Polymorphic Self-Assembly with Procedural Flexibility for Monodisperse Quaternary Protein Structures of DegQ Enzymes.

As large molecular tertiary structures, some proteins can act as small robots that find, bind, and chaperone target protein clients, showing the potential to serve as smart building blocks in self-assembly fields. Instead of using such intrinsic functions, most self-assembly methodologies for proteins aim for de novo-designed structures with accurate geometric assemblies, which can limit procedural flexibility. Here, a strategy enabling polymorphic clustering of quaternary proteins, exhibiting simplicity and flexibility of self-assembling paths for proteins in forming monodisperse quaternary cage particles is presented. It is proposed that the enzyme protomer DegQ, previously solved at low resolution, may potentially be usable as a threefold symmetric building block, which can form polyhedral cages incorporated by the chaperone action of DegQ in the presence of protein clients. To obtain highly monodisperse cage particles, soft, and hence, less resistive client proteins, which can program the inherent chaperone activity of DegQ to efficient formations of polymorphic cages, depending on the size of clients are utilized. By reconstructing the atomic resolution cryogenic electron microscopy DegQ structures using obtained 12- and 24-meric clusters, the polymorphic clustering of DegQ enzymes is validated in terms of soft and rigid domains, which will provide effective routes for protein self-assemblies with procedural flexibility.

Risk factors and clinical features for pulmonary paragonimiasis-associated pneumothorax.

BACKGROUND: Pulmonary paragonimiasis, a food-borne zoonotic helminthiasis, is a parasitic disease of the lung caused by infection with trematodes species of the genus Paragonimus. Although pneumothorax has been reported as occuring with paragonimiasis, to date no study has been performed concerning the clinical features and predictive risk factors for this condition. METHODS: This retrospective study, which aims to fill this gap, was conducted at Jeonbuk National University Hospital. All patients (aged ≥19 years) were diagnosed with paragonimiasis between May 2011 and December 2021. Medical records were reviewed and information concerning age, sex, vital signs, underlying diseases, clinical signs and symptoms, laboratory findings, radiologic findings, treatment, and clinical outcomes was collected. An odds ratio (OR) for the risk factors associated with pneumothorax was calculated using the binary logistic regression model. RESULTS: Among 179 consecutive patients diagnosed with pulmonary paragonimiasis, the postive rate of pneumothorax was 10.6% (19/179). Pneumothorax occurred mostly in the right lung (78.9%, 15/19), and intrapulmonary parenchymal lesions showed an ipsilateral relationship with pneumothorax (94.7%, 18/19). Fifteen patients (78.9%, 15/19) of pneumothorax associated with pulmonary paragonimiasis are accompanied by pleural effusion. Most of patients with pneumothorax (89.5%, 17/19) underwent chest tube insertion as a first treatment. Three patients (15.8%) showed relapses but in no case was a death recorded. Asthma (odds ratio [OR] 8.10, 95% confidence interval [CI] 1.43-45.91), chest pain (OR 8.15, 95% CI 2.70-24.58), and intrapulmonary lesions (OR 8.94, 95% CI 1.12-71.36) were independent risk factors for pulmonary paragonimiasis-associated pneumothorax. CONCLUSIONS: Our findings suggest that clinicians should keep in mind the possibility of pneumothorax when approached by patients with pulmonary paragonimiasis complaining of chest pain, accompanied by intrapulmonary lesions or with asthma as an underlying disease.

Empirical vs pre-emptive broad-spectrum antifungal therapy for acute myelogenous leukaemia in the era of antimould prophylaxis.

INTRODUCTION: This study compared clinical outcomes in patients with acute myelogenous leukaemia (AML) who developed prolonged (≥4 days) febrile neutropenia (FN) and received either empirical or pre-emptive antimould prophylaxis in order to evaluate the need for routine empirical antifungal therapy. METHODS: This retrospective study reviewed adult patients (aged ≥18 years) with AML who developed prolonged FN and received antimould prophylaxis during induction or re-induction chemotherapy at a single centre between September 2016 and December 2020. Patients were categorized into pre-emptive or empirical groups based on whether or not there was clinical evidence of invasive fungal infection (IFI) at the start of antifungal treatment, respectively. Clinical outcomes were compared between the two groups after propensity score matching (PSM). RESULTS: In total, 229 chemotherapy episodes (36 and 193 in the empirical and pre-emptive groups, respectively) were analysed. In the pre-emptive group, broad-spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 PSM, there were no significant differences between the empirical and pre-emptive groups in terms of the incidence of proven or probable IFI [0/36 (0%) vs 5/97 (5.2%); P=0.323], all-cause mortality [3/36 (8.3%) vs 4/97 (4.1%); P=0.388] and IFI-related mortality [0/36 (0.0%) vs 1/45 (2.2%); P=0.556]. CONCLUSION: The differences in clinical outcomes between empirical and pre-emptive antifungal therapy in patients with AML who received antimould prophylaxis were not significant. Therefore, broad-spectrum antifungal therapy in patients receiving antimould prophylaxis may be delayed until there is clear evidence of IFI.

