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The Journal of Clinical Investigation Jun 2024Neutrophil infiltration occurs in a variety of liver diseases, but it is unclear how neutrophils and hepatocytes interact. Neutrophils generally use granule proteases to...
Neutrophil infiltration occurs in a variety of liver diseases, but it is unclear how neutrophils and hepatocytes interact. Neutrophils generally use granule proteases to digest phagocytosed bacteria and foreign substances or neutralize them in neutrophil extracellular traps. In certain pathological states, granule proteases play a destructive role against the host as well. More recently, non-destructive actions of neutrophil granule proteins have been reported, such as modulation of tissue remodeling and metabolism. Here we report a completely different mechanism by which neutrophils act non-destructively, by inserting granules directly into hepatocytes. Specifically, elastase-containing granules were transferred to hepatocytes where elastase selectively degraded intracellular calcium channels to reduce cell proliferation without cytotoxicity. In response, hepatocytes increased expression of serpin E2 and A3, which inhibited elastase activity. Elastase insertion was seen in patient specimens of alcohol-associated hepatitis, and the relationship between elastase-mediated ITPR2 degradation and reduced cell proliferation was confirmed in mouse models. Moreover, neutrophils from patients with alcohol-associated hepatitis were more prone to degranulation and more potent in reducing calcium channel expression than neutrophils from healthy subjects. This non-destructive and reversible action on hepatocytes defines a previously unrecognized role for neutrophils in the transient regulation of epithelial calcium signaling mechanisms.
PubMed: 38916955
DOI: 10.1172/JCI171691 -
Anatomy & Cell Biology Jun 2024The 7th cervical vertebra (C7) is described as having the most prominent spinous process (SP) and is characterized as the "vertebra prominens" (VP) of the cervical spine...
The 7th cervical vertebra (C7) is described as having the most prominent spinous process (SP) and is characterized as the "vertebra prominens" (VP) of the cervical spine in anatomy textbooks. The VP is an important anatomical landmark of the neck for clinical examination and therapeutic intervention. The present study identifies the level of the most prominent SP of the cervical and uppermost thoracic vertebrae in a cadaveric cohort. Thirty-nine (23 female and 16 male) cadavers of a mean age of 77.5 years were investigated in a prone position and a certain cervical kyphotic bending. The most prominent SP, at the base of the neck, was palpated and marked with a wedging nail into the SP of the vertebra. The cervical region was dissected, and a blind investigator examined whether the nail was placed into the SP of C7 or the SP of another upper or lower vertebra. In 19 out of 39 cadavers (48.7%), the C7 was identified as the VP (typical anatomy), followed by the C6 (in 14 cadavers, 35.9%), C5 (in 4 cadavers, 10.3%). In 2 cadavers (5.1%) the first thoracic vertebra was identified as having the most prominent SP. Although C7 is described as the VP, in the present study the SP of C7 was the most prominent in less than 50%. The high variable projection level of the most prominent SP of the cervical vertebra holds great clinical significance for spine examination, neck surgery, and spinal anesthesia.
PubMed: 38916082
DOI: 10.5115/acb.24.061 -
BioRxiv : the Preprint Server For... Jun 2024La-related protein 6 regulates the highly organized biosynthesis of type I procollagen polypeptides and affects proper assembly of procollagen peptides into...
La-related protein 6 regulates the highly organized biosynthesis of type I procollagen polypeptides and affects proper assembly of procollagen peptides into heterotrimers of type I procollagen. LARP6-mediated regulation of collagen biosynthesis is mediated through interaction with the 5' stem loop motif found in type I and III collagen mRNA. Recent studies highlight the involvement of HsLARP6 in fibroproliferative diseases and its potential as a target for therapeutic intervention. The intrinsic instability of the La domain of HsLARP6 hampers studies probing the molecular basis of biologically- and disease-relevant structure-function relationship, particularly when high concentrations are required. This work provides detailed procedures to produce milligram amounts of RNase-free and functional La domain of HsLARP6. Furthermore, we investigated the effect of the construct length as well as RNA binding on protein stability. N- and C-terminal extensions greatly impact stability based on interactions with the core domain and modulation of the pI. When in complex with its cognate 5'SL RNA, the La domain shows unprecedented stability compared to the aggregation-prone unbound state. The protein-RNA complex remains stable for at least 50x longer than the unbound state, under identical conditions, likely due to a global change in conformational plasticity upon RNA binding. These results provide a foundation for further studies of the molecular recognition of 5'SL by HsLARP6 as well as a platform for refining potential antifibrotic therapeutics.
