ACE2-Independent Alternative Receptors for SARS-CoV-2.

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is highly contagious and remains a major public health challenge despite the availability of effective vaccines. SARS-CoV-2 enters cells through the binding of its spike receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 (ACE2) receptor in concert with accessory receptors/molecules that facilitate viral attachment, internalization, and fusion. Although ACE2 plays a critical role in SARS-CoV-2 replication, its expression profiles are not completely associated with infection patterns, immune responses, and clinical manifestations. Additionally, SARS-CoV-2 infects cells that lack ACE2, and the infection is resistant to monoclonal antibodies against spike RBD in vitro, indicating that some human cells possess ACE2-independent alternative receptors, which can mediate SARS-CoV-2 entry. Here, we discuss these alternative receptors and their interactions with SARS-CoV-2 components for ACE2-independent viral entry. These receptors include CD147, AXL, CD209L/L-SIGN/CLEC4M, CD209/DC-SIGN/CLEC4L, CLEC4G/LSECtin, ASGR1/CLEC4H1, LDLRAD3, TMEM30A, and KREMEN1. Most of these receptors are known to be involved in the entry of other viruses and to modulate cellular functions and immune responses. The SARS-CoV-2 omicron variant exhibits altered cell tropism and an associated change in the cell entry pathway, indicating that emerging variants may use alternative receptors to escape the immune pressure against ACE2-dependent viral entry provided by vaccination against RBD. Understanding the role of ACE2-independent alternative receptors in SARS-CoV-2 viral entry and pathogenesis may provide avenues for the prevention of infection by SARS-CoV-2 variants and for the treatment of COVID-19.

Dynamic Optics with Transparency and Color Changes under Ambient Conditions.

Mechanochromic materials have recently received tremendous attention because of their potential applications in humanoid robots, smart windows, strain sensors, anti-counterfeit tags, etc. However, improvements in device design are highly desired for practical implementation in a broader working environment with a high stability. In this article, a novel and robust mechanochromism was designed and fabricated via a facile method. Silica nanoparticles (NPs) that serve as a trigger of color switch were embedded in elastomer to form a bi-layer hybrid film. Upon stretching under ambient conditions, the hybrid film can change color as well as transparency. Furthermore, it demonstrates excellent reversibility and reproducibility and is promising for widespread application.

Safety of Rectal Administration of Acetaminophen in Neonates.

BACKGROUND: On the basis of pharmacokinetic modelling, high-dose acetaminophen by rectal administration has been recommended for neonates needing antipyretic or analgesic therapy, but the safety and efficacy of this approach have not been established in vivo. OBJECTIVES: The primary objective was to assess the safety of rectal acetaminophen administration for neonates, as indicated by changes in the results of hepatic and renal function tests. The secondary objective was to assess the efficacy of rectal acetaminophen administration in terms of the Premature Infant Pain Profile-Revised (PIPP-R) score. METHODS: This single-centre retrospective chart analysis was conducted in the neonatal intensive care unit at a quaternary care children's hospital. Neonates who received all prescribed doses of acetaminophen by continu - ous rectal administration for 24 h or more, from January 1, 2011, to December 31, 2012, were included. For the primary objective, hepatotoxicity was assessed in terms of changes in liver enzyme levels, and nephrotoxicity was assessed in terms of changes from baseline serum creatinine values. RESULTS: Twenty-five patients, who received a total of 27 courses of acetaminophen by rectal administration, met the inclusion criteria. Median gestational age at initiation of acetaminophen was 37.0 weeks (interquartile range 35.0-39.8 weeks). Values of alanine aminotransferase remained within normal limits during acetaminophen therapy for all but 3 patients, for whom the changes were attributable to confounding factors. Renal function remained unchanged. The secondary outcome of efficacy (based on PIPP-R score) could not be evaluated because of concurrent use of opioids for most patients. CONCLUSIONS: Continuous rectal administration of acetaminophen over a short period (< 48 h) appeared to be well tolerated. The conclusions that can be drawn from these results are limited because of small sample size, the prescribing of doses lower than those recommended by the hospital's formulary, and limited blood sampling. Further studies are required.

