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In the chloroplast, the 54 kDa subunit of the signal recognition particle (cpSRP54) is involved in the post-translational transport of the light-harvesting chlorophyll a / b -binding proteins (LHCPs) and the co-translational transport of plastid-encoded subunits of the photosynthetic complexes to the thylakoid membrane. It forms a high-affinity complex with plastid-specific cpSRP43 for post-translational transport, while a ribosome-associated pool coordinates its co-translational function. CpSRP54 constitutes a conserved multidomain protein, comprising a GTPase (NG) and a methionine-rich (M) domain linked by a flexible region. It is further characterized by a plastid-specific C-terminal tail region containing the cpSRP43-binding motif. To characterize the physiological role of the various regions of cpSRP54 in thylakoid membrane protein transport, we generated Arabidopsis cpSRP54 knockout (ffc1-2) lines producing truncated cpSRP54 variants or a GTPase point mutation variant. Phenotypic characterization of the complementation lines demonstrated that the C-terminal tail region of cpSRP54 plays an important role exclusively in post-translational LHCP transport. Furthermore, we show that the GTPase activity of cpSRP54 plays an essential role in the transport pathways for both nuclear as well as plastid-encoded proteins. In addition, our data revealed that plants expressing cpSRP54 without the C-terminal region exhibit a strongly increased accumulation of a photosystem I assembly intermediate. [ABSTRACT FROM AUTHOR]

Precise and efficient processing of nascent polypeptides by appropriate ribosome-associated factors is essential for proper protein function and localization. Recent studies demonstrate that nascent chain binding by cotranslational factors is precisely orchestrated and not only triggered by random collisions of the factors with translating ribosomes. Newly synthesized proteins are sorted at the ribosomal tunnel exit and directed into specific cotranslational protein biogenesis pathways. The nascent polypeptide-associated complex (NAC) is important for the regulation of cotranslational processing. Ribosomes interact with a variety of different protein biogenesis factors that guide newly synthesized proteins to their native 3D shapes and cellular localization. Depending on the type of translated substrate, a distinct set of cotranslational factors must interact with the ribosome in a timely and coordinated manner to ensure proper protein biogenesis. While cytonuclear proteins require cotranslational maturation and folding factors, secretory proteins must be maintained in an unfolded state and processed cotranslationally by transport and membrane translocation factors. Here we explore the specific cotranslational processing steps for cytonuclear, secretory, and membrane proteins in eukaryotes and then discuss how the nascent polypeptide-associated complex (NAC) cotranslationally sorts these proteins into the correct protein biogenesis pathway. [ABSTRACT FROM AUTHOR]

To elucidate the redundancy in the components for the targeting of membrane proteins to the endoplasmic reticulum (ER) and/or their insertion into the ER membrane under physiological conditions, we previously analyzed different human cells by label-free quantitative mass spectrometry. The HeLa and HEK293 cells had been depleted of a certain component by siRNA or CRISPR/Cas9 treatment or were deficient patient fibroblasts and compared to the respective control cells by differential protein abundance analysis. In addition to clients of the SRP and Sec61 complex, we identified membrane protein clients of components of the TRC/GET, SND, and PEX3 pathways for ER targeting, and Sec62, Sec63, TRAM1, and TRAP as putative auxiliary components of the Sec61 complex. Here, a comprehensive evaluation of these previously described differential protein abundance analyses, as well as similar analyses on the Sec61-co-operating EMC and the characteristics of the topogenic sequences of the various membrane protein clients, i.e., the client spectra of the components, are reported. As expected, the analysis characterized membrane protein precursors with cleavable amino-terminal signal peptides or amino-terminal transmembrane helices as predominant clients of SRP, as well as the Sec61 complex, while precursors with more central or even carboxy-terminal ones were found to dominate the client spectra of the SND and TRC/GET pathways for membrane targeting. For membrane protein insertion, the auxiliary Sec61 channel components indeed share the client spectra of the Sec61 complex to a large extent. However, we also detected some unexpected differences, particularly related to EMC, TRAP, and TRAM1. The possible mechanistic implications for membrane protein biogenesis at the human ER are discussed and can be expected to eventually advance our understanding of the mechanisms that are involved in the so-called Sec61-channelopathies, resulting from deficient ER protein import. [ABSTRACT FROM AUTHOR]

