Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

Journal of inflammation research

2022 Sep 09

Liu, XG;
PMID: 36110505 | DOI: 10.2147/JIR.S379093

Chronic pain, which affects around 1/3 of the world population and is often comorbid with memory deficit and mood depression, is a leading source of suffering and disability. Studies in past decades have shown that hyperexcitability of primary sensory neurons resulting from abnormal expression of ion channels and central sensitization mediated pathological synaptic plasticity, such as long-term potentiation in spinal dorsal horn, underlie the persistent pain. The memory/emotional deficits are associated with impaired synaptic connectivity in hippocampus. Dysregulation of numerous endogenous proteins including receptors and intracellular signaling molecules is involved in the pathological processes. However, increasing knowledge contributes little to clinical treatment. Emerging evidence has demonstrated that the neuroinflammation, characterized by overproduction of pro-inflammatory cytokines and glial activation, is reliably detected in humans and animals with chronic pain, and is sufficient to induce persistent pain and memory/emotional deficits. The abnormal expression of ion channels and pathological synaptic plasticity in spinal dorsal horn and in hippocampus are resulting from neuroinflammation. The neuroinflammation is initiated and maintained by the interactions of circulating monocytes, glial cells and neurons. Obviously, unlike infectious diseases and cancer, which are caused by pathogens or malignant cells, chronic pain is resulting from alterations of cells and molecules which have numerous physiological functions. Therefore, normalization (counterbalance) but not simple inhibition of the neuroinflammation is the right strategy for treating neuronal disorders. Currently, no such agent is available in clinic. While experimental studies have demonstrated that intracellular Mg2+ deficiency is a common feature of chronic pain in animal models and supplement Mg2+ are capable of normalizing the neuroinflammation, activation of upregulated proteins that promote recovery, such as translocator protein (18k Da) or liver X receptors, has a similar effect. In this article, relevant experimental and clinical evidence is reviewed and discussed.

Molecular identification of spatially distinct anabolic responses to mechanical loading in murine cortical bone

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2022 Aug 24

Chlebek, C;Moore, JA;Ross, FP;van der Meulen, MCH;
PMID: 36054133 | DOI: 10.1002/jbmr.4686

Osteoporosis affects over 200 million women worldwide, one third of whom are predicted to suffer from an osteoporotic fracture in their lifetime. The most promising anabolic drugs involve administration of expensive antibodies. Because mechanical loading stimulates bone formation, our current data, using a mouse model, replicates the anabolic effects of loading in humans and may identify novel pathways amenable to oral treatment. Murine tibial compression produces axially-varying deformations along the cortical bone, inducing highest strains at the mid-diaphysis and lowest at the metaphyseal shell. To test the hypothesis that load-induced transcriptomic responses at different axial locations of cortical bone would vary as a function of strain magnitude, we loaded the left tibiae of 10wk female C57Bl/6 mice in vivo in compression, with contralateral limbs as controls. Animals were euthanized at 1, 3 or 24 h post-loading or loaded for 1 wk (n=4-5/group). Bone marrow and cancellous bone were removed, cortical bone was segmented into the metaphyseal shell, proximal diaphysis and mid-diaphysis, and load-induced differential gene expression and enriched biological processes were examined for the three segments. At each time point, the mid-diaphysis (highest strain) had the greatest transcriptomic response. Similarly, biological processes regulating bone formation and turnover increased earlier and to the greatest extent at the mid-diaphysis. Higher strain induced greater levels of osteoblast and osteocyte genes, whereas expression was lower in osteoclasts. Among the top differentially-expressed genes at 24-hours post-loading, seventeen had known functions in bone biology, of which twelve were present only in osteoblasts, three exclusively in osteoclasts, and two were present in both cell types. Based on these results, we conclude that murine tibial loading induces spatially-unique transcriptomic responses correlating with strain magnitude in cortical bone. This article is protected by

Chemogenetic activation of noradrenergic A5 neurons increases blood pressure and visceral sympathetic activity in adult rats

