Narrative review of radiofrequency ablation applications in peripheral nerves.

BACKGROUND AND OBJECTIVE: Chronic pain is a pervasive and often-complex condition that can severely detract from an individual's quality of life. When conservative measures of treatment fail, radiofrequency ablation (RFA) has emerged as a potential alternative. This narrative review subsequently explores recent advancements in the use of RFA on peripheral nerves as a means of attenuating chronic pain and providing relief to patients. METHODS: A comprehensive literature search was conducted on the PubMed database using the keywords "Radiofrequency", "Ablation", "Pain", "Chronic", "Peripheral", and "Nerve". The search focused on articles published between 2018 to 2023 that discussed an application of RFA in a peripheral nerve. In total, 30 articles were selected for inclusion in this review. KEY CONTENT AND FINDINGS: Results indicate the successful use of RFA in an array of chronic pain conditions and anatomical sites. Applications include the treatment of trigeminal neuralgia (TN), occipital neuralgia, cluster headaches, knee pain derived from osteoarthritis (OA), hip pain, abdominal pain associated with pancreatic cancer, and several other chronic pain conditions. CONCLUSIONS: These findings suggest RFA is a viable option for reducing patient's pain scores and improving quality of life. Future research should build off extensive case reports/series with double-blind, randomized controlled studies to further investigate anecdotal successes.

Applications of Artificial Intelligence in Pain Medicine.

PURPOSE OF REVIEW: This review explores the current applications of artificial intelligence (AI) in the field of pain medicine with a focus on machine learning. RECENT FINDINGS: Utilizing a literature search conducted through the PubMed database, several current trends were identified, including the use of AI as a tool for diagnostics, predicting pain progression, predicting treatment response, and performance of therapy and pain management. Results of these studies show promise for the improvement of patient outcomes. Current gaps in the research and subsequent directions for future study involve AI in optimizing and improving nerve stimulation and more thoroughly predicting patients' responses to treatment.

Long-term ice phenology records spanning up to 578 years for 78 lakes around the Northern Hemisphere.

In recent decades, lakes have experienced unprecedented ice loss with widespread ramifications for winter ecological processes. The rapid loss of ice, resurgence of winter biology, and proliferation of remote sensing technologies, presents a unique opportunity to integrate disciplines to further understand the broad spatial and temporal patterns in ice loss and its consequences. Here, we summarize ice phenology records for 78 lakes in 12 countries across North America, Europe, and Asia to permit the inclusion and harmonization of in situ ice phenology observations in future interdisciplinary studies. These ice records represent some of the longest climate observations directly collected by people. We highlight the importance of applying the same definition of ice-on and ice-off within a lake across the time-series, regardless of how the ice is observed, to broaden our understanding of ice loss across vast spatial and temporal scales.

Natural Genetic Variation in Yeast Reveals That NEDD4 Is a Conserved Modifier of Mutant Polyglutamine Aggregation.

A feature common to late onset proteinopathic disorders is an accumulation of toxic protein conformers and aggregates in affected tissues. In the search for potential drug targets, many studies used high-throughput screens to find genes that modify the cytotoxicity of misfolded proteins. A complement to this approach is to focus on strategies that use protein aggregation as a phenotypic readout to identify pathways that control aggregate formation and maintenance. Here we use natural variation between strains of budding yeast to genetically map loci that influence the aggregation of a polyglutamine-containing protein derived from a mutant form of huntingtin, the causative agent in Huntington disease. Linkage analysis of progeny derived from a cross between wild and laboratory yeast strains revealed two polymorphic loci that modify polyglutamine aggregation. One locus contains the gene RFU1 which modifies ubiquitination states of misfolded proteins targeted by the E3-ubiquitin ligase complex Rsp5 Activity of the Rsp5 complex, and the mammalian homolog NEDD4, are critical in maintaining protein homeostasis in response to proteomic stress. Our analysis also showed linkage of the aggregation phenotype to a distinct locus containing a gene encoding the Rsp5-interacting Bul2 protein. Allele-swap experiments validated the impact of both RFU1 and BUL2 on huntingtin aggregation. Furthermore, we found that the nematode Caenorhabditis elegans' ortholog of Rsp5, wwp-1, also negatively regulates polyglutamine aggregation. Knockdown of the NEDD4 in human cells likewise altered polyglutamine aggregation. Taken together, these results implicate conserved processes involving the ubiquitin regulation network that modify protein aggregation and provide novel therapeutic targets for polyglutamine and other protein folding diseases.

Genomic Analysis of ATP Efflux in Saccharomyces cerevisiae.

