Uncommon Mechanisms Research Articles

Kidneys and commonly used medications: how to reduce a risk of acute kidney injury in everyday practice?

Medications are a common cause of acute kidney injury (AKI). There are various mechanisms in which medications can induce AKI, and better understanding of their pathophysiology can aid in clinical recognition, treatment, and prevention of this condition. Hemodynamic‑mediated AKI is often associated with drugs that alter renal perfusion and its autoregulation. Acute tubular injury is a result of direct renal tubular cell toxicity. Acute interstitial nephritis is a T‑cell-mediated immune hypersensitivity reaction to drugs leading to tubule‑interstitial inflammation and AKI. Crystalline nephropathy can be caused by crystallization of medications or by altered urinary chemistry caused by medications. Some medications can evoke AKI through uncommon mechanisms, such as glomerulonephritis and thrombotic microangiopathy. Notably, some medications may cause a phenomenon called "pseudo‑AKI," where serum creatinine is elevated without actual reduction in kidney function. Medications commonly used in clinical practice are reviewed with a focus on their mechanisms of injury, diagnosis, treatment, and prevention. Recognizing common medications associated with AKI is an important first step in reducing the risk of this condition. For each medication, understanding general and specific risk factors for AKI allows for early identification and timely discontinuation of offending agents. These measures can help mitigate the risk of AKI and promote renal recovery.

Non-canonical BRAF variants and rearrangements in hairy cell leukemia.

Hairy cell leukemia (HCL) is an uncommon mature B-cell malignancy characterized by a typical morphology, immunophenotype, and clinical profile. The vast majority of HCL patients harbor the canonical BRAF V600E mutation which has become a rationalized target of the subsequently deregulated RAS-RAF-MEK-MAPK signaling pathway in HCL patients who have relapsed or who are refractory to front-line therapy. However, several HCL patients with a classical phenotype display non-canonical BRAF mutations or rearrangements. These include sequence variants within alternative exons and an oncogenic fusion with the IGH gene. Care must be taken in the molecular diagnostic work-up of patients with typical HCL but without the BRAF V600E to include investigation of these uncommon mechanisms. Identification, functional characterization, and reporting of further such patients is likely to provide insights into the pathogenesis of HCL and enable rational selection of targeted inhibitors in such patients if required.

Review of the detection of metal ions using fluorescent probes

Metal ions, essential for numerous physiological functions of the human body require accurate monitoring in order to gain precise knowledge of the health status of people. As fluorescent probes advances, the level of metal ions can be measured with high selectivity and sensitivity. Allowing the homeostasis of numerous metal ions to be maintained easily. Fluorescent probes are a hot area of research, providing a prospective tool for the detection of metal ions and to provide critical statistics in maintaining the homeostasis of the human body. This article introduces several fluorescent probes on the detection of both essential and toxic metal ions. It gives a review about the recent development in the detection of metal ions using fluorescent probes. This article explains the mechanism of recognition of each fluorescent probe and summarizes the results obtained from experiments. Outlining the advantages and shortcomings of each fluorescent probe. It includes novel fluorescent probes based on uncommon mechanisms.

Pyrazinamide-resistant Tuberculosis Obscured From Common Targeted Molecular Diagnostics