American journal of physiology. Regulatory, integrative and comparative physiology

2022 Aug 22

Souza, GMPR;Stornetta, DS;Vitali, AJ;Wildner, H;Zeilhofer, HU;Campbell, JN;Abbott, SBG;
PMID: 35993562 | DOI: 10.1152/ajpregu.00119.2022

In mammals, the pontine noradrenergic system influences nearly every aspect of central nervous system function. A subpopulation of pontine noradrenergic neurons, called A5, are thought to be important in the cardiovascular response to physical stressors, yet their function is poorly defined. We hypothesized that activation of A5 neurons stimulates a sympathetically-mediated increase in BP. To test this hypothesis, we conducted a comprehensive assessment of the cardiovascular effects of chemogenetic stimulation of A5 neurons in male and female adult rats using intersectional genetic and anatomical targeting approaches. Chemogenetic stimulation of A5 neurons in freely behaving rats elevated BP by 15 mmHg and increased cardiac baroreflex sensitivity with a negligible effect on resting HR. Importantly, A5 stimulation had no detectable effect on locomotor activity, metabolic rate or respiration. Under anesthesia, stimulation of A5 neurons produced a marked elevation in visceral sympathetic nerve activity (SNA) and no change in skeletal muscle SNA, showing that A5 neurons preferentially stimulate visceral SNA. Interestingly, projection mapping indicates that A5 neurons target sympathetic preganglionic neurons throughout the spinal cord and parasympathetic preganglionic neurons throughout in the brainstem, as well as the nucleus of the solitary tract, and ventrolateral medulla. Moreover, in situ hybridization and immunohistochemistry indicate that a sub-population of A5 neurons co-release glutamate and monoamines. Collectively, this study suggests A5 neurons are a central modulator of autonomic function with a potentially important role in sympathetically-driven redistribution of blood flow from the visceral circulation to critical organs and skeletal muscle.

Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non-alcoholic steatohepatitis

Acta physiologica (Oxford, England)

2022 May 02

Luo, Z;Ji, Y;Zhang, D;Gao, H;Jin, Z;Yang, M;Ying, W;
PMID: 35500155 | DOI: 10.1111/apha.13827

Low-grade inflammation is the hallmark of non-alcoholic fatty liver diseases (NAFLD) and non-alcoholic steatohepatitis (NASH). The leakage of microbiota-derived products can contribute to liver inflammation during NAFLD/NASH development. Here, we assessed the roles of gut microbial DNA-containing extracellular vesicles (mEVs) in regulating liver cellular abnormalities in the course of NAFLD/NASH.We performed studies with Vsig4-/- , C3-/- , cGAS-/- , and their wild-type littermate mice. Vsig4+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut mEVs were adoptively transferred into Vsig4-/- , C3-/- , cGAS-/- , or littermate WT mice, and hepatocyte inflammation and HSC fibrogenic activation were measured in these mice.Non-alcoholic fatty liver diseases and non-alcoholic steatohepatitis development was concomitant with a diminished liver Vsig4+ macrophage population and a marked bacterial DNA enrichment in both hepatocytes and HSCs. In the absence of Vsig4+ macrophages, gut mEVs translocation led to microbial DNA accumulation in hepatocytes and HSCs, resulting elevated hepatocyte inflammation and HSC fibrogenic activation. In contrast, in lean WT mice, Vsig4+ macrophages remove gut mEVs from bloodstream through a C3-dependent opsonization mechanism and prevent the infiltration of gut mEVs into hepatic cells. Additionally, Vsig4-/- mice more quickly developed significant liver steatosis and fibrosis than WT mice after Western diet feeding. In vitro treatment with NASH mEVs triggered hepatocyte inflammation and HSC fibrogenic activation. Microbial DNAs are key cargo for the effects of gut mEVs by activating cGAS/STING.Accumulation of microbial DNAs fuels the development of NAFLD/NASH-associated liver abnormalities.