Background: Knowledge about Immune-Mediated Necrotizing Myopathy (IMNM) has received significantly attention in recent years. In this study, we report a rare case of IMNM with increased Creatine Phosphokinase (CPK) and positive Signal Recognition Particle (SRP). Clinical Presentation and Intervention: The case was a 67-year-old male patient referred to Firozgar hospital affiliated to the Iran University of Medical Science, Tehran, Iran in June 2018 with a chief complaint of pain in the proximal lower extremity. According to Medical Research Council Scale for muscle strength, the motor function of proximal upper extremities was 4/5 and for the proximal of the lower extremities, it was 3/5. Laboratory findings showed an increase in CPK, CK-MB, lactate dehydrogenase, creatinine, alanine aminotransferase, aspartate aminotransferase and aldolase levels. Six days after admission, autoantibody test was requested which showed positive SRP. In muscle biopsy, the myopathic atrophy with multiple necrotic and many degenerative/regenerative fibers was associated with mild endomysial fibrosis, and no inflammation was observed. Two g/kg dose of Intravenous Immunoglobulin (IVIG) was administrated after diagnosis of IMNM. Prednisone 50 mg/day orally, calcium vitamin D daily, pantoprazole 40 mg/day, physiotherapy, and occupational therapy were administrated for after discharge. Conclusion: Reporting a case of anti-SRP associated IMNM and reviewing its pathophysiology, diagnosis and treatment options can help increase the physicians’ knowledge of this rare and debilitating condition.

Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies. • The classical complement pathway activation may only be involved in the onset of IMNM. • Comprehensive multi-omics analyses can potentially unveil new insights in pathogenesis. • IMNM and malignancy may not be correlated. • Comparison of three subtypes of IMNM. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is one of the most common causes of death in patients with systemic sclerosis (SSc). The complexity of SSc-PH and the heterogeneity of clinical features in SSc-PH patients contribute to the difficulty of diagnosis. Therefore, there is a pressing need to develop and optimize models for the diagnosis of SSc-PH. Signal recognition particle (SRP) deficiency has been found to promote the progression of multiple cancers, but the relationship between SRP and SSc-PH has not been explored. Methods: First, we obtained the GSE19617 and GSE33463 datasets from the Gene Expression Omnibus (GEO) database as the training set, GSE22356 as the test set, and the SRP-related gene set from the MSigDB database. Next, we identified differentially expressed SRP-related genes (DE-SRPGs) and performed unsupervised clustering and gene enrichment analyses. Then, we used least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) to identify SRP-related diagnostic genes (SRP-DGs). We constructed an SRP scoring system and a nomogram model based on the SRP-DGs and established an artificial neural network (ANN) for diagnosis. We used receiver operating characteristic (ROC) curves to identify the SRP-related signature in the training and test sets. Finally, we analyzed immune features, signaling pathways, and drugs associated with SRP and investigated SRP-DGs' functions using single gene batch correlation analysis-based GSEA. Results: We obtained 30 DE-SRPGs and found that they were enriched in functions and pathways such as "protein targeting to ER," "cytosolic ribosome," and "coronavirus disease--COVID-19". Subsequently, we identified seven SRPDGs whose expression levels and diagnostic efficacy were validated in the test set. As one signature, the area under the ROC curve (AUC) values for seven SRPDGs were 0.769 and 1.000 in the training and test sets, respectively. Predictions made using the nomogram model are likely beneficial for SSc-PH patients. The AUC values of the ANN were 0.999 and 0.860 in the training and test sets, respectively. Finally, we discovered that some immune cells and pathways, such as activated dendritic cells, complement activation, and heme metabolism, were significantly associated with SRP-DGs and identified ten drugs targeting SRP-DGs. Conclusion: We constructed a reliable SRP-related ANN model for the diagnosis of SSc-PH and investigated the possible role of SRP in the etiopathogenesis of SSc-PH by bioinformatics methods to provide a basis for precision and personalized medicine. [ABSTRACT FROM AUTHOR]