Resistance Trends of Antiretroviral Agents in People with Human Immunodeficiency Virus in Korea, 2012 - 2020.

BACKGROUND: Domestic data on antiretroviral drug (ARV) resistance are limited, while alterations in ARV resistance are expected as the incidence of human immunodeficiency virus (HIV) infection increases. We evaluated the ten-year change in ARV resistance in people with HIV (PWH) in Korea. MATERIALS AND METHODS: Adults aged ≥19 years and diagnosed with HIV infection between January 2010 and December 2020 at a 750-bed municipal hospital were retrospectively reviewed. Data on clinical characteristics and resistance mutation test results were collected. The study population was divided into three-year intervals according to diagnosed year and their clinical characteristics were compared. RESULTS: A total of 248 PWH were analyzed, and ARV resistance was detected in 30 of them (12.1%). Resistance was detected most frequently in PWH aged ≤29 years (16, 6.5%), and the median percentage of resistance detection per year was 14.3% (interquartile range, 12.7 - 16.1). The trend of the overall prevalence of ARV resistance mutations slightly decreased and then increased over time (15.3% in 2012 - 2014, 9.6% in 2015 - 2017, and 12.9% in 2018 - 2020). The prevalence of the non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance markedly decreased over time (15.3% in 2012 - 2014, 8.7% in 2015 - 2017, and 2.4% in 2018-2020), while that of protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) increased from 0 until 2018 to 3.5% and 8.2% in 2018 - 2020, respectively. CONCLUSION: The trend of NNRTI resistance has decreased over time, and resistance to PIs and INSTIs increased from 2018. Therefore, continuous monitoring of ARV resistance pattern is necessary.

Clinical application of the Panbio™ COVID-19 Ag rapid test device and SSf-COVID19 kit for the detection of SARS-CoV-2 infection.

OBJECTIVE: We evaluated the sensitivity and specificity of the Panbio™ COVID-19 Ag rapid test device using nasal swabs and those of the SSf-COVID19 kit, one of RT-PCR tests, using saliva specimens. These tests were compared with RT-PCR tests using nasopharyngeal swabs for the diagnosis of SARS-CoV-2 infection. The three diagnostic tests were simultaneously conducted for patients aged ≥ 18 years, who were about to be hospitalized or had been admitted for COVID-19 confirmed by RT-PCR in two research hospitals from August 20 to October 29, 2021. Nasal swabs were tested using the Panbio™ COVID-19 Ag rapid test device. More than 1 mL of saliva was self-collected and tested using the SSf-COVID19 kit. RESULTS: In total, 157 patients were investigated; 124 patients who were about to be hospitalized and 33 patients already admitted for COVID-19. The overall sensitivity and specificity of the Panbio™ COVID-19 Ag rapid test device with nasal swabs were 64.7% (95% confidence interval [CI] 47.9-78.5%) and 100.0% (95% CI 97.0-100.0%), respectively. The median time to confirm a positive result was 180 s (interquartile range 60-255 s). The overall sensitivity and specificity of the SSf-COVID19 kit with saliva specimens were 94.1% (95% CI 80.9-98.4%) and 100.0% (95% CI 97.0-100.0%), respectively.

Clinical Characteristics of COVID-19: Use of Steroids in Mostly Unvaccinated COVID-19 Patients Before the Omicron Variant.