Adenosine triphosphate (ATP) plays an important role as a primary molecule for the transfer of chemical energy to drive biological processes. ATP also functions as an extracellular signaling molecule in a diverse array of eukaryotic taxa in a conserved process known as purinergic signaling. Given the important roles of extracellular ATP in cell signaling, we sought to comprehensively elucidate the pathways and mechanisms governing ATP efflux from eukaryotic cells. Here, we present results of a genomic analysis of ATP efflux from Saccharomyces cerevisiae by measuring extracellular ATP levels in cultures of 4609 deletion mutants. This screen revealed key cellular processes that regulate extracellular ATP levels, including mitochondrial translation and vesicle sorting in the late endosome, indicating that ATP production and transport through vesicles are required for efflux. We also observed evidence for altered ATP efflux in strains deleted for genes involved in amino acid signaling, and mitochondrial retrograde signaling. Based on these results, we propose a model in which the retrograde signaling pathway potentiates amino acid signaling to promote mitochondrial respiration. This study advances our understanding of the mechanism of ATP secretion in eukaryotes and implicates TOR complex 1 (TORC1) and nutrient signaling pathways in the regulation of ATP efflux. These results will facilitate analysis of ATP efflux mechanisms in higher eukaryotes.

Multiplexed, Scheduled, High-Resolution Parallel Reaction Monitoring on a Full Scan QqTOF Instrument with Integrated Data-Dependent and Targeted Mass Spectrometric Workflows.

Recent advances in commercial mass spectrometers with higher resolving power and faster scanning capabilities have expanded their functionality beyond traditional data-dependent acquisition (DDA) to targeted proteomics with higher precision and multiplexing. Using an orthogonal quadrupole time-of flight (QqTOF) LC-MS system, we investigated the feasibility of implementing large-scale targeted quantitative assays using scheduled, high resolution multiple reaction monitoring (sMRM-HR), also referred to as parallel reaction monitoring (sPRM). We assessed the selectivity and reproducibility of PRM, also referred to as parallel reaction monitoring, by measuring standard peptide concentration curves and system suitability assays. By evaluating up to 500 peptides in a single assay, the robustness and accuracy of PRM assays were compared to traditional SRM workflows on triple quadrupole instruments. The high resolution and high mass accuracy of the full scan MS/MS spectra resulted in sufficient selectivity to monitor 6-10 MS/MS fragment ions per target precursor, providing flexibility in postacquisition assay refinement and optimization. The general applicability of the sPRM workflow was assessed in complex biological samples by first targeting 532 peptide precursor ions in a yeast lysate, and then 466 peptide precursors from a previously generated candidate list of differentially expressed proteins in whole cell lysates from E. coli. Lastly, we found that sPRM assays could be rapidly and efficiently developed in Skyline from DDA libraries when acquired on the same QqTOF platform, greatly facilitating their successful implementation. These results establish a robust sPRM workflow on a QqTOF platform to rapidly transition from discovery analysis to highly multiplexed, targeted peptide quantitation.

Congenital analbuminaemia: molecular defects and biochemical and clinical aspects.

BACKGROUND: DNA and mRNA sequencing of the coding regions of the human albumin gene (ALB) and of its intron/exon junctions has revealed twenty-one different molecular defects causing congenital analbuminaemia (CAA). SCOPE OF REVIEW: To describe the mutations in molecular terms and to present the current knowledge about the most important biochemical and clinical effects of CAA. MAJOR CONCLUSIONS: CAA is rare, but its frequency seems to be significantly higher in restricted and minimally admixed populations. The condition affects especially the lipid metabolism but apart from a possible increased risk for atherosclerotic complications, it is generally associated with mild clinical symptoms in adults. By contrast, several reports indicate that analbuminaemic individuals may be at risk during the perinatal and childhood periods, in which they seem to show increased morbidity and mortality. The twenty-one causative defects include seven nonsense mutations, seven changes affecting splicing, five frame-shift/deletions, one frame-shift/insertion and one mutation in the start codon. These results indicate that the trait is an allelic heterogeneous disorder caused by homozygous (nineteen cases) or compound heterozygous (single case) inheritance of defects. Most mutations are unique, but one, named Kayseri, is responsible for about half of the known cases. GENERAL SIGNIFICANCE: Study of the defects in the ALB resulting in CAA allows the identification of "hot spot" regions and contributes to understanding the molecular mechanism underlying the trait. Such studies could also give molecular information about different aspects of ALB regulation and shed light on the regulatory mechanisms involved in the synthesis of the protein. This article is part of a Special Issue entitled Serum Albumin.

Human serum albumin isoforms: genetic and molecular aspects and functional consequences.