Importing proteins into the endoplasmic reticulum (ER) is essential for about 30% of the human proteome. It involves the targeting of precursor proteins to the ER and their insertion into or translocation across the ER membrane. Furthermore, it relies on signals in the precursor polypeptides and components, which read the signals and facilitate their targeting to a protein-conducting channel in the ER membrane, the Sec61 complex. Compared to the SRP- and TRC-dependent pathways, little is known about the SRP-independent/SND pathway. Our aim was to identify additional components and characterize the client spectrum of the human SND pathway. The established strategy of combining the depletion of the central hSnd2 component from HeLa cells with proteomic and differential protein abundance analysis was used. The SRP and TRC targeting pathways were analyzed in comparison. TMEM109 was characterized as hSnd3. Unlike SRP but similar to TRC, the SND clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals. [ABSTRACT FROM AUTHOR]

Autosomal dominant mutations in the signal recognition particle (SRP) 54 gene were recently described in patients with severe congenital neutropenia (SCN). SRP54 deficiency cause a chronic and profound neutropenia with maturation arrest at the promyelocyte stage, occurring in the first months of life. Nearly all reported patients with SRP54 mutations had neutropenia without a cyclic pattern and showed a poor or no response to granulocyte colonystimulating factor (G-CSF) therapy. We report here an 11-year-old female patient with cyclic neutropenia and recurrent heterozygous p. T117del (c.349_351del) in-frame deletion mutation in SRP54, who showed remarkable therapeutic response to G-CSF treatment. The diagnosis of cyclic pattern of neutropenia was established by acceptable standards. ELANE gene mutation was excluded by using various genetic approaches. The patient described here also had dolichocolon which has not been described before in association with SCN. [ABSTRACT FROM AUTHOR]

Autosomal dominant mutations in the signal recognition particle (SRP) 54 gene were recently described in patients with severe congenital neutropenia (SCN). SRP54 deficiency cause a chronic and profound neutropenia with maturation arrest at the promyelocyte stage, occurring in the first months of life. Nearly all reported patients with SRP54 mutations had neutropenia without a cyclic pattern and showed a poor or no response to granulocyte colony-stimulating factor (G-CSF) therapy. We report here an 11-year-old female patient with cyclic neutropenia and recurrent heterozygous p.T117del (c.349_351del) in-frame deletion mutation in SRP54, who showed remarkable therapeutic response to G-CSF treatment. The diagnosis of cyclic pattern of neutropenia was established by acceptable standards. ELANE gene mutation was excluded by using various genetic approaches. The patient described here also had dolichocolon which has not been described before in association with SCN.

The authors present the case of a 76-year-old female patient with progressive decrease in proximal muscle strength, fatigue, dyspnea, diffuse hand edema and painful triphasic Raynaud's phenomenon. Anti-SRP and anti-SSA antibodies were detected, muscle biopsy revealed changes consistent with necrotizing myopathy and capillaroscopy had findings compatible with systemic sclerosis. High-resolution chest computed tomography revealed interstitial lung disease with a non-specific interstitial pneumonia pattern. Lung function tests demonstrated a forced vital capacity 93% and a diffusing capacity for carbon monoxide of 65% predicted. After multidisciplinary discussion, she was diagnosed with immune-mediated necrotizing myopathy/systemic sclerosis overlap syndrome with pulmonary involvement. Initially, dual immunomodulation therapy with high-dose steroids and intravenous immunoglobulin was started, but after 4 weeks, the patient had clinical and analytical deterioration. At this time, she was started on rituximab, with an excellent and sustained response at both muscle and lung, sustained after 12 months. [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR) relieves endoplasmic reticulum (ER) stress through multiple strategies, including reducing protein synthesis, increasing protein folding capabilities, and enhancing misfolded protein degradation. After a multi-omics analysis, we find that signal recognition particle 14 (SRP14), an essential component of the SRP, is markedly reduced in cells undergoing ER stress. Further experiments indicate that SRP14 reduction requires PRKR-like ER kinase (PERK)-mediated eukaryotic translation initiation factor 2α (eIF2α) phosphorylation but is independent of ATF4 or ATF3 transcription factors. The decrease of SRP14 correlates with reduced translocation of fusion proteins and endogenous cathepsin D. Enforced expression of an SRP14 variant with elongation arrest capability prevents the reduced translocation of cathepsin D in stressed cells, whereas an SRP14 mutant without the activity does not. Finally, overexpression of SRP14 augments the UPR and aggravates ER-stress-induced cell death. These data suggest that translocational attenuation mediated by the PERK-SRP14 axis is a protective measure for the UPR to mitigate ER stress. [Display omitted] • SRP14 is significantly down-regulated upon ER stress • The down-regulation of SRP14 is mediated by ubiquitination and proteasomal degradation • The PERK branch of UPR is required for ER-stress-induced SRP14 down-regulation • Enforced expression of SRP14 in ER-stressed cells aggravates UPR and cell death Liu et al. find a mechanism deployed by cells to respond to ER stress. The unfolded protein response (UPR) selectively down-regulates a subunit of the signal recognition particle, SRP14. This causes a decrease of protein translocation into the ER lumen, thus reducing ER burden to alleviate cellular stress. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum represents the gateway to the secretory pathway. Here, proteins destined for secretion, as well as soluble and membrane proteins that reside in the endomembrane system and plasma membrane, are triaged from proteins that will remain in the cytosol or be targeted to other cellular organelles. This process requires the faithful recognition of specific targeting signals and subsequent delivery mechanisms to then target them to the translocases present at the ER membrane, which can either translocate them into the ER lumen or insert them into the lipid bilayer. This review focuses on the current understanding of the first step in this process representing the targeting phase. Targeting is typically mediated by cleavable N-terminal hydrophobic signal sequences or internal membrane anchor sequences; these can either be captured co-translationally at the ribosome or recognised post-translationally and then delivered to the ER translocases. Location and features of the targeting sequence dictate which of several overlapping targeting pathway substrates will be used. Mutations in the targeting machinery or targeting signals can be linked to diseases. [ABSTRACT FROM AUTHOR]