BACKGROUND: Glucocorticoids are one of the current standard agents for moderate to severe coronavirus disease 2019 (COVID-19) treatment based on the RECOVERY trial. Data on the real clinical application of steroids for COVID-19 are scarce and will help guide the optimal use of steroids. We described the current prescription pattern of steroids for COVID-19 and investigated the factors related to specific practices. METHODS: All adults aged ≥ 19 years who were diagnosed with COVID-19 by real-time reverse transcription-polymerase chain reaction and admitted to one of 3 study hospitals from 8 December 2020 to 30 June 2021 were enrolled. Demographic and clinical data, including medications and oxygen therapy, were retrospectively collected from electronic medical records. The severity of comorbidities and COVID-19 were measured. The subjects were divided into steroid and nonsteroid groups, and the steroid group was then subdivided into standard and higher/longer groups. RESULTS: Among a total of 805 patients, 217 (27.0%) were treated with steroids. The steroid group showed a higher rate of oxygen therapy (81.1% vs. 2.7%), more concomitant use of remdesivir (77.4% vs. 1.4%) or antibiotics (79.3% vs. 4.3%), and a higher proportion of high risk according to National Early Warning Score-2 score (30.0% vs. 0.9%) or severe risk according to National Institute of Allergy and Infectious Disease Ordinal Scale score (81.1% vs. 2.7%) than the nonsteroid group. The mortality of the steroid group was 4.6%. In the steroid group, 82.5% received a standard or lower dose of steroids within ten days, and 17.5% (38/217) received a higher or longer dose of steroids. Multivariate analysis showed that initial lymphopenia (adjusted odds ratio [aOR], 0.94; 95% confidence interval [CI], 0.89-0.99) and high level of lactate dehydrogenase (LDH) (aOR, 1.00; 95% CI, 1.00-1.01) were independent risk factors for higher doses or longer steroid use. CONCLUSION: The dose and duration of steroids were in line with current guidelines in 82.5% of COVID-19 patients, but the outliers may need tailored therapy according to surrogate markers, such as initial lymphopenia or high level of LDH.

Data Collection Framework for Context-Aware Virtual Reality Application Development in Unity: Case of Avatar Embodiment.

Virtual Reality (VR) has been adopted as a leading technology for the metaverse, yet most previous VR systems provide one-size-fits-all experiences to users. Context-awareness in VR enables personalized experiences in the metaverse, such as improved embodiment and deeper integration of the real world and virtual worlds. Personalization requires context data from diverse sources. We proposed a reusable and extensible context data collection framework, ManySense VR, which unifies data collection from diverse sources for VR applications. ManySense VR was implemented in Unity based on extensible context data managers collecting data from data sources such as an eye tracker, electroencephalogram, pulse, respiration, galvanic skin response, facial tracker, and Open Weather Map. We used ManySense VR to build a context-aware embodiment VR scene where the user's avatar is synchronized with their bodily actions. The performance evaluation of ManySense VR showed good performance in processor usage, frame rate, and memory footprint. Additionally, we conducted a qualitative formative evaluation by interviewing five developers (two males and three females; mean age: 22) after they used and extended ManySense VR. The participants expressed advantages (e.g., ease-of-use, learnability, familiarity, quickness, and extensibility), disadvantages (e.g., inconvenient/error-prone data query method and lack of diversity in callback methods), future application ideas, and improvement suggestions that indicate potential and can guide future development. In conclusion, ManySense VR is an efficient tool for researchers and developers to easily integrate context data into their Unity-based VR applications for the metaverse.

Treatment for Immune Thrombocytopenia in Coronavirus Disease 2019 (COVID-19) Infection after COVID-19 Vaccination: A Case Report.

Thrombocytopenia is one of the rare signs of both the coronavirus disease 2019 (COVID-19) and COVID-19 vaccination. An 85-year-old man was diagnosed with immune thrombocytopenia and COVID-19, 7 days after COVID-19 vaccination. The patient was successfully treated with a short course of intravenous immunoglobulin and oral corticosteroids.

Incidence of invasive fungal infection in acute lymphoblastic and acute myelogenous leukemia in the era of antimold prophylaxis.