CONTEXTE: Selon une modélisation pharmacocinétique, des doses élevées d'acétaminophène administré par voie rectale ont été recommandées comme traitement antipyrétique ou analgésique chez le nouveau-né, mais l'innocuité et l'efficacité de cette modalité d'administration n'ont pas été établies in vivo. OBJECTIFS: L'objectif principal était d'évaluer l'innocuité de l'acétaminophène administré par voie rectale chez le nouveau-né en observant les changements dans les résultats des bilans hépatique et rénal. L'objectif secondaire était d'évaluer l'efficacité de l'acétaminophène administré par voie rectale à l'aide du score obtenu dans le Premature Infant Pain Profile-Revised (PIPP-R). MÉTHODES: La présente étude rétrospective menée dans un seul centre comportait une analyse des dossiers médicaux de patients admis à l'unité de soins intensifs néonatals d'un établissement de soins quaternaires pour enfants. Les nouveau-nés ayant reçu toutes les doses prescrites d'acétaminophène par administration rectale ininterrompue pendant 24 heures ou plus, entre le 1er janvier 2011 et le 31 décembre 2012, étaient admissibles à l'étude. Pour l'objectif principal, l'hépatotoxicité a été évaluée en fonction des variations observées dans les taux d'enzymes hépatiques et la néphrotoxicité a été évaluée en fonction des changements observés dans la créatininémie par rapport aux valeurs de départ. RÉSULTATS: Vingt-cinq patients qui ont reçu un total de 27 traitements par acétaminophène administré par voie rectale répondaient aux critères d'inclusion. L'âge gestationnel médian lors de l'amorce du traitement par acétaminophène était de 37,0 semaines (écart interquartile de 35,0 semaines à 39,8 semaines). Les valeurs d'alanine-aminotransférase demeuraient à l'intérieur des limites normales pendant le traitement par acétaminophène pour tous les patients à l'exception de trois pour lesquels les changements étaient attribués à des facteurs de confusion. La fonction rénale demeurait inchangée. Le critère d'évaluation secondaire quant à l'efficacité (s'appuyant sur le score obtenu dans le PIPP-R) n'a pu être évalué en raison de la prise concomitante d'opioïdes chez la plupart des patients. CONCLUSIONS: L'administration rectale ininterrompue d'acétaminophène pendant une courte période (moins de 48 heures) semblait être bien tolérée. Cependant, les conclusions qui peuvent être tirées de ces résultats sont limitées en raison de la petite taille de l'échantillon, de la prescription de doses plus faibles que celles recommandées dans la liste des médicaments de l'hôpital et de l'insuffisance des échantillons sanguins. De plus amples études sont nécessaires.

Restoration of Retarded Influenza Virus-specific Immunoglobulin Class Switch in Aged Mice.