The nascent polypeptide–associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC’s globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization. [ABSTRACT FROM AUTHOR]

The article presents the discussion on research in various fields. Topics include Natural killer (NK) cells being the innate immune cells under investigation as a cell therapy for multiple types of cancer; signal recognition particle (SRP) targeting membrane and secretory proteins to the endoplasmic reticulum (ER); and adoptive cell therapy being a type of cancer immunotherapy where an individual's immune system being trained for eliminating the tumor.

In order to solve the problems of weak generalization ability and low classification accuracy in motor imagery EEG signal classification, this paper proposes a channel space weighted fusion-oriented feature pyramid network for motor imagery EEG signal recognition. First, the short-time Fourier transform is used to obtain the EEG time-frequency map. Then, it builds a new feature pyramid network(FPN). The attention mechanism module is integrated into the FPN module, and the channel spatial weighted fusion-oriented feature pyramid network is proposed. This new structure can not only learn the weight of important channel features in the feature map, but also learn the representation of important feature areas in the network layers. Meanwhile, Skip-FPN module is added into the network structure, which fuses more details of EEG signals through short connections. The Dropout layer is added to prevent network training from over-fitting. In the classification model, we improve the AdaBoost algorithm to automatically update the base learner according to the classification error rate. Finally, the proposed model is used to classify the test data and the Kappa value is used as the evaluation index. Compared with the state-of-the-art motor image EEG signal recognition methods, the proposed method achieves better performance on the BCI Competition IV 2b data set. It has good generalization ability and can improve the classification effect. [ABSTRACT FROM AUTHOR]

Peptide nucleic acid (PNA) based antisense strategy is a promising therapeutic approach to specifically inhibit target gene expression. However, unlike protein coding genes, identification of an ideal PNA binding site for non-coding RNA is not straightforward. Here, we compare the inhibitory activities of PNA molecules that bind a non-coding 4.5S RNA called SRP RNA, a key component of the bacterial signal recognition particle (SRP). A 9-mer PNA (PNA 9 ) complementary to the tetraloop region of the RNA was more potent in inhibiting its interaction with the SRP protein, compared to an 8-mer PNA (PNA 8 ) targeting a stem-loop. PNA 9 , which contained a homo-pyrimidine sequence could form a triplex with the complementary stretch of RNA in vitro as confirmed using a fluorescent derivative of PNA 9 (F-PNA 13 ). The RNA-PNA complex formation resulted in inhibition of SRP function with PNA 9 and F-PNA 13 , but not PNA 8 highlighting the importance of target site selection. Surprisingly, F-PNA 13 which was more potent in inhibiting SRP function in vitro, showed weaker antibacterial activity compared to PNA 9 likely due to poor cell penetration of the longer PNA. Our results underscore the importance of suitable target site selection and optimum PNA length to develop better antisense molecules against non-coding RNA., (© 2024 Wiley-VCH GmbH.)