Global Analyses of mRNA Expression in Human Sensory Neurons Reveals eIF5a as a Conserved Target for Inflammation-associated Pain

The Journal of Pain

2022 May 01

Chase, R;de la Peña, J;Smith, P;Lawson, J;Lou, T;Stanowick, A;Black, B;Campbell, Z;
| DOI: 10.1016/j.jpain.2022.03.144

Sensory neurons derived from human induced pluripotent stem cells (hiPSCs) are a promising model. One limitation posed by the use of monocultures is the loss of cellular heterogeneity found in tissues. Here we make use of high-throughput RNA sequencing to quantify gene expression in hiPSC-derived mono-cultured and co-cultured sensory neurons. The following groups were compared: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse dorsal root ganglion (DRG) tissues, and mouse DRG cultures. We find that co-culture of sensory neurons and astrocytes enhances expression of transcripts enriched in native DRG tissues. Numerous well-established genes linked to pain and most translation factors are consistently expressed in both hiPSC and mouse samples. Marker genes for various neuronal subtypes are also present in the hiPSC cultures. As a proof of concept for the potential use of the dataset for hypothesis generation, we validated the expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissue and hiPSC samples. eIF5A is a unique translation factor in that it requires a post-translational hypusine modification to be active. We show that inhibition of hypusine synthesis prevents hyperalgesic priming by inflammatory mediators in vivo and diminishes hiPSC neuronal firing in vitro. In total, we present the transcriptomes of hiPSC sensory neuron models and evaluate the requirement of a functional translation factor. This work was supported by NIH grants R01NS100788 (ZTC), R01NS114018 (ZTC), and 1UG3TR003149 (BJB).

Different Murine Models of Kidney Injury Reveal a Common Pattern of Dysregulation within the Polyamine System in Favour of its Catabolic Pathways

The FASEB Journal

2022 May 01

Sieckmann, T;Ögel, N;Kelterborn, S;Boivin, F;Schley, G;Fähling, M;Ashraf, M;Reichel, M;Vigolo, E;Hartner, A;Knauf, F;Rosenberger, C;Aigner, F;Smidt‐Ott, K;Scholz, H;Kirschner, K;
| DOI: 10.1096/fasebj.2022.36.S1.R3345

The polyamines putrescine, spermidine and spermine are organic polycations that regulate many cell functions including proliferation and differentiation. It is known that certain genes of the polyamine system are dysregulated after kidney ischemia reperfusion injury. Here we examined the hypothesis that different forms of acute and chronic kidney injury lead to similar changes in the expression patterns of the polyamine system. In different models of acute and chronic kidney injury expression of genes involved in polyamine homeostasis were analyzed by RT-qPCR and RNAScope. In these models, expression of catabolic enzymes (Aoc1 and Sat1) was upregulated, and the anabolic enzymes (Odc1, Sms) were downregulated. The putrescine-degrading enzyme AOC1 exhibits the most striking changes. Interestingly, it can act together with ODC1 as gatekeepers of the polyamine system. The detected increase of Aoc1 takes place in the injured but regenerating proximal tubules. As a screening for stimuli of increased Aoc1 expression, we used mouse embryonic kidney explants. Here we observed changes of Aoc1expression under hypoxia and hyperosmotic conditions. These changes were further examined in mouse models of hypoxia. However, in vivo, hypoxia did not lead to changes of Aoc1 expression. Hyperosmolarity was confirmed as a stimulus by using the kidney cell lines M15 and 209/MDCT as well as cultured primary proximal tubules. Using reporter gene and RNA-stability assays, we could show that the increase in Aoc1 expression is based on mRNA-stabilization and transcriptional activation of one certain isoform. The activated isoform contains an additional set of 22 amino acids N-terminally that lead to an altered subcellular localization. In conclusion, different models of kidney injury exhibit a similar pattern of dysregulation of the polyamine system with the most striking change being the upregulation of Aoc1 in proximal tubules. Using hyperosmolarity as a stimulus, we provide first insights into the regulation of Aoc1 under harmful conditions.