OBJECTIVE: The declined immune response to infection causes significant higher morbidity and mortality in aging in spite of the coexisted hyperimmunoglobulinemia (HIG). This study is to reveal the cellular basis of HIG and mechanism of weakened HA-specific IgG response in aged mice and to test cell therapy in the treatment of age-related IgG antibody production deficiency with immunocyte adoptive transfer. METHODS: BALB/c mice was immunized with Influenza A/Taiwan vaccine and challenged with the same strain of virus. ELISA was used to assess the levels of total immunoglobulins and antigen specific antibody response. The flow cytometry and ELISPOT were used to evaluate the frequencies of total immunoglobulin- and specific antibody-producing and secreting B lymphocytes. In vitro expanded mononuclear cells, CD4+ T lymphocytes and CD20+ B lymphocytes from old and young mice were adoptively transferred into influenza virus-challenged aged mice, and HA-specific IgG responses were observed. RESULTS: It is found that old mice exhibited higher levels of total serum IgG, IgM and IgA, higher frequencies of IgG+, IgM+ and IgA+ cells, and greater antigen-specific IgM and IgA responses to influenza infection, in comparison to young mice. However, influenza antigen- specific IgG and its subclass responses in old mice were significantly lower. CONCLUSION: The retarded specific IgG response could be attributed to an insufficiency of immunoglobulin class switch in aging. Correlation analysis indicated that HIG and deficient specific IgG production in aged mice could be independent to each other in their pathogenesis. Correction of deficient specific IgG production by adoptive transfer of in vitro expanded and unexpanded CD4+ cells from immunized young mice suggests the CD4+ cell dysfunction contributes to the insufficiency of immunoglobulin class switch in aged mice. The transfusion of in vitro expanded lymphocytes could be a potential effective therapy for the age-related immunodeficiency and could play a role in the infection prevention in aging.

Enhancing Cognitive Function Using Perceptual-Cognitive Training.

Three-dimensional multiple object tracking (3D-MOT) is a perceptual-cognitive training system based on a 3D virtual environment. This is the first study to examine the effects of 3D-MOT training on attention, working memory, and visual information processing speed as well as using functional brain imaging on a normative population. Twenty university-aged students were recruited and divided into a training (NT) and nonactive control (CON) group. Cognitive functions were assessed using neuropsychological tests, and correlates of brain functions were assessed using quantitative electroencephalography (qEEG). Results indicate that 10 sessions of 3D-MOT training can enhance attention, visual information processing speed, and working memory, and also leads to quantifiable changes in resting-state neuroelectric brain function.

Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.

Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.

Strabismus surgery outcomes after scleral buckling procedures for retinal reattachment.

OBJECTIVE: To investigate the outcomes of strabismus surgery in patients with a prior history of a scleral buckling procedure for retinal reattachment. METHODS: We reviewed the medical records of 18 patients who underwent strabismus surgery following a scleral buckling procedure and investigated the effect of multiple variables on postoperative alignment after strabismus surgery including gender, age, surgeon, number of strabismus surgeries, adjustable suture use, previous pars plana vitrectomy, preoperative best-corrected visual acuity, and scleral buckle removal. Outcomes were considered successful if there was ≤ 10 prism diopters (PD) residual horizontal and/or ≤ 4 PD residual vertical deviations. Statistical analyses were performed using Fisher's exact test, Mann-Whitney test, and nominal logistic regression. RESULTS: Success using our criteria of motor alignment was achieved in 6 of 18 eyes (33%). A higher rate of success was found in the scleral buckle removal group (success with buckle removal, 62.5%; success without buckle removal, 10.0%; p = 0.04). Nominal logistic regression analysis showed scleral buckle removal was the most significant factor associated with successful surgical alignment (p = 0.03; odds ratio = 16.67). Although the success rate was higher in the adjustable suture group (50% in adjustable group vs 14.3% in non-adjustable group: Fisher's exact test, p = 0.30), this difference was not statistically significant. No retinal redetachments occurred after scleral buckle removal. CONCLUSIONS: These results suggest that scleral buckles can be safely removed in selected patients with strabismus following retinal reattachment surgery and scleral buckle removal may improve ocular alignment following strabismus surgery.

The association between compliance with recommended follow-up and glaucomatous disease severity in a county hospital population.