Here, we describe a clinical case of pyrazinamide-resistant (PZA-R) tuberculosis (TB) reported as PZA-susceptible (PZA-S) by common molecular diagnostics. Phenotypic susceptibility testing (pDST) indicated PZA-R TB. Targeted Sanger sequencing reported wild-type PncA, indicating PZA-S TB. Whole Genome Sequencing (WGS) by PacBio and IonTorrent both detected deletion of a large portion of pncA, indicating PZA-R. Importantly, both WGS methods showed deletion of part of the primer region targeted by Sanger sequencing. Repeating Sanger sequencing from a culture in presence of PZA returned no result, revealing that 1) two minority susceptible subpopulations had vanished, 2) the PZA-R majority subpopulation harboring the pncA deletion could not be amplified by Sanger primers, and was thus obscured by amplification process. This case demonstrates how a small susceptible subpopulation can entirely obscure majority resistant populations from targeted molecular diagnostics and falsely imply homogenous susceptibility, leading to incorrect diagnosis. To our knowledge, this is the first report of a minority susceptible subpopulation masking a majority resistant population, causing targeted molecular diagnostics to call false susceptibility. The consequence of such genomic events is not limited to PZA. This phenomenon can impact molecular diagnostics’ sensitivity whenever the resistance-conferring mutation is not fully within primer-targeted regions. This can be caused by structural changes of genomic context with phenotypic consequence as we report here, or by uncommon mechanisms of resistance. Such false susceptibility calls promote suboptimal treatment and spread of strains that challenge targeted molecular diagnostics. This motivates development of molecular diagnostics unreliant on primer conservation, and impels frequent WGS surveillance for variants that evade prevailing molecular diagnostics.

Preprint Highlight: Kinesin-binding protein remodels the kinesin motor to prevent microtubule binding

Kinesin-binding protein (KIFBP) interacts with a subset of 8 of the 45 human kinesin family members and prevents their binding to microtubules, yet it was unclear how KIFBP selectively binds to this subset. By combining cryoelectron microscopy and cross-linking mass spectrometry, it was revealed that KIFBP uses a multivalent interaction to bind to at least two different kinesins, Kif18a and Kif15. This confirms a recent study of Kif15, extends the structural analysis to Kif18a, and uses molecular dynamics simulations to suggest KIFBP selectivity is determined by whether a kinesin loop prefers secondary structure or disorder. This work will be important to researchers studying molecular motors and structural biologists because it reveals uncommon mechanisms for molecular interaction.

Additional Thrombocytopenia after Cardiac Surgery with Extracorporeal Circulation: A Case Report

Thrombocytopenia occurs almost systematically in cardiac surgery under extracorporeal circulation (ECC). Its usual causes are multiple and recognized, but sometimes uncommon mechanisms are added, posing the problem of etiological diagnosis and the dilemma of optimal adequate management. The etiological diagnosis of thrombocytopenia after extracorporeal circulation requires a careful analysis of the chronology of the thrombocytopenia and also of the clinical and biological context. The authors report the observation of a case of additional thrombocytopenia after cardiovascular surgery under extracorporeal circulation, detailing the diagnostic modalities and describing the different usual clinical and biological characteristics of platelet changes induced by extracorporeal circulation.

Systematic Review of Mutations Associated with Isoniazid Resistance Points to Continuing Evolution and Subsequent Evasion of Molecular Detection, and Potential for Emergence of Multidrug Resistance in Clinical Strains of Mycobacterium tuberculosis.

Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, and fabG1, and the intergenic region oxyR'-ahpC were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INHr] and 3,502 INH susceptible [INHs]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of katG (katG315; n = 4,271), locus -15 of inhA (inhA-15; n = 787), and locus -8 of inhA (inhA-8; 106). However, the diagnostic value of inhA-8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INHr isolates lacking the first two mutations. I catalogued 45 new loci (29 katG, nine inhA, and seven ahpC) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates, no mechanism of resistance was detected, making them likely to escape molecular detection, and in the case of INH monoresistance, likely to convert to multidrug-resistant TB (MDR-TB). Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.

A rare case of pacemaker mediated tachycardia caused by intrinsic conduction search function of a dual chamber pacemaker

Pacemaker-mediated tachycardia (PMT) is a well-described cause of tachyarrhythmia in patients with dual chamber pacemakers (Barold, 1991 [1]). PMT is usually caused by common triggers including premature ventricular or atrial complexes (Alasti et al., 2018 [2]). However, PMT can also be triggered by other uncommon mechanisms. Intrinsic conduction search function is a feature available in some dual chamber permanent pacemakers that periodically looks for intrinsic conduction by gradually prolonging the preprogrammed AV delay in an attempt to minimize ventricular pacing (Calvi et al., 2017; Pakarinen and Toivonen, 2013 [3,4]). Here, we report a rare case of PMT triggered by intrinsic conduction search function.

