition of cytokines present in PC survival niches. Moreover, blood Ag-induced, but not BM, PCs exhibit the expression of molecules involved in the interaction between memory B cells and T follicular helper (Tfh) cells. In fact, purified circulating and tonsil Tfh cells increased IgG secretion by blood Ag-induced, but not by BM, PCs. This effect is exerted by augmenting blood PC survival through a mechanism partly dependent on cell contact. These results strongly suggest that the proliferating capacity of circulating Ag-induced PCs contributes to their competitive migration to survival niches, either to long-living PC niches or to temporal niches present in reactive lymphoid organs and inflamed tissues, structures where Tfh cells appear to participate.

STAT-3 activation by differential cytokines is critical for human in vivo-generated plasma cell survival and Ig secretion.

Maturation and survival of plasma cells (PCs) depends on extrinsic factors provided in specialized niches. In addition, B lymphocyte differentiation into PCs requires the activation of the JAK-STAT-3 pathway. However, whether STAT-3 is needed only during the transition of B lymphocytes to PC, or it is also involved in the survival and function of PCs at different stages of maturation, has not been unequivocally clarified. This study analyzes the effect of IL-10, IL-21, and IL-6 on human in vivo-generated PCs isolated from secondary lymphoid organs, blood (circulating, recently Ag-induced PCs), and bone marrow. PCs from these different organs show specific profiles of receptors for, and responsiveness to, these cytokines required for their survival and sustained Ab secretion. However, IL-10, IL-21, and IL-6 commonly induce STAT-3 phosphorylation in the three PC subsets, and all of their effects are exerted strictly through the STAT-3 activation. The inhibition or nonactivation of this pathway in the three PC populations impairs not only the effect of STAT-3-activating cytokines, but also the action of other cytokines important at the PC level, including a proliferation-induced ligand, BAFF, insulin-like growth factor 1, vascular endothelial growth factor, and stromal cell-derived factor-1α. These results indicate that STAT-3 activation is critical for human PCs throughout their maturation.

End-to-side portacaval shunt: a simplified technique.

A simplified technique of end-to-side portacaval shunt in the rat is described, consisting in using a microsuture with a looped end. By using this technique, combined with two-step portal vein venotomy, the portal vein and caval vein can be brought closer together in a single movement, with no need for a knot at the start of the shunt. As a result, this modified technique makes it easier and reduces the time required to perform the shunt, without any rise in associated mortality.