Air pollution nanoparticle and alpha-synuclein fibrils synergistically decrease glutamate receptor A1, depending upon nPM batch activity.

Background: Epidemiological studies have variably linked air pollution to increased risk of Parkinson's disease (PD). However, there is little experimental evidence for this association. Alpha-synuclein (α-syn) propagation plays central roles in PD and glutamate receptor A1 (GluA1) is involved in memory and olfaction function. Methods: Each mouse was exposed to one of three different batches of nano-particulate matter (nPM) (300 µg/m3, 5 h/d, 3 d/week), collected at different dates, 2017-2019, in the same urban site. After these experiments, these nPM batches were found to vary in activity. C57BL/6 female mice (3 mo) were injected with pre-formed murine α-synuclein fibrils (PFFs) (0.4 µg), which act as seeds for α-syn aggregation. Two exposure paradigms were used: in Paradigm 1, PFFs were injected into olfactory bulb (OB) prior to 4-week nPM (Batch 5b) exposure and in Paradigm 2, PFFs were injected at 4th week during 10-week nPM exposure (Batches 7 and 9). α-syn pSer129, microglia Iba1, inflammatory cytokines, and Gria1 expression were measured by immunohistochemistry or qPCR assays. Results: As expected, α-syn pSer129 was detected in ipsilateral OB, anterior olfactory nucleus, amygdala and piriform cortex. One of the three batches of nPM caused a trend for elevated α-syn pSer129 in Paradigm 1, but two other batches showed no effect in Paradigm 2. However, the combination of nPM and PFF significantly decreased Gria1 mRNA in both the ipsi- and contra-lateral OB and frontal cortex for the most active two nPM batches. Neither nPM nor PFFs alone induced responses of microglia Iba1 and expression of Gria1 in the OB and cortex. Conclusion: Exposures to ambient nPM had weak effect on α-syn propagation in the brain in current experimental paradigms; however, nPM and α-syn synergistically downregulated the expression of Gria1 in both OB and cortex.

A novel automated morphological analysis of Iba1+ microglia using a deep learning assisted model.

There is growing evidence for the key role of microglial functional state in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools Aiforia® Cloud (Aifoira Inc., Cambridge, MA, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinson's disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are available within the Aiforia® platform for study-specific adaptation and validation.

Evolution of Stronger SARS-CoV-2 Variants as Revealed Through the Lens of Molecular Dynamics Simulations.

Using molecular dynamics simulations, the protein-protein interactions of the receptor-binding domain of the wild-type and seven variants of the severe acute respiratory syndrome coronavirus 2 spike protein and the peptidase domain of human angiotensin-converting enzyme 2 were investigated. These variants are alpha, beta, gamma, delta, eta, kappa, and omicron. Using 100 ns simulation data, the residue interaction networks at the protein-protein interface were identified. Also, the impact of mutations on essential protein dynamics, backbone flexibility, and interaction energy of the simulated protein-protein complexes were studied. The protein-protein interface for the wild-type, delta, and omicron variants contained several stronger interactions, while the alpha, beta, gamma, eta, and kappa variants exhibited an opposite scenario as evident from the analysis of the inter-residue interaction distances and pair-wise interaction energies. The study reveals that two distinct residue networks at the central and right contact regions forge stronger binding affinity between the protein partners. The study provides a molecular-level insight into how enhanced transmissibility and infectivity by delta and omicron variants are most likely tied to a handful of interacting residues at the binding interface, which could potentially be utilized for future antibody constructs and structure-based antiviral drug design.

Vitamin D and COVID-19: A review on the role of vitamin D in preventing and reducing the severity of COVID-19 infection.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus causing COVID-19 infection. The interaction between the SARS-CoV-2 spike protein and the human receptor angiotensin-converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide-thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID-19. However, the molecular-level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID-19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID-19 infection or reducing the severity of the disease.

A novel approach to excision of distal tracheal granulation tissue in tracheostomy patients with difficult anatomy.

Tracheostomy predisposes patients to various complications. The most common late complication is granuloma formation; others include tracheal stenosis, bleeding, infection, and fistula development. Small granulomas may not require treatment, but large ones necessitate removal to prevent bleeding, obstruction, respiratory distress and, in rare cases, death. Various treatment options have been described, but no single modality has proved to be superior. We describe a novel approach to treating substomal tracheal granulation by using trans-stomal Coblation for patients whose granulation is difficult to visualize. This procedure offers several advantages over other means, including better hemostasis, less risk of distal tissue loss, ease of use, and potentially less operative time.

Nonsurgical options to treat giant-cell tumors of the head and neck: A case report and brief review of the literature.