BACKGROUND: At present, 67 different genetic variants of human serum albumin and proalbumin have been molecularly characterized at the protein and/or gene level. SCOPE OF REVIEW: This review summarizes present knowledge about genetic and molecular aspects, functional consequences and potential uses of the variants. MAJOR CONCLUSIONS: The frequency of bisalbuminemia in the general population is probably about 1:1000, but it can be much higher in isolated populations. Mutations are often due to hypermutable CpG dinucleotides, and in addition to single-amino acid substitutions, glycosylated variants and C-terminally modified alloalbumins have been found. Some mutants show altered stability in vivo and/or in vitro. High-affinity binding of Ni(++) and Cu(++) is blocked, or almost so, by amino acid changes at the N-terminus. In contrast, substitution of Leu90 and Arg242 leads to strong binding of triiodothyronine and l-thyroxine, respectively, resulting in two clinically important syndromes. Variants often have modified plasma half-lives and organ uptakes when studied in mice. GENERAL SIGNIFICANCE: Because alloalbumins do not seem to be associated with disease, they can be used as markers of migration and provide a model for study of neutral molecular evolution. They can also give valuable molecular information about albumins binding sites, antioxidant and enzymatic properties, as well as stability. Mutants with increased affinity for endogenous or exogenous ligands could be therapeutically relevant as antidotes, both for in vivo and extracorporeal treatment. Variants with modified biodistribution could be used for drug targeting. In most cases, the desired function can be further elaborated by producing site-directed, recombinant mutants. This article is part of a Special Issue entitled Serum Albumin.

Tor1 regulates protein solubility in Saccharomyces cerevisiae.

Accumulation of insoluble protein in cells is associated with aging and aging-related diseases; however, the roles of insoluble protein in these processes are uncertain. The nature and impact of changes to protein solubility during normal aging are less well understood. Using quantitative mass spectrometry, we identify 480 proteins that become insoluble during postmitotic aging in Saccharomyces cerevisiae and show that this ensemble of insoluble proteins is similar to those that accumulate in aging nematodes. SDS-insoluble protein is present exclusively in a nonquiescent subpopulation of postmitotic cells, indicating an asymmetrical distribution of this protein. In addition, we show that nitrogen starvation of young cells is sufficient to cause accumulation of a similar group of insoluble proteins. Although many of the insoluble proteins identified are known to be autophagic substrates, induction of macroautophagy is not required for insoluble protein formation. However, genetic or chemical inhibition of the Tor1 kinase is sufficient to promote accumulation of insoluble protein. We conclude that target of rapamycin complex 1 regulates accumulation of insoluble proteins via mechanisms acting upstream of macroautophagy. Our data indicate that the accumulation of proteins in an SDS-insoluble state in postmitotic cells represents a novel autophagic cargo preparation process that is regulated by the Tor1 kinase.

Proteomic analysis of age-dependent changes in protein solubility identifies genes that modulate lifespan.

While it is generally recognized that misfolding of specific proteins can cause late-onset disease, the contribution of protein aggregation to the normal aging process is less well understood. To address this issue, a mass spectrometry-based proteomic analysis was performed to identify proteins that adopt sodium dodecyl sulfate (SDS)-insoluble conformations during aging in Caenorhabditis elegans. SDS-insoluble proteins extracted from young and aged C. elegans were chemically labeled by isobaric tagging for relative and absolute quantification (iTRAQ) and identified by liquid chromatography and mass spectrometry. Two hundred and three proteins were identified as being significantly enriched in an SDS-insoluble fraction in aged nematodes and were largely absent from a similar protein fraction in young nematodes. The SDS-insoluble fraction in aged animals contains a diverse range of proteins including a large number of ribosomal proteins. Gene ontology analysis revealed highly significant enrichments for energy production and translation functions. Expression of genes encoding insoluble proteins observed in aged nematodes was knocked down using RNAi, and effects on lifespan were measured. 41% of genes tested were shown to extend lifespan after RNAi treatment, compared with 18% in a control group of genes. These data indicate that genes encoding proteins that become insoluble with age are enriched for modifiers of lifespan. This demonstrates that proteomic approaches can be used to identify genes that modify lifespan. Finally, these observations indicate that the accumulation of insoluble proteins with diverse functions may be a general feature of aging.

Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib.

Multiple pathways have been proposed to explain how proteasome inhibition induces cell death, but mechanisms remain unclear. To approach this issue, we performed a genome-wide siRNA screen to evaluate the genetic determinants that confer sensitivity to bortezomib (Velcade (R); PS-341). This screen identified 100 genes whose knockdown affected lethality to bortezomib and to a structurally diverse set of other proteasome inhibitors. A comparison of three cell lines revealed that 39 of 100 genes were commonly linked to cell death. We causally linked bortezomib-induced cell death to the accumulation of ASF1B, Myc, ODC1, Noxa, BNIP3, Gadd45alpha, p-SMC1A, SREBF1, and p53. Our results suggest that proteasome inhibition promotes cell death primarily by dysregulating Myc and polyamines, interfering with protein translation, and disrupting essential DNA damage repair pathways, leading to programmed cell death.