PubMed: 38915490
DOI: 10.1101/2024.06.11.598414 -
International Journal of General... 2024Dementia is a common neurogenerative disease among older adults. Therefore, they are more prone to potentially inappropriate medication (PIM), which is medication that...
BACKGROUND
Dementia is a common neurogenerative disease among older adults. Therefore, they are more prone to potentially inappropriate medication (PIM), which is medication that causes more harm rather than protecting the health of an individual. Hence, the American Geriatrics Society (AGS) has recognized the risk of certain medication classes on this population and released PIM according to Beers criteria, which is a helpful guide for clinicians to ensure the safety of medication before it is prescribed. The aim of this study is to assess the prevalence of PIM use among older adults with dementia as a risk factor in comparison to other older adults without dementia.
METHODS
A retrospective study was conducted in an outpatient setting in a tertiary hospital targeting elderly patients aged 65 years old or over from January 2020 to September 2022. A total of 598 patients were screened, and 270 patients met the inclusion criteria. The eligible patients were then divided into two groups: 168 were in a non-dementia group and 102 were in a dementia group.
RESULTS
PIM use was reported in patients with and without dementia. The most inappropriate medication that was prescribed comprised atypical antipsychotics PIM for both patients with and without dementia. However, the prevalence was higher in the dementia group for quetiapine (75% vs 24% respectively), olanzapine (82% vs 17% respectively) or risperidone (92% vs 7%, respectively). Anticholinergics were highly prescribed in older adult without dementia as compared to dementia patient and was statistically significant for solifenacin (96% vs.3.6% respectively) and amitriptyline (88% vs 11% respectively).
CONCLUSION
Among elderly patients in outpatient care settings, the prevalence of PIM use is considered high in dementia patients for antipsychotics, while a higher use of benzodiazepine and anticholinergics was found in non-dementia patients.
PubMed: 38912331
DOI: 10.2147/IJGM.S456091 -
Iranian Journal of Public Health May 2024Compared with able-bodied people, speech disabilities are more prone to various mental health problems. We aimed to explore the impact of positive psychology-based...
BACKGROUND
Compared with able-bodied people, speech disabilities are more prone to various mental health problems. We aimed to explore the impact of positive psychology-based intervention strategies on emotional cognition, mental health, and recovery of speech function in speech disabilities.
METHODS
In May 2023, 306 cases of speech disabilities were selected from 112 village committees and 129 neighborhood committees in Jingmen City, China. The control group was given routine speech rehabilitation training, and the observation group was given an intervention strategies-based on positive psychology based on the above training. The Symptom Checklist-90 (SCL-90), Chinese Facial Emotion Test (CFET), Comprehensive Function Assessment for Disabled Children (CFADC), and Boston Diagnostic Aphasia Examination (BDAE) were used to evaluate the two groups of patients before and after intervention.
RESULTS
After the intervention, the mental state scores (psychotic, obsessive-compulsive symptoms, somatization, paranoia, terror, hostility, anxiety, and depression) of the observation group were lower than those of the control group (<0.05). The correct emotional scores in the observation group were higher than those in the control group were. However, the remote error scores of the observation group were lower than those of the control group were. The difference was also statistically significant (<0.05). The cognitive function score, speech function score, and BDAE score (retelling, writing, fluency, and reading comprehension) of the observation group were all higher than those of the control group (<0.05).
CONCLUSION
The intervention strategies-based on positive psychology could promote the improvement of health problems and speech function in speech disabilities.
PubMed: 38912140
DOI: 10.18502/ijph.v53i5.15588 -
Annals of Translational Medicine Jun 2024Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of...
BACKGROUND
Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of sex, is the infrapatellar fat pad (IFP). We previously demonstrated that removal of the IFP had short-term beneficial effects for a cohort of male Dunkin-Hartley guinea pigs. The present project was designed to elucidate the influence of IFP removal in females of this OA-prone strain. It was hypothesized that resection of the IFP would reduce the development of OA in knees of a rodent model predisposed to the disease.