Immune-mediated necrotizing myopathy (IMNM) represents a rare category of inflammatory myopathies characterized by more severe and rapid progression of symmetrical proximal muscle weakness. It is also marked by notably elevated serum muscle enzyme levels and distinct histological features, setting it apart from other types of myositis. Moreover, acute chronic lung respiratory dysfunction is a major comorbidity of great concern. We herein present two cases of IMNM associated with anti-signal recognition particle antibodies complicated by acute respiratory distress syndrome., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Fang et al.)

Objective: Characteristics of myositis with anti-Ku antibodies are poorly understood. The purpose of this study was to elucidate the pathologic features of myositis associated with anti-Ku antibodies, compared with immune-mediated necrotizing myopathy (IMNM) with anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, in muscle biopsy-oriented registration cohorts in Japan and Germany., Methods: We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping., Results: Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 ( p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls ( p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing., Discussion: While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.

Translation of messenger ribonucleic acids (mRNAs) encoding integral membrane proteins or secreted proteins occurs on the surface of the endoplasmic reticulum (ER). When a nascent signal peptide is synthesized from the mRNAs, the ribosome-nascent chain complex (RNC) is recognized by the signal recognition particle (SRP) and then transported to the surface of the ER. The appropriate targeting of the RNC-SRP complex to the ER is monitored by a quality control pathway, a nuclear cap-binding complex (CBC)-ensured translational repression of RNC-SRP (CENTRE). In this study, using ribosome profiling of CBC-associated and eukaryotic translation initiation factor 4E-associated mRNAs, we reveal that, at the transcriptomic level, CENTRE is in charge of the translational repression of the CBC-RNC-SRP until the complex is specifically transported to the ER. We also find that CENTRE inhibits the nonsense-mediated mRNA decay (NMD) of mRNAs within the CBC-RNC-SRP. The NMD occurs only after the CBC-RNC-SRP is targeted to the ER and after eukaryotic translation initiation factor 4E replaces CBC. Our data indicate dual surveillance for properly targeting mRNAs encoding integral membrane or secretory proteins to the ER. CENTRE blocks gene expression at the translation level before the CBC-RNC-SRP delivery to the ER, and NMD monitors mRNA quality after its delivery to the ER., Competing Interests: Declaration of Competing Interests The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for (MOL CELLS) and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The significant role of long non-coding 7S RNA in controlling mitochondrial transcription highlights its importance in mitochondrial function. Considering the suggested connection between mitochondrial dysfunction and the onset of mental disorders, this study aimed to explore the potential involvement of 7S RNA in the context of depression/anxiety., Results: A total of 181 patients in primary health care (age 20-64 years) with depression/anxiety and 59 healthy controls were included in the study. 7S RNA was measured using quantitative real-time PCR in plasma samples collected before (baseline) and after 8 weeks of treatment (mindfulness or cognitive-based behavioral therapy). Upon adjustment for age and sex, the baseline plasma levels of 7S RNA were significantly higher in patients than in healthy controls (p < 0.001). Notably, post-treatment, there was a significant reduction in 7S RNA levels (p = 0.03). These changes in 7S RNA were related to the treatment response, as indicated by HADS-D (Hospital Anxiety and Depression Scale) scores (ß = -0.04, p = 0.04), even after accounting for baseline scores and other cofounders., Conclusion: The findings of this study indicate an association between plasma 7S RNA levels and depression/anxiety, as well as treatment response. While further confirmatory analyses are necessary, plasma 7S RNA holds promise as a potential predictive biomarker for both depression/anxiety and the treatment response within these disorders., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest associated with this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Improving the wheat (Triticum aestivum L.) root system is important for enhancing grain yield and climate resilience. Total root length (RL) and root dry mass (RM) significantly contribute to water and nutrient acquisition directly impacting grain yield and stress tolerance. This study used label-free quantitative proteomics to identify proteins associated with RL and RM in wheat near-isogenic lines (NILs). NIL pair 6 had 113 and NIL pair 9 had 30 differentially abundant proteins (DAPs). Three of identified DAPs located within the targeted genomic regions (GRs) of NIL pairs 6 (qDT.4A.1) and 9 (QHtscc.ksu-7A), showed consistent gene expressions at the protein and mRNA transcription (qRT-PCR) levels for asparagine synthetase (TraesCS4A02G109900), signal recognition particle 19 kDa protein (TraesCS7A02G333600) and 3,4-dihydroxy-2-butanone 4-phosphate synthase (TraesCS7A02G415600). This study discovered, for the first time, the involvement of these proteins as candidate biomarkers for increased RL and RM in wheat. However, further functional validation is required to ascertain their practical applicability in wheat root breeding. Climate change has impacted global demand for wheat (Triticum aestivum L.). Root traits such as total root length (RL) and root dry mass (RM) are crucial for water and nutrient uptake and tolerance to abiotic stresses such as drought, salinity, and nutrient imbalance in wheat. Improving RL and RM could significantly enhance wheat grain yield and climate resilience. However, breeding for these traits has been limited by lack of appropriate root phenotyping methods, advanced genotypes, and the complex nature of the wheat genome. In this study, we used a semi-hydroponic root phenotyping system to collect accurate root data, near-isogenic lines (NILs; isolines with similar genetic backgrounds but contrasting target genomic regions (GRs)) and label-free quantitative proteomics to explore the molecular mechanisms underlying high RL and RM in wheat. We identified differentially abundant proteins (DAPs) and their molecular pathways in NIL pairs 6 (GR: qDT.4A.1) and 9 (GR: QHtscc.ksu-7A), providing a foundation for further molecular investigations. Furthermore, we identified three DAPs within the target GRs of the NIL pairs with differential expression at the transcript level, as confirmed by qRT-PCR analysis which could serve as candidate protein biomarkers for RL and RM improvement. [Display omitted] • Wheat near-isogenic lines with contrasting genomic regions show significant variation in total root length and root dry mass. • Target genomic regions on chromosomes 4A and 7A have differentially abundant proteins to control root traits in wheat. • Three candidate protein biomarkers show consistent gene expression at protein and mRNA transcription levels. [ABSTRACT FROM AUTHOR]