Location of the mutation site in the first two reported cases of analbuminemia.

OBJECTIVE: To find the mutation causing the first two reported cases of analbuminemia. DESIGN AND METHODS: DNA was extracted from blocks of fixed embedded liver. Exons of the albumin gene were amplified and sequenced. RESULTS: A substitution of C>T in exon 12 was found in both subjects, changing the codon CGA for arginine (aa509) to TGA, a stop codon. CONCLUSIONS: The data suggest that analbuminemia is the result of widely scattered random mutations.

Novel frameshift in the serum albumin gene results in analbuminemia through premature truncation and post translational modification.

OBJECTIVES: To identify the molecular lesion in a patient with analbuminemia. DESIGN AND METHODS: DNA sequencing, genome-wide SNP microarray and synthetic peptide assays to investigate DNA and protein aberrations. RESULTS: A homozygous frameshift deletion in exon 12 of HSA is predicted to cause truncation of the albumin protein. A proalbumin-like sequence identified in the novel C-terminal sequence has the potential to be post-translationally modified. CONCLUSIONS: The truncated albumin molecule is potentially edited by proteolytic cleavage before it enters the circulation.

Mutations and polymorphisms of the gene of the major human blood protein, serum albumin.

We have tabulated the 77 currently known mutations of the familiar human blood protein, serum albumin (ALB). A total of 65 mutations result in bisalbuminemia. Physiological and structural effects of these mutations are included where observed. Most of the changes are benign. The majority of them were detected upon clinical electrophoretic studies, as a result of a point mutation of a charged amino acid residue. Three were discovered by their strong binding of thyroxine or triiodothyronine. A total of 12 of the tabulated mutations result in analbuminemia, defined as a serum albumin concentration of <1 g/L. These were generally detected upon finding a low albumin concentration in patients with mild edema, and involve either splicing errors negating translation or premature stop codons producing truncated albumin molecules. A total of nine mutations, five of those with analbuminemia and four resulting in variants modified near the C-terminal end, cause frameshifts. Allotypes from three of the point mutations become N-glycosylated and one C-terminal frameshift mutation shows O-glycosylation.

Protein aggregation and polyasparagine-mediated cellular toxicity in Saccharomyces cerevisiae.

It is well established that protein aggregation is associated with many neurodegenerative disorders including polyglutamine diseases, but a mechanistic understanding of the role of protein aggregates in the disease pathogenesis remains elusive. Previously thought to be the cause of cellular toxicity such as cellular dysfunction and cell death, protein aggregation is now proposed to serve a protective role by sequestering toxic oligomers from interfering with essential physiological processes. To investigate the relationship between protein aggregation and cellular toxicity, we have characterized and compared the effects of two GFP-fusion proteins that form aggregates in Saccharomyces cerevisiae, one with a polyasparagine repeat (GFP(N104)) and one without (GFP(C)). Although both proteins can form microscopically visible GFP-positive aggregates, only the GFP(N104)-containing aggregates exhibit morphological and biochemical characteristics that resemble the aggregates formed by mutant huntingtin in yeast cells. Formation of both the GFP(C) and GFP(N104) aggregates depends on microtubules, while only the GFP(N104) aggregate requires the chaperone Hsp104 and the prion Rnq1 and is resistant to SDS. Although no microscopically visible GFP(N104) aggregates were observed in the hsp104Delta and rnq1Delta mutant cells, SDS-insoluble aggregates can still be detected by the filter trap assay. These observations argue that the GFP(N104)-containing aggregates can exist in at least two distinct states in vivo. We also show that a nucleus-targeted GFP(N104) interferes with transcription from two SAGA-dependant promoters and results in a decrease in cell viability. Overall, the results imply that the GFP(N104) protein behaves similarly to the mutant huntingtin in yeast cells and provides a new model for investigating the interplay between protein aggregates and the associated phenotypes.

Albumin locust valley: a new case of analbuminemia.

OBJECTIVE: To discover and document cases of the rare disease analbuminemia. DESIGN AND METHODS: Blood specimens of a subject were analyzed by routine clinical laboratory procedures, by immunochemical tests for albumin, and by electrophoresis with immunofixation using anti-human serum albumin (HSA). Single-strand conformational polymorphism (SSCP), heteroduplex analysis (HA), and DNA sequencing of the 14 exons of the HSA gene were conducted on DNA from leukocytes. RESULTS: Albumin concentration was 0.003 g/L; serum globulins and cholesterol were elevated. Immunoelectrophoresis showed no trace of albumin in any of the serum components. The coding region plus all mRNA splice sites were normal and mutation-free, and SSCP and HA showed no abnormalities. CONCLUSIONS: Data define a bona fide case of analbuminemia. We suggest that the mutation causing the analbuminemic trait in this subject might involve a remote regulatory element.