Pilot-scale investigation on nutrient removal characteristics of mineral-rich aerobic granular sludge: Identification of uncommon mechanisms

This study investigated nutrient removal characteristics and the related pathways in aerobic granular reactors using three pilot-scale granular sequencing batch reactors (GSBRs) treating wastewaters of diverse carbon and nutrient strength. The GSBRs were operated with alternating (AN/O/AX/O_SBR and AN/O_SBR) and purely-aerobic (O_SBR) operation modes. Mineral-rich aerobic granules with hydroxyapatite (HAp) core were cultivated in all the three GSBRs. The highest nitrogen removal efficiency (75%) was achieved in AN/O/AX/O_SBR and O_SBR and the lowest (22%) in AN/O_SBR, establishing a quasi-linear relationship with organic loading rate (OLR). Phosphorus removal efficiencies of 55–63% were achieved in the GSBRs despite different influent PO4–P concentrations. Heterotrophic nitrification and biologically-induced phosphate precipitation (BIPP) became the dominant nutrient depletion pathways, contributing 61–84% and 39–96% to overall ammonium nitrogen and phosphorus removal, respectively. A direct relation was noted between heterotrophic nitrification efficiency (ηHeterotrophic nitrification) and nutrient availability, as nitrification efficiencies of 18 and 64% were observed for COD:Ninf of 5 and 20, respectively. Whereas, BIPP efficiency (ηBIPP) established inverse relation with (COD:P)inf and (Ca:P)inf and direct relation with phosphorus concentration beyond microbial growth requirement. Core heterotrophic nitrifiers and bio-calcifying species were identified as {Thauera and Flavobacterium} and {Flavobacterium, Acinetobacter, Pseudomonas, and Corynebacterium}, respectively. Ca–P crystallization was proposed to be via phosphate precipitation on calcite surfaces. Granulation mechanism was proposed as crystallization on bio-aggregates’ periphery and then crystal growth toward the core.

Uncommon Presentations of Idiosyncratic Drug-Induced Liver Injury

Idiosyncratic drug-induced liver injury (DILI) typically presents acutely with liver test abnormalities, sometimes with associated symptoms of abdominal pain, nausea, vomiting, jaundice, fevers, and rash. Histologic abnormalities in such cases of DILI typically range from lobular or portal hepatitis to hepatocyte necrosis. However, sometimes the drug-related liver injuries present with clinical and/or histological features atypical of garden variety DILI and they may be related to uncommon mechanisms of injury, histologic features, or clinical presentation. Multiple agents or classes of agents can result in uncommon forms of liver injury that are phenotypically unique and differ from commonly recognized acute DILI. These include unusual presentations of drugs commonly associated with typical acute DILI, such as drug-induced autoimmune hepatitis. Atypical DILI also includes histologically atypical manifestations of DILI, such as nodular regenerative hyperplasia, sinusoidal obstruction syndrome, granulomatous hepatitis, and steatosis/steatohepatitis. Atypical DILI encompasses recognized patterns of injury associated with specific agents or drug classes. These can manifest by atypical biochemical, clinical, and histopathological signatures. An understanding of these types of liver injury is important for the timely recognition of such atypical DILI.

P.105 Missed vertebral artery dissection: a case series

Background: Vertebral artery dissections are the second most common cause of posterior circulation stroke. Particularly in young people, they must be considered as causes of acute infarction, especially with a history of cervical trauma. Here, we present three cases of vertebral artery dissection that were initially not diagnosed as such. All were caused by uncommon mechanisms; one by self-inflicted neck manipulation, and one as a sequela of falling from a trampoline, and one from minor trauma to the head while standing. Methods: This is a series of three cases seen by the authors of posterior circulation stroke secondary to vertebral artery dissection caused by uncommon mechanisms. Results: N/A Conclusions: Vertebral artery dissection should be considered as a differential diagnosis in patients presenting with acute head and/or neck pain and any neurological findings in relation to acute neck trauma.