The incidence of invasive fungal infection (IFI) in patients with acute myeloid leukemia (AML) has decreased with the introduction of antimold prophylaxis. Although acute lymphoblastic leukemia (ALL) has a lower risk of IFI than does AML, the incidences of IFI in both AML and ALL in the era of antimold prophylaxis should be re-evaluated. We analyzed adults with AML or ALL who had undergone induction, re-induction, or consolidation chemotherapy from January 2017 to December 2019 at Seoul National University Hospital. Their clinical characteristics during each chemotherapy episode were reviewed, and cases with proven or probable diagnoses were regarded as positive for IFI. Of 552 episodes (393 in AML and 159 in ALL), 40 (7.2%) were IFI events. Of the IFI episodes, 8.1% (12/148) and 5.9% (13/220) (P = 0.856) occurred in cases of ALL without antimold prophylaxis and AML with antimold prophylaxis, respectively. After adjusting for clinical factors, a lack of antimold prophylaxis (adjusted odds ratio [aOR], 3.52; 95% confidence interval [CI], 1.35-9.22; P = 0.010) and a longer duration of neutropenia (per one day, aOR, 1.02; 95% CI, 1.01-1.04; P = 0.001) were independently associated with IFI. In conclusion, the incidence of IFI in ALL without antimold prophylaxis was not lower than that in AML. A lack of antimold prophylaxis and prolonged neutropenia were independent risk factors for IFI. Clinicians should be on guard for detecting IFI in patients with ALL, especially those with risk factors.

Dynamics of viral load and anti-SARS-CoV-2 antibodies in patients with positive RT-PCR results after recovery from COVID-19.

Recently, the number of patients with coronavirus disease 2019 (COVID-19) who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), via the reverse transcription polymerase chain reaction (RT-PCR) test, after recovery has increased; this has caused a dilemma regarding the medical measures and policies. We evaluated the dynamics of viral load and anti-SARS-CoV-2 antibodies in four patients with positive RT-PCR results after recovery. In all patients, the highest levels of immunoglobulin G (IgG) and IgM antibodies were reached after about a month of the onset of the initial symptoms. Then, the IgG titers plateaued, and the IgM titers decreased, regardless of RT-PCR results. The IgG and IgM levels did not increase after the post-negative positive RT-PCR results in any of the patients. Our results reinforced that the post-negative positive RT-PCR results may be due to the detection of RNA particles rather than reinfection in individuals who have recovered from COVID-19.

Therapeutic Effects of HIF-1α on Bone Formation around Implants in Diabetic Mice Using Cell-Penetrating DNA-Binding Protein.

Patients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-inducible factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen during bone repair, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. This study thus evaluates the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice and normal mice via a protein transduction domain (PTD)-mediated DNA delivery system. Implants were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively. We found that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the HIF-1α treated group than placebo in diabetic mice (p < 0.05). Bioinformatic analysis showed that diabetic mice had 216 differentially expressed genes (DEGs) and 21 target genes. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16, and TRIM63 were found to be associated with bone formation. Based on these results, we conclude that local administration of HIF-1α via PTD may boost bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson's disease model.

Transplantation of neural progenitor cells (NPCs) is a potential therapy for treating neurodegenerative disorders, but this approach has faced many challenges and limited success, primarily because of inhospitable host brain environments that interfere with enriched neuron engraftment and function. Astrocytes play neurotrophic roles in the developing and adult brain, making them potential candidates for helping with modification of hostile brain environments. In this study, we examined whether astrocytic function could be utilized to overcome the current limitations of cell-based therapies in a murine model of Parkinson's disease (PD) that is characterized by dopamine (DA) neuron degeneration in the midbrain. We show here that cografting astrocytes, especially those derived from the midbrain, remarkably enhanced NPC-based cell therapeutic outcomes along with robust DA neuron engraftment in PD rats for at least 6 months after transplantation. We further show that engineering of donor astrocytes with Nurr1 and Foxa2, transcription factors that were recently reported to polarize harmful immunogenic glia into the neuroprotective form, further promoted the neurotrophic actions of grafted astrocytes in the cell therapeutic approach. Collectively, these findings suggest that cografting astrocytes could be a potential strategy for successful cell therapeutic outcomes in neurodegenerative disorders.

Videography-Based Unconstrained Video Analysis.

Video analysis and understanding play a central role in visual intelligence. In this paper, we aim to analyze unconstrained videos, by designing features and approaches to represent and analyze videography styles in the videos. Videography denotes the process of making videos. The unconstrained videos are defined as the long duration consumer videos that usually have diverse editing artifacts and significant complexity of contents. We propose to construct a videography dictionary, which can be utilized to represent every video clip as a sequence of videography words. In addition to semantic features, such as foreground object motion and camera motion, we also incorporate two novel interpretable features to characterize videography, including the scale information and the motion correlations. We then demonstrate that, by using statistical analysis methods, the unique videography signatures extracted from different events can be automatically identified. For real-world applications, we explore the use of videography analysis for three types of applications, including content-based video retrieval, video summarization (both visual and textual), and videography-based feature pooling. In the experiments, we evaluate the performance of our approach and other methods on a large-scale unconstrained video dataset, and show that the proposed approach significantly benefits video analysis in various ways.