PURPOSE: To assess the association between insufficient follow-up and clinical parameters such as disease severity and medication use among glaucoma patients at a metropolitan county hospital. DESIGN: Cross-sectional study. METHODS: Two-hundred and six patients with established glaucoma were recruited from San Francisco General Hospital. Subjects were classified based on compliance with recommended follow-up examination intervals over the year preceding commencement of the study, as determined by patient medical records. Glaucoma severity was determined based on the American Academy of Ophthalmology Preferred Practice Patterns guidelines. Multivariate logistic regression analysis was used to assess the relationship between adherence with follow-up visits and disease severity. RESULTS: After adjustment for the impact of potential confounding variables, subjects with severe glaucomatous disease were found to have been less adherent to their recommended follow-up than those patients with mild or moderate glaucomatous disease (adjusted OR 1.89, 95% CI 1.21-2.94; P = .01). Subjects who were on glaucoma medications were found to be less adherent to follow-up recommendations (adjusted OR 3.29, 95% CI 1.41-7.65, P = .01). CONCLUSION: Subjects with poor follow-up adherence were significantly more likely to have severe glaucomatous disease, suggesting that poor follow-up may contribute to disease worsening or, alternatively, those with more severe disease are less inclined to follow up at appropriate intervals.

Glaucoma severity and medication adherence in a county hospital population.

OBJECTIVE: To assess the association between disease severity and adherence with glaucoma medications in a county hospital population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 126 patients diagnosed with glaucoma receiving intraocular pressure (IOP)-lowering medication were recruited from the San Francisco General Hospital Ophthalmology Clinic. METHODS: Subjects completed an oral questionnaire to assess demographic information, knowledge of glaucoma, and perceptions of glaucoma medication adherence. Glaucoma disease severity was classified according to the American Academy of Ophthalmology's Preferred Practice Pattern guidelines. Medication adherence was measured for each patient by obtaining pharmacy refill data and calculating medication possession ratio (MPR), that is, the ratio of total days' supply of medication during a 365-day period. Adherence was measured retrospectively over the 18-month period before study entry. Subjects with an MPR >80% were considered adherent. MAIN OUTCOME MEASURE: Medication adherence. RESULTS: Subjects with mild or moderate glaucoma were more likely to be nonadherent to their prescribed glaucoma medications than those with severe disease (adjusted odds ratio [OR], 1.54; 95% confidence interval [CI], 1.03-2.31; P = 0.04). Age, gender, race, education level, years of glaucoma, number of medications, and glaucoma diagnosis were not found to be statistically significantly associated with adherence. CONCLUSION: Patients with severe glaucoma were more likely to adhere to their topical IOP-lowering medication regimen than those with milder glaucomatous disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The societal burden of blindness secondary to retinopathy of prematurity in Lima, Peru.

PURPOSE: To determine the cost-effectiveness of laser treatment for retinopathy of prematurity (ROP) in Lima, Peru. DESIGN: A cost-of-illness study (in US dollars) to determine the direct cost of treatment, the indirect lifetime cost of blindness, and the quality-adjusted life years. METHODS: The direct cost of ROP-related treatment was determined by reviewing data retrospectively from a social security sector hospital. The indirect cost was determined using national economic data of Peru published by the Central Information Agency (CIA), including the per capita gross domestic product, the sex-adjusted income distribution, and years spent in the work force. Indirect costs per child that were avoided by treatment were calculated using the known natural history of ROP vs evidence-based treatment. RESULTS: For ROP-related neonatal blindness in Peru, we estimate the total indirect cost saving at $197,753 per child and the direct cost of laser treatment at $2496 per child. The societal lifetime cost saving per child is estimated at $195,257. The mean annual income per educated adult in Peru is $8000 and treating 1 child is equivalent to employing 24 educated Peruvians per year. The generational cost savings for society is approximately $516 million, or the equivalent of 64,500 educated Peruvian work years. CONCLUSIONS: The societal burden of blindness far exceeds the costs of treatment per child. Proper screening and treatment of ROP prevents blindness and leads to substantial cost savings for society. Public health policy in Peru and other middle-income countries should consider financial impact when allocating healthcare resources.

Improved ocular alignment with adjustable sutures in adults undergoing strabismus surgery.