Disruption of protein function by pathogenic mutations: common and uncommon mechanisms 1.

Mutations in protein-coding regions underlie almost all Mendelian disorders, drive tumorigenesis, and contribute to susceptibility to common diseases. Despite the great diversity of diseases that are caused by coding mutations, the cellular processes that affect, and are affected by, pathogenic variants at the molecular level are fundamentally conserved. Experimental and computational approaches have revealed that a substantial fraction of disease mutations are not simple loss-of-function alleles. Rather, these pathogenic variants disrupt protein function in more subtle ways by tuning protein folding pathways, altering subcellular trafficking, interrupting signaling cascades, and rewiring highly connected interaction networks. Focusing mainly on Mendelian disorders, this review discusses the common mechanisms by which deleterious mutations disrupt protein function and how these disruptions can be exploited in the development of novel therapies.

Interactions between Giardia duodenalis Sm proteins and their association with spliceosomal snRNAs.

Giardia duodenalis is a parasite that colonises the intestines of humans and other vertebrates, causing diarrhoea and poor nutrient absorption. G. duodenalis is sometimes considered an early diverging eukaryote, and its genome exhibits simplified molecular machinery for many cellular processes, which makes it an interesting model to study. The spliceosome, one of the most complex molecular machines in the eukaryotic cell, is responsible for intron excision and exon splicing. Just over a decade ago, it was believed that the G. duodenalis genome did not contain introns or undergo splicing. Research now shows that this speculation was incorrect and that uncommon mechanisms, such as trans-splicing from different genes, occur. In silico studies of the parasite suggest the possibility of a simplified spliceosome and spliceosomal small nuclear RNA (snRNA) candidates; however, none of these components have been identified in vivo. Here, we developed a strategy to study the in vivo expression, interactions and localisation of these spliceosome components in G. duodenalis. Haemagglutinin (HA)-tagged SmB and SmD3 proteins, which form part of the spliceosome core, were overexpressed in the parasite. Immunoprecipitation with anti-HA revealed that the SmD3 protein is associated with the proteins SmB, SmD1, SmD2, SmE and SmF in vivo. In addition, the U1, U2 and U4 snRNA candidates reported previously were found in the protein complex, suggesting that these molecules are spliceosomal snRNAs of G. duodenalis and they contained a 2,2,7-trimethylguanosine modification at their 5' end. Our data indicate that the actively expressed spliceosome in G. duodenalis is similar to that of highly evolved protists and higher animals.

Oral contact dermatitis spicy chewing gum

Background The oral contact dermatitis caused by cinnamon was initially described by Drake in 1976, in a patient with stomatitis caused by toothpaste containing cinnamon. It is an uncommon mechanisms due to the oral mucosa s own mechanisms such as saliva that acts as a diluent and buffer, and a low number of antigen presenting cells present. Cases with multiple forms of presentation are described in the literature, the actual incidence is unknown due to the multitude of compounds used mainly in dental prosthetics. The oral contact dermatitis is an uncommon condition caused by various agents. We present the case of a patient with a recurrent glossitis and pain in the oral mucosa, caused by a reaction to the consumption of cinnamon-flavoured chewing gums.

Natural antimicrobial peptides against Mycobacterium tuberculosis.