METHODS
Female guinea pigs (n=16) were acquired at an age of 2.5 months. Surgical removal of the IFP and associated synovium complex (IFP/SC) was executed at 3 months of age. One knee had the IFP/SC resected; a comparable sham surgery was performed on the contralateral knee. All animals were subjected to voluntary enclosure monitoring and dynamic weight-bearing, as well as compulsory treadmill-based gait analysis monthly; baseline data was collected prior to surgery. Guinea pigs were euthanized at 7 months. Knees from eight animals were evaluated via histology, mRNA expression, and immunohistochemistry (IHC); knees from the remaining eight animals were allocated to microcomputed tomography (microCT), biomechanical analyses (whole joint testing and indentation relaxation testing), and atomic absorption spectroscopy (AAS).
RESULTS
Fibrous connective tissue (FCT) replaced the IFP/SC. Mobility/gait data indicated that unilateral IFP/SC removal did not affect bilateral hindlimb movement. MicroCT demonstrated that osteophytes were not a significant feature of OA in this sex; however, trabecular thickness (TbTh) in medial femorae decreased in knees containing the FCT. Histopathology scores were predominantly influenced by changes in the lateral tibia, which demonstrated that histologic signs of OA were increased in knees containing the native IFP/SC versus those with the FCT. Similarly, indentation testing demonstrated higher instantaneous and equilibrium moduli in the lateral tibial articular cartilage of control knees with native IFPs. AAS of multiple tissue types associated with the knee revealed that zinc was the major trace element influenced by removal of the IFP/SC.
CONCLUSIONS
Our data suggest that the IFP/SC is a significant component driving knee OA in female guinea pigs and that resection of this tissue prior to disease has short-term benefits. Specifically, the formation of the FCT in place of the native tissue resulted in decreased cartilage-related OA changes, as demonstrated by reduced Osteoarthritis Research Society International (OARSI) histology scores, as well as changes in transcript, protein, and cartilage indentation analyses. Importantly, this model provides evidence that sex needs to be considered when investigating responses and associated mechanisms seen with this intervention.
PubMed: 38911554
DOI: 10.21037/atm-23-1886 -
MicroPublication Biology 2024CasDinG is an ATP-dependent 5'-3' DNA helicase essential for bacterial Type IV-A1 CRISPR associated immunity. CasDinG contains an essential N-terminal domain predicted...
CasDinG is an ATP-dependent 5'-3' DNA helicase essential for bacterial Type IV-A1 CRISPR associated immunity. CasDinG contains an essential N-terminal domain predicted to bind DNA. To better understand the role of the N-terminal domain, we attempted to co-crystallize CasDinG with DNA substrates. We successfully crystallized CasDinG in a tightly packed, crystal conformation with previously unobserved unit cell dimensions. However, the structure lacked electron density for a bound DNA substrate and the CasDinG N-terminal domain. Additionally, the tight crystal packing disallowed space for the N-terminal domain, indicating that the N-terminal domain was proteolyzed before crystallization. Follow up experiments revealed that the N-terminal domain of CasDinG is proteolyzed after a few days at room temperature, but is protected from proteolysis at 4°C. These data provide a distinct x-ray crystal structure of CasDinG and indicate the essential N-terminal domain of CasDinG is prone to proteolysis.
PubMed: 38911435
DOI: 10.17912/micropub.biology.001226 -
Journal of Cancer 2024Skin cutaneous melanoma (SKCM) is a highly malignant tumor that is prone to immune escape and distant metastasis. Immunotherapy is considered to be the best treatment...