OBJECTIVE: To assess whether outcomes of strabismus surgery are improved by using the adjustable suture technique and to determine which subgroups of strabismus patients benefit most from the adjustable suture technique. DESIGN: A retrospective chart review. PARTICIPANTS: A total of 535 adults who underwent strabismus surgery between 1989 and 2010. METHODS: Success was defined as ≤10 prism diopters (PD) for horizontal deviations and ≤2 PD for vertical deviations. Differences in the proportion of successful strabismus surgery were analyzed using a chi-square test with an alpha of 0.05. MAIN OUTCOME MEASURES: Ocular alignment in primary position at a 7-day to 12-week follow-up examination. RESULTS: A total of 491 patients met the inclusion criteria (nonadjustable suture, n = 186; adjustable suture, n = 305). The success rates for the nonadjustable and adjustable groups were 61.3% and 74.8%, respectively (χ(2)=9.91, P=0.0016). Adjustable suture use was particularly beneficial for patients undergoing a reoperation for childhood strabismus (success rate: nonadjustable, 42.4%; adjustable, 65.7%; P=0.0268; n = 100). The differences in outcomes were not statistically significant for patients with childhood strabismus undergoing a primary surgery (nonadjustable, 65.0%; adjustable, 81.4%; P=0.1354; n = 90) or with thyroid orbitopathy (nonadjustable, 76.7%; adjustable, 74.1%; P=0.8204; n = 57). CONCLUSIONS: Strabismus surgery using adjustable sutures was associated with improved short-term ocular alignment compared with strabismus surgery without the use of adjustable sutures. Adjustable sutures were most beneficial for patients undergoing reoperations for childhood strabismus.

Disrupted postnatal lung development in heme oxygenase-1 deficient mice.

BACKGROUND: Heme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin. The HO-1 isoform is both inducible and cyto-protective during oxidative stress, inflammation and lung injury. However, little is known about its precise role and function in lung development. We hypothesized that HO-1 is required for mouse postnatal lung alveolar development and that vascular expression of HO-1 is essential and protective during postnatal alveolar development. METHODS: Neonatal lung development in wildtype and HO-1 mutant mice was evaluated by histological and molecular methods. Furthermore, these newborn mice were treated with postnatal dexamethasone (Dex) till postnatal 14 days, and evaluated for lung development. RESULTS: Compared to wildtype littermates, HO-1 mutant mice exhibited disrupted lung alveolar structure including simplification, disorganization and reduced secondary crest formation. These defects in alveolar development were more pronounced when these mice were challenged with Dex treatment. Expression levels of both vascular endothelial and alveolar epithelial markers were also further decreased in HO-1 mutants after Dex treatment. CONCLUSIONS: These experiments demonstrate that HO-1 is required in normal lung development and that HO-1 disruption and dexamethasone exposure are additive in the disruption of postnatal lung growth. We speculate that HO-1 is involved in postnatal lung development through modulation of pulmonary vascular development.

Mass spectrometric genomic data mining: Novel insights into bioenergetic pathways in Chlamydomonas reinhardtii.

A new high-throughput computational strategy was established that improves genomic data mining from MS experiments. The MS/MS data were analyzed by the SEQUEST search algorithm and a combination of de novo amino acid sequencing in conjunction with an error-tolerant database search tool, operating on a 256 processor computer cluster. The error-tolerant search tool, previously established as GenomicPeptideFinder (GPF), enables detection of intron-split and/or alternatively spliced peptides from MS/MS data when deduced from genomic DNA. Isolated thylakoid membranes from the eukaryotic green alga Chlamydomonas reinhardtii were separated by 1-D SDS gel electrophoresis, protein bands were excised from the gel, digested in-gel with trypsin and analyzed by coupling nano-flow LC with MS/MS. The concerted action of SEQUEST and GPF allowed identification of 2622 distinct peptides. In total 448 peptides were identified by GPF analysis alone, including 98 intron-split peptides, resulting in the identification of novel proteins, improved annotation of gene models, and evidence of alternative splicing.