An afucosylated anti-CD32b monoclonal antibody induced platelet-mediated adverse events in a human Fcγ receptor transgenic mouse model and its potential human translatability

Toxicological sciences : an official journal of the Society of Toxicology

2021 Oct 23

Wolf, B;Jeliazkova-Mecheva, V;Del Rio-Espinola, A;Boisclair, J;Walker, D;Cochin De Billy, B;Flaherty, M;Flandre, T;
PMID: 34687301 | DOI: 10.1093/toxsci/kfab124

To assess the safety and tolerability of NVS32b, a monoclonal, afucosylated, anti-CD32b (FCGR2B) antibody we used a humanized transgenic (Tg) mouse model that expresses all human Fc gamma receptors (FCGRs) while lacking all mouse FCGRs. Prior to its use, we extensively characterized the model. We found expression of all human FCGRs in a pattern similar to humans with some exceptions, such as low CD32 expression on T cells (detected with the pan CD32 antibody but more notably with the CD32b-specific antibody), variation in the transgene copy number, integration of additional human genes, and overall higher expression of all FCGRs on myeloid cells compared to human. Unexpectedly, NVS32b induced severe acute generalized thrombosis in huFCGR mice upon iv dosing. Mechanistic evaluation on huFCGR and human platelets revealed distinct binding, activation and aggregation driven by NVS32b in both species. In huFCGR mice, the anti-CD32b antibody NVS32b binds platelet CD32a via both Fc and/or CDR (complementarity determining region) causing their activation while in human, NVS32b-binding requires platelet pre-activation and interaction of platelet CD32a via the Fc portion and an unknown platelet epitope via the CDR portion of NVS32b. We deemed the huFCGR mice to be over-predictive of the NVS32b-associated human thrombotic risk. Impact: In this study we elucidated the mechanism based on the thrombotic adverse events observed in huFCGR mice upon NVS32B dosing and were able to identify this safety liability which led to program termination. Therefore, this mouse model could be useful in research of immunotherapies targeting or involving FCGRs. Potential biological implications resulting from species differences in the FCGR expression pattern are nevertheless important to consider.

Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model

Cell and tissue research

2021 Jul 21

Namba, T;Ichii, O;Nakamura, T;Masum, MA;Otani, Y;Hosotani, M;Elewa, YHA;Kon, Y;
PMID: 34287716 | DOI: 10.1007/s00441-021-03495-8

The interleukin (IL) 36 subfamily belongs to the IL-1 family and is comprised of agonists (IL-36α, IL-36β, IL-36γ) and antagonists (IL-36Ra, IL-38). We previously reported IL-36α overexpression in renal tubules of chronic nephritis mice. To understand the localization status and biological relationships among each member of the IL-36 subfamily in the kidneys, MRL/MpJ-Faslpr/lpr mice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ-Faslpr/lpr mice exhibited disease onset from 3 months and severe nephritis at 6-7 months (early and late stages, respectively). Briefly, IL-36γ and IL-36Ra were constitutively expressed in murine kidneys, while the expression of IL-36α, IL-36β, IL-36Ra, and IL-38 was induced in MRL/MpJ-Faslpr/lpr mice. IL-36α expression was significantly increased and localized to injured tubular epithelial cells (TECs). CD44+-activated parietal epithelial cells (PECs) also exhibited higher IL-36α-positive rates, particularly in males. IL-36β and IL-38 are expressed in interstitial plasma cells. Quantitative indices for IL-36α and IL-38 positively correlated with nephritis severity. Similar to IL-36α, IL-36Ra localized to TECs and PECs at the late stage; however, MRL/MpJ-Faslpr/lpr and healthy MRL/MpJ mice possessed IL-36Ra+ smooth muscle cells in kidney arterial tunica media at both stages. IL-36γ was constitutively expressed in renal sympathetic axons regardless of strain and stage. IL-36 receptor gene was ubiquitously expressed in the kidneys and was induced proportional to disease severity. MRL/MpJ-Faslpr/lpr mice kidneys possessed significantly upregulated IL-36 downstream candidates, including NF-κB- or MAPK-pathway organizing molecules. Thus, the IL-36 subfamily contributes to homeostasis and inflammation in the kidneys, and especially, an IL-36α-dominant imbalance could strongly impact nephritis deterioration.

APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer\'s disease and age-matched non-demented brains

Molecular brain

2021 Jul 08

Ojo, JO;Reed, JM;Crynen, G;Vallabhaneni, P;Evans, J;Shackleton, B;Eisenbaum, M;Ringland, C;Edsell, A;Mullan, M;Crawford, F;Bachmeier, C;
PMID: 34238312 | DOI: 10.1186/s13041-021-00803-9

Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its direct influence on the molecular integrity of the cerebrovasculature compared to other APOE variants (APOE2 and APOE3) has been largely unexplored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains with different APOE genotypes. We first interrogated changes between healthy control cases to identify underlying genotype specific effects in cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. Oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction were the top significant pathways in E2E2 vs E3/E3cases. We also identified AD-dependent changes and their interactions with APOE genotype and found the highest number of significant proteins from this interaction was observed in the E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell-type specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E3/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E4/E4 cases. These proteomic changes provide novel insights into the longstanding link between APOE4 and cerebrovascular dysfunction, implicating a role for impaired autophagy, ER stress, and mitochondrial bioenergetics. These APOE4 dependent changes we identified could provide novel cerebrovascular targets for developing disease modifying strategies to mitigate the effects of APOE4 genotype on AD pathogenesis.

Peripheral Contribution of BDNF/TrkB signaling in Mediating Oral Cancer Pain

The Journal of Pain

2021 May 01

Arris, D;Grayson, M;Wu, P;Ganatra, S;Valenzuela, V;Ruparl, S;
| DOI: 10.1016/j.jpain.2021.03.012

Background: Oral cancer pain is debilitating and understanding mechanisms for it is critical to develop treatment strategies. Brain-derived neurotrophic factor (BDNF) signaling is elevated in oral tumor biopsies and has been reported to promote tumor progression. However, whether BDNF signaling in oral tumors contributes to cancer-induced pain is not known. Therefore, the current study evaluates a novel peripheral role of BDNF/TrkB signaling in oral cancer pain. Using an orthotopic mouse tongue cancer pain model, we determine BDNF levels and expression tumor-tongue and normal tongue tissues using ELISA and immunohistochemistry. Additionally, we evaluated the effect of local administration of BDNF neutralizing Ab as well as TrkB receptor antagonist (ANA12) in reversing pain-like behaviors in vivo. Further, we identified the sensory fiber type affected by local ANA12 treatment in tumor-bearing tongues using single-fiber tongue-nerve electrophysiology and characterized TrkB isoform expression in sensory neuronal subtypes innervating mouse tongue. Our data demonstrated that BDNF levels were up-regulated in superfusates and lysates of tumor tongues over normal tongues and that BDNF was expressed by the cancer cells within the tumor. Neutralization of BDNF or inhibition of TrkB activity (ANA12) within the tumor-bearing tongue reversed tongue-tumor induced pain-like behaviors. Single-fiber recordings of tongue-nerve preparations revealed that ANA12 reversed tumor-induced mechanical sensitivity of A-slow high threshold mechanoreceptors. Single-cell RTPCR of lingual neurons demonstrated expression of full-form TrkB and truncated TrkB in distinct neuronal subtypes. Our data suggests that BDNF is released from oral cancer cells at the site of tumor growth and activates TrkB-expressing lingual sensory fibers, thereby contributing to oral cancer pain. This is a novel finding and the first demonstration of a peripheral role for BDNF signaling in oral cancer pain. Targeting BDNF signaling peripherally may prove to be an effective treatment for cancer-induced pain as well as tumorigenesis.