Skin cutaneous melanoma (SKCM) is a highly malignant tumor that is prone to immune escape and distant metastasis. Immunotherapy is considered to be the best treatment for patients with SKCM. However, not all patients benefit from it. We observed a significant differential expression of the lncRNA CYTOR in patients with SKCM based on single-cell and bulk RNA sequencing data mining results. The results showed that compared to normal tissue lncRNA CYTOR expression was significantly upregulated in SKCM tissue. Subsequently, we validated this finding in clinical samples, and we also found that the expression of lncRNA CYTOR in SKCM was higher as it progressed. lncRNA CYTOR was differentially expressed in patients who responded to immunotherapy, suggesting that it may serve as a biomarker to predict the efficacy of SKCM immunotherapy. In-depth analysis revealed that lncRNA CYTOR expression was strongly correlated with immune cell infiltration, immune response, and immune checkpoint expression. Meanwhile, our experiments revealed that CYTOR affects SKCM cell invasion and clone formation and is associated with the activation of the EMT pathway. In summary, our findings illustrate, for the first time, the value of CYTOR as a potential prognostic and immunotherapeutic response marker in SKCM.
PubMed: 38911384
DOI: 10.7150/jca.94823 -
Frontiers in Pediatrics 2024Multiple-breath washout (MBW) is a sensitive method for assessing lung volumes and ventilation inhomogeneity in infants, but remains prone to artefacts (e.g., sighs)....
BACKGROUND
Multiple-breath washout (MBW) is a sensitive method for assessing lung volumes and ventilation inhomogeneity in infants, but remains prone to artefacts (e.g., sighs). There is a lack of tools for systematic retrospective analysis of existing datasets, and unlike N-MBW in older children, there are few specific quality control (QC) criteria for artefacts in infant SF-MBW.
AIM
We aimed to develop a computer-based tool for systematic evaluation of visual QC criteria of SF-MBW measurements and to investigate interrater agreement and effects on MBW outcomes among three independent examiners.
METHODS
We developed a software package for visualization of raw Spiroware (Eco Medics AG, Switzerland) and signal processed WBreath (ndd Medizintechnik AG, Switzerland) SF-MBW signal traces. Interrater agreement among three independent examiners (two experienced, one novice) who systematically reviewed 400 MBW trials for visual artefacts and the decision to accept/reject the washin and washout were assessed.
RESULTS
Our tool visualizes MBW signals and provides the user with (i) display options (e.g., zoom), (ii) options for a systematic QC assessment [e.g., decision to accept or reject, identification of artefacts (leak, sigh, irregular breathing pattern, breath hold), and comments], and (iii) additional information (e.g., automatic identification of sighs). Reviewer agreement was good using pre-defined QC criteria (κ 0.637-0.725). Differences in the decision to accept/reject had no substantial effect on MBW outcomes.
CONCLUSION
Our visual quality control tool supports a systematic retrospective analysis of existing data sets. Based on predefined QC criteria, even inexperienced users can achieve comparable MBW results.
PubMed: 38910962
DOI: 10.3389/fped.2024.1393291 -
Cureus May 2024Eosinophilic chronic rhinosinusitis (ECRS) is a refractory type 2 inflammation-based airway allergic disease that is prone to complications such as bronchial asthma....
Eosinophilic chronic rhinosinusitis (ECRS) is a refractory type 2 inflammation-based airway allergic disease that is prone to complications such as bronchial asthma. Pott's puffy tumor (PPT) is a rare clinical entity characterized by osteomyelitis of the frontal bone accompanied by a subperiosteal abscess. A 56-year-old female with a history of cranial surgery and bronchial asthma presented to an otolaryngology clinic with nasal obstruction and loss of smell, later developing swelling and redness on her forehead. She was diagnosed and treated for ECRS and was thought to have developed PPT during her course. Nasal endoscopy reveals bilateral polyp formation originating from the middle meatus. Paranasal computed tomography (CT) indicates substantial swelling extending from the opening of the frontal sinus to the adjacent subcutaneous tissue, accompanied by a defect in the frontal bone and osteolysis at the base of the frontal skull. Her management included conservative antibiotic therapy adjusted due to a drug eruption and, subsequently, endoscopic sinus surgery (ESS). The case was complicated by the patient's medical history and the absence of detailed surgical records, which limited the use of enhanced imaging techniques. This underscores the complexity of diagnosing and managing PPT in adults, particularly those with prior surgeries, emphasizing the need for a tailored diagnostic and therapeutic approach that integrates detailed patient history with current clinical indicators to effectively guide treatment. This case contributes to the limited literature on adult PPT and underscores the critical need for careful patient monitoring and detailed surgical history.
PubMed: 38910757
DOI: 10.7759/cureus.60893