Central giant-cell granulomas (CGCGs) are relatively uncommon. When they do occur, they typically arise in the mandible and maxilla. Some lesions are more destructive than others, and the destructive subtype has a tendency to recur. Unfortunately, there is no reproducible way to differentiate aggressive from nonaggressive subtypes. Treatment of CGCG has historically been based on surgical curettage or wide local excision. However, surgery has been associated with significant morbidity, disfigurement, and expense, as well as a high recurrence rate. Pharmacologic treatments-either as an alternative or an adjunct to surgery-have been shown to yield acceptable results. These agents include intralesional and/or systemic corticosteroids, bisphosphonates, calcitonin, and interferon alfa. These options are typically less expensive than surgery, and they are associated with few side effects, which makes them potentially more desirable. We report the case of a 36-year-old woman with a CGCG who was successfully treated with a combination of an intralesional steroid and an oral steroid over a period of 5 months. As evidenced by this case, medical management can be effective for tumor regression in treating CGCG of the head and neck, and it is ultimately associated with less morbidity and is less costly. To the best of our knowledge, no randomized controlled studies have been published on this topic. Such a study would be welcome, particularly considering the presence of both aggressive and nonaggressive subtypes of CGCG. We also briefly review the literature.

Synchronous bilateral tonsillar squamous cell carcinoma related to human papillomavirus: Two case reports and a brief review of the literature.

Human papillomavirus (HPV) was recently identified as a risk factor for oropharyngeal squamous cell carcinoma (SCC) independent of tobacco and alcohol use. The prognosis of patients with HPV-related oropharyngeal carcinomas is better than that for patients with non-HPV-related cancers. Researchers and clinicians can test for HPV infection in cancer by (1) testing directly for HPV DNA and (2) testing for overexpression of the downstream p16 protein; there is currently no consensus regarding which is the better test. The chances of developing a reliable oropharyngeal HPV screening test for high-risk populations are promising. Such a test would allow for secondary prevention by identifying individuals with precursor or early-stage cancerous lesions that are more amenable to treatment. HPV testing has particular significance in SCC of an unknown primary site in head and neck cancer. Successful HPV testing of nodal metastasis can localize cancer specifically to the oropharynx. The optimal evaluation for SCC of an unknown primary in the head and neck has yet to be determined. Some studies have shown that the tonsillar fossa is the most probable primary site, followed closely by the base of the tongue. Biopsies often miss tonsillar carcinoma in the deep crypts of the lymph tissue, as well as in those rare cases in which the primary tumor is located contralateral to the metastatic lymph node. Recently, there has been an increase in the number of reports of diagnosed synchronous bilateral HPV-related tonsillar carcinomas. This increase has profound implications for the surgical approach of SCC of an unknown primary site in the head and neck and in tonsillar carcinoma, and it supports the need for bilateral tonsillectomy. We present 2 cases of incidentally discovered synchronous bilateral tonsillar carcinoma, and we review the literature.

Unusual hard palate foreign body: a case report.

Foreign bodies embedded in the palate are exceedingly rare, and may imitate oral lesions. The majority of cases occur in infants and children. The following report discusses the unique presentation of a foreign body in the hard palate of an infant. This report emphasizes that foreign bodies must be considered in the differential of lesions found in the oral cavity of children.

Trimester of maternal gestational weight gain and offspring body weight at birth and age five.

To investigate associations of trimester-specific GWG with fetal birth size and BMI at age 5 years. We examined 3,015 singleton births to women without pregnancy complications from the Child Health and Development Studies prospective cohort with measured weights during pregnancy. We used multivariable regression to examine the associations between total and trimester gestational weight gain (GWG) and birth weight for gestational age and child BMI outcomes, adjusting for maternal age, race/ethnicity, education, marital status, parity, pre-pregnancy body mass index (BMI), and smoking; paternal overweight, gestational age, and infant sex. We explored differences in associations by maternal BMI and infant sex. GWG in all trimesters was significantly and independently associated with birth weight with associations stronger, though not significantly, in the second trimester. First trimester GWG was associated with child BMI outcomes (OR for child overweight = 1.05; 95% CI = 1.02, 1.09). Each kg of first trimester GWG was significantly associated with increased child BMI z-score in women of low (ß = 0.099; 95% CI = 0.034, 0.163) and normal (ß = 0.028; 95% CI = 0.012, 0.044), but not high pre-pregnancy BMI. GWG in all trimesters was associated with birth weight; only first trimester GWG was associated with child BMI. If replicated, this information could help specify recommendations for maternal GWG and elucidate mechanisms connecting GWG to child BMI.