Objectives: To compare the findings of muscle magnetic resonance imaging (MRI) between anti-signal recognition particle antibody-positive myopathy (anti-SRP myopathy) and anti-aminoacyl-tRNA synthetase antibody-positive myositis (anti-ARS myositis)., Methods: Of the patients newly diagnosed with polymyositis (PM)/dermatomyositis (DM) and immune-mediated necrotising myopathy (IMNM) admitted to our Department between April 2012 and December 2021, those who met the eligibility criteria of positive for anti-SRP or anti-ARS antibodies and thigh MRI at the time of diagnosis were included. We compared the lesion sites and MRI findings of the thigh muscles that were classified into oedema, fascial oedema, fatty replacement, and muscle atrophy between the three groups of anti-SRP myopathy, anti-Jo-1 antibody-positive myositis, and non-Jo-1 antibody-positive myositis., Results: Of the 98 PM/DM and IMNM patients, five anti-SRP myopathy patients and 11 anti-Jo-1-positive and 22 non-Jo-1 antibody-positive patients with myositis were included. The SRP group showed significantly higher blood levels of myogenic enzymes such as serum creatinine kinase (CK) than the other groups (p=0.01). In thigh MRI findings, despite oedema in most cases in anti-SRP and anti-ARS groups, fascial oedema was identified only in the ARS group, frequently in Jo-1 positive patients in particular. Moreover, gluteus maximus muscle lesions occurred more frequently in the SRP group than in the ARS group (p=0.008)., Conclusions: A comparison of thigh MRI between anti-SRP myopathy and anti-ARS myositis showed different findings and lesion sites reflecting the different pathophysiology that may contribute to their diagnosis.