TB, caused by Mycobacterium tuberculosis, is one the leading infectious diseases worldwide. There is an urgent need to discover new drugs with unique structures and uncommon mechanisms of action to treat M. tuberculosis and combat antimycobacterial resistance. Naturally occurring compounds contain a wide diversity of chemical structures, displaying a wide range of in vitro potency towards M. tuberculosis. A number of recent studies have shown that natural antimycobacterial peptides can disrupt the function of the mycobacterial cell wall through different modes of action and thereafter interact with intracellular targets, including nucleic acids, enzymes and even organelles. More importantly, the probability of antimycobacterial resistance is low. This review presents several natural antimicrobial peptides isolated from different organism sources, including bacteria, fungi, plants and animals. In addition, the molecular features of these molecules are the subject of much attention. Such peptides have common traits among their chemical features, which may be correlated with their biological activities; hence, different parts of the molecular structures can be modified in order to increase penetration into the target cells. This review also summarizes the available information on the properties of antimycobacterial peptides associated with their biological activities.

Buprenorphine-related deaths: unusual forensic situations

The success of high-dose buprenorphine (HDB) as substitution therapy for major opioid dependence is related to its partial agonist effect on opioid receptors, which in theory makes it very safe to use. However, numerous deaths directly attributable to buprenorphine have been described in the literature. These deaths are generally related to misuse of HDB with intravenous administration and/or concomitant use of benzodiazepines, and they usually occur in patients on HDB substitution therapy for opioid dependence. We present three deaths attributed to HDB which arose from uncommon mechanisms and led to unusual forensic situations. The first death was that of a patient admitted to hospital after simultaneous prescription of HDB, clonazepam, oxazepam, and cyamemazine. The second death followed forcible administration of a very low dose of HDB to a patient with post-hepatitis C cirrhosis and heart failure. The third death was subsequent to an HDB overdose, probably with suicidal intent, in a young woman who had not been prescribed the drug as opiate substitute. Such deaths raise the question of the mechanisms involved and draw attention to the resulting unusual forensic situations.

CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors

The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in approximately 70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5'-untranslated region (5'-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5'-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.

Parts drying vs. drying of coatings: Understanding the respective nuances requires knowledge of both common and uncommon mechanisms

Parts drying vs. drying of coatings: Understanding the respective nuances requires knowledge of both common and uncommon mechanisms

Chemical Ligation—An Unusual Paradigm in Protease Inhibition

Some protease inhibitors use uncommon mechanisms to restrain the activity of their target enzymes. A recent paper in Chemistry and Biology (Lu et al., 2006) demonstrates a curious mechanism of inhibition of a caspase, relying on principles of native peptide ligation.

Apoptosis in cerebellar granule neurons is associated with reduced interaction between CREB-binding protein and NF-kappaB.

Cerebellar granule neurons undergo apoptosis when switched from medium containing depolarizing levels of potassium (high K+ medium, HK) to medium containing low K+ (LK). NF-kappaB, a ubiquitously expressed transcription factor, is involved in the survival-promoting effects of HK. However, neither the expression nor the intracellular localization of the five NF-kappaB proteins, or of IkappaB-alpha and IkappaB-beta, are altered in neurons primed to undergo apoptosis by LK, suggesting that uncommon mechanisms regulate NF-kappaB activity in granule neurons. In this study, we show that p65 interacts with the transcriptional co-activator, CREB-binding protein (CBP), in healthy neurons. The decrease in NF-kappaB transcriptional activity caused by LK treatment is accompanied by a reduction in the interaction between p65 and CBP, an alteration that is accompanied by hyperphosporylation of CBP. LK-induced CBP hyperphosphorylation can be mimicked by inhibitors of protein phosphatase (PP) 2A and PP2A-like phosphatases such as okadaic acid and cantharidin, which also causes a reduction in p65-CBP association. In addition, treatment with these inhibitors induces cell death. Treatment with high concentrations of the broad-spectrum kinase inhibitor staurosporine prevents LK-mediated CBP hyperphosphorylation and inhibits cell death. In vitro kinase assays using glutathione-S-transferase (GST)-CBP fusion proteins map the LK-regulated site of phosphorylation to a region spanning residues 1662-1840 of CBP. Our results are consistent with possibility that LK-induced apoptosis is triggered by CBP hyperphosphorylation, an alteration that causes the dissociation of CBP and NF-kappaB.