High-fat diet induces follicular hyperkeratinization and predisposes to develop neutrophilic folliculitis in mice

The Journal of allergy and clinical immunology

2021 Mar 10

Nakamizo, S;Honda, T;Sato, T;Mamun, MA;Chow, Z;Duan, K;Lum, J;Tan, KJ;Tomari, K;Sato, R;Kitoh, A;Tay, ASL;Common, JEA;Guan, NL;Setou, M;Ginhoux, F;Kabashima, K;
PMID: 33713763 | DOI: 10.1016/j.jaci.2021.02.032

Neutrophilic folliculitis is an inflammatory condition of hair follicles. In some neutrophilic folliculitis, such as acne and hidradenitis suppurativa, follicular hyperkeratosis is also observed. Neutrophilic folliculitis is often induced and/or exacerbated by high-fat diet (HFD). However, the molecular mechanisms by which HFD affects neutrophilic folliculitis are not fully understood. To elucidate how HFD promotes the development of neutrophilic folliculitis. Mice were fed with HFD, and the skin was subjected to histological, RNA-sequencing and imaging mass spectrometry analyses. Phorbol 12-myristate 13-acetate (PMA) was used as an irritant to the skin to examine the effect of HFD on neutrophil accumulation around the hair follicles. Histological analysis revealed follicular hyperkeratosis in the skin of HFD-fed mice. RNA-sequencing analysis showed that genes related to keratinization, especially in upper hair follicular keratinocytes, were significantly upregulated in HFD-fed mice. Application of PMA to the skin induced neutrophilic folliculitis in HFD-fed mice, but not in normal diet (ND)-fed mice. Accumulation of neutrophils in the skin and around hair follicles was dependent on CXCR2 signaling, and CXCL1, a CXCR2 ligand, was produced mainly by hair follicular keratinocytes. Imaging mass spectrometry analysis revealed an increase of fatty acids in the skin, including oleic acids and palmitoleic acids in HFD-fed mice. Application of these fatty acids to the skin induced follicular hyperkeratosis, and caused PMA-induced neutrophilic folliculitis even in ND-fed mice. HFD can facilitate the development of neutrophilic folliculitis with the induction of hyperkeratosis of hair follicles and increased neutrophil infiltration around the hair follicles via CXCR2 signaling.

Cytopathology of Bronchoalveolar Lavages in COVID-19 Pneumonia: A Pilot Study

Cancer cytopathology

2021 Mar 10

Canini, V;Bono, F;Calzavacca, P;Capitoli, G;Foti, G;Fraggetta, F;Galimberti, S;Gianatti, A;Giani, M;Nasr, A;Paciocco, G;Pagni, F;Rona, R;L'Imperio, V;
PMID: 33690991 | DOI: 10.1002/cncy.22422

Bronchoalveolar lavage (BAL) in patients with severe coronavirus disease 2019 (COVID-19) may provide additional and complementary findings for the management of these patients admitted to intensive care units (ICUs). This study addresses the cytological features of the infection and highlights the more influential inflammatory components. The correlation between pathological variables and clinical data is also analyzed. The authors performed a retrospective analysis of the cytopathological features of BAL in 20 COVID-19 patients and 20 members of a matched cohort from a critical ICU who had acute respiratory distress syndrome caused by other pulmonary conditions. A comparison of the controls (n = 20) and the COVID-19 patients (n = 20) revealed that the latter had a higher neutrophil count (median, 63.8% of the cell count) with lower percentages of macrophages and lymphocytes. An increase in the expression of CD68-positive, monocytic multinucleated giant cells (MGCs) was reported; megakaryocytes were not detected on CD61 staining. Perls staining showed isolated elements. In situ RNA analysis demonstrated scattered chromogenic signals in type II pneumocytes. An ultrastructural analysis confirmed the presence of intracytoplasmic vacuoles containing rounded structures measuring 140 nm in diameter (putative viral particles). In COVID-19 patients, the clinicopathological correlation revealed a positive correlation between lactate dehydrogenase values and MGCs (r = 0.54). The analysis of BAL samples might be implemented as a routine practice for the evaluation of COVID-19 patients in ICUs in the appropriate clinical scenario. Additional studies using a larger sample size of patients who developed COVID-19 during the second wave of the epidemic in the autumn of 2020 are needed to further support our findings.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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