Splenic infarction associated with acute infectious mononucleosis due to Epstein-Barr virus infection.

The purpose of this study was to report a case of a previously healthy 20-year-old woman diagnosed with splenic infarction following infectious mononucleosis (IM) by Epstein-Barr virus (EBV) infection and to perform the first systematic review of the clinical characteristics of splenic infarction associated with IM. A systematic review was conducted using English, French, and Japanese literatures of splenic infarction associated with IM due to EBV infection published between 1961 and 2015 in PubMed Medline. A total of 19 cases were extracted from the collected articles. Left upper quadrant (LUQ) pain was observed in 15 (79%) patients. Splenectomy was performed in five (26%) cases, among which four patients presented with stable vital signs. Splenic rupture was accompanied in two (10%) patients. The median time from the onset of IM symptoms to the diagnosis of splenic infarction was 5 days (range, 1-25 days). Fourteen (74%) of 19 patients experienced improvement through medical treatment, and there were no deaths. Splenic infarction associated with IM due to EBV infection can show a favorable clinical outcome after medical treatment. Clinicians should consider the possibility of splenic infarction when patients with IM experience LUQ pain. J. Med. Virol. 89:332-336, 2017. © 2016 Wiley Periodicals, Inc.

LIN28A enhances the therapeutic potential of cultured neural stem cells in a Parkinson's disease model.

The original properties of tissue-specific stem cells, regardless of their tissue origins, are inevitably altered during in vitro culturing, lessening the clinical and research utility of stem cell cultures. Specifically, neural stem cells derived from the ventral midbrain lose their dopamine neurogenic potential, ventral midbrain-specific phenotypes, and repair capacity during in vitro cell expansion, all of which are critical concerns in using the cultured neural stem cells in therapeutic approaches for Parkinson's disease. In this study, we observed that the culture-dependent changes of neural stem cells derived from the ventral midbrain coincided with loss of RNA-binding protein LIN28A expression. When LIN28A expression was forced and sustained during neural stem cell expansion using an inducible expression-vector system, loss of dopamine neurogenic potential and midbrain phenotypes after long-term culturing was blocked. Furthermore, dopamine neurons that differentiated from neural stem cells exhibited remarkable survival and resistance against toxic insults. The observed effects were not due to a direct action of LIN28A on the differentiated dopamine neurons, but rather its action on precursor neural stem cells as exogene expression was switched off in the differentiating/differentiated cultures. Remarkable and reproducible behavioural recovery was shown in all Parkinson's disease rats grafted with neural stem cells expanded with LIN28A expression, along with extensive engraftment of dopamine neurons expressing mature neuronal and midbrain-specific markers. These findings suggest that LIN28A expression during stem cell expansion could be used to prepare therapeutically competent donor cells.

Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease.

Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.

Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid synoviocytes.

Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of PlGF transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy.

Highly acidic C-terminal domain of pp32 is required for the interaction with histone chaperone, TAF-Ibeta.

We have previously reported that INHAT (inhibitor of acetyltransferases) complex subunits, TAF (template activating factor)-Ialpha, TAF-Ibeta and pp32 can inhibit histone acetylation and HAT (histone acetyltransferase)-dependent transcription by binding to histones. Evidences are accumulating that INHAT complex subunits have important regulatory roles in various cellular activities such as replication, transcription, and apoptosis etc. However, how these subunits interact each other remains largely unknown. Using immunoprecipitation (IP) and protein-protein interaction assays with TAF-Ibeta and pp32 deletion mutant proteins, we identify INHAT complex subunits, TAF-Ibeta and pp32 interaction requires highly acidic C-terminal domain of pp32. We also show that the interaction between the INHAT complex subunits is stronger in the presence of histones. In this study, we report that the synergistic inhibition of HAT-mediated transcription by TAF-Ibeta and pp32 is dependent on the highly acidic C-terminal domain of pp32.