Immune-mediated necrotizing myopathy (IMNM) is a rare subtype of idiopathic inflammatory myopathy that is characterized by severe subacute proximal weakness, myofiber necrosis, and significantly elevated serum creatine kinase. Anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme-A reductase autoantibodies have been found in about two-thirds of patients with IMNM. This myopathy is usually idiopathic and there is a scarce literature concerning its association with connective tissue diseases. Herein, we report an unusual case of a young woman who presented with both rheumatoid arthritis and severe anti-SRP IMNM. Thankfully to a therapeutic protocol combining rituximab and cyclophosphamide, an important improvement was achieved, and notably no serious side effect was observed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Anti-signal recognition particle (anti-SRP)-positive necrotising myopathy causes severe progressive proximal weakness with a propensity to involve pharyngeal, laryngeal and respiratory muscles. It is one of the aggressive inflammatory myopathies. First-line treatment is with high-dose steroids followed by other immunosuppressants, but this conventional therapy is often ineffective. Second-line treatment involves use of either rituximab or intravenous immunonoglobulin (IVIG). Anti-SRP-positive necrotising myopathy is frequently treated as refractory myositis due to its poor responsiveness to steroid monotherapy and conventional immunosuppressive therapies. Therefore, anti-SRP-positive necrotising myopathy differs from immune-mediated myopathy. Although anti-SRP autoantibody is found in only 4-6% of patients with idiopathic inflammatory myopathy, the actual proportion of patients with refractory anti-SRP-positive necrotising myopathy is unknown. We describe a patient with multiple comorbidities who had subacute-onset anti-SRP-positive immune-mediated necrotising myopathy (IMNM). After failing steroids, methotrexate and IVIG therapy, she made a considerable recovery with rituximab. She was later diagnosed to have breast malignancy. Malignancy-associated anti-SRP-positive IMNM is rarely reported., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to verify whether the immune system may represent a source of potential biomarkers for the stratification of immune-mediated necrotizing myopathies (IMNMs) subtypes. A group of 22 patients diagnosed with IMNM [7 with autoantibodies against signal recognition particle (SRP) and 15 against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR)] and 12 controls were included. A significant preponderance of M1 macrophages was observed in both SRP + and HMGCR + muscle samples (p < 0.0001 in SRP + and p = 0.0316 for HMGCR + ), with higher values for SRP + (p = 0.01). Despite the significant increase observed in the expression of TLR4 and all endosomal Toll-like receptors (TLRs) at protein level in IMNM muscle tissue, only TLR7 has been shown considerably upregulated compared to controls at transcript level (p = 0.0026), whereas TLR9 was even decreased (p = 0.0223). Within IMNM subgroups, TLR4 (p = 0.0116) mRNA was significantly increased in SRP + compared to HMGCR + patients. Within IMNM group, only IL-7 was differentially expressed between SRP + and HMGCR + patients, with higher values in SRP + patients (p = 0.0468). Overall, innate immunity represents a key player in pathological mechanisms of IMNM. TLR4 and the inflammatory cytokine IL-7 represent potential immune biomarkers able to differentiate between SRP + and HMGCR + patients., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Maintaining a functional proteome under different environmental conditions is challenging for every organism, in particular for unicellular organisms, such as bacteria. In order to cope with changing environments and stress conditions, bacteria depend on strictly coordinated proteostasis networks that control protein production, folding, trafficking, and degradation. Regulation of ribosome biogenesis and protein synthesis are cornerstones of this cellular adaptation in all domains of life, which is rationalized by the high energy demand of both processes and the increased resistance of translationally silent cells against internal or external poisons. Reduced protein synthesis ultimately also reduces the substrate load for protein transport systems, which are required for maintaining the periplasmic, inner, and outer membrane subproteomes. Consequences of impaired protein transport have been analyzed in several studies and generally induce a multifaceted response that includes the upregulation of chaperones and proteases and the simultaneous downregulation of protein synthesis. In contrast, generally less is known on how bacteria adjust the protein targeting and transport machineries to reduced protein synthesis, e.g., when cells encounter stress conditions or face nutrient deprivation. In the current review, which is mainly focused on studies using Escherichia coli as a model organism, we summarize basic concepts on how ribosome biogenesis and activity are regulated under stress conditions. In addition, we highlight some recent developments on how stress conditions directly impair protein targeting to the bacterial membrane. Finally, we describe mechanisms that allow bacteria to maintain the transport of stress-responsive proteins under conditions when the canonical protein targeting pathways are impaired., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)