High mobility group box 1 in the central nervous system: regeneration hidden beneath inflammation.

High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields, including neurology and neuroscience. High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern, which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, epilepsy, and traumatic brain injury. Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern, such as glycyrrhizin, ethyl pyruvate, and neutralizing anti-high-mobility group box 1 antibodies, are commonly used to target high-mobility group box 1 activity in central nervous system disorders. Although it is commonly known for its detrimental inflammatory effect, high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders. In this narrative review, we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern, its downstream receptors, and intracellular signaling pathways, how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system, and clues on how to differentiate the pro-regenerative from the pro-inflammatory role. Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.

Risk factors for toxoplasmosis in people living with HIV in the Asia-Pacific region.

INTRODUCTION: Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of the reactivation of latent infection. We assessed the prevalence of toxoplasmosis and its associated risk factors in PLWH in the Asia-Pacific region using data from the TREAT Asia Human Immunodeficiency Virus (HIV) Observational Database (TAHOD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA) Asia-Pacific. METHODS: This study included both retrospective and prospective cases of toxoplasmosis reported between 1997 and 2020. A matched case-control method was employed, where PLWH diagnosed with toxoplasmosis (cases) were each matched to two PLWH without a toxoplasmosis diagnosis (controls) from the same site. Sites without toxoplasmosis were excluded. Risk factors for toxoplasmosis were analyzed using conditional logistic regression. RESULTS: A total of 269/9576 (2.8%) PLWH were diagnosed with toxoplasmosis in 19 TAHOD sites. Of these, 227 (84%) were reported retrospectively and 42 (16%) were prospective diagnoses after cohort enrollment. At the time of toxoplasmosis diagnosis, the median age was 33 years (interquartile range 28-38), and 80% participants were male, 75% were not on antiretroviral therapy (ART). Excluding 63 out of 269 people without CD4 values, 192 (93.2%) had CD4 ≤200 cells/µL and 162 (78.6%) had CD4 ≤100 cells/µL. By employing 538 matched controls, we found that factors associated with toxoplasmosis included abstaining from ART (odds ratio [OR] 3.62, 95% CI 1.81-7.24), in comparison to receiving nucleoside reverse transcriptase inhibitors plus non-nucleoside reverse transcriptase inhibitors, HIV exposure through injection drug use (OR 2.27, 95% CI 1.15-4.47) as opposed to engaging in heterosexual intercourse and testing positive for hepatitis B virus surface antigen (OR 3.19, 95% CI 1.41-7.21). Toxoplasmosis was less likely with increasing CD4 counts (51-100 cells/µL: OR 0.41, 95% CI 0.18-0.96; 101-200 cells/µL: OR 0.14, 95% CI 0.06-0.34; >200 cells/µL: OR 0.02, 95% CI 0.01-0.06), when compared to CD4 ≤50 cells/µL. Moreover, the use of prophylactic cotrimoxazole was not associated with toxoplasmosis. CONCLUSIONS: Symptomatic toxoplasmosis is rare but still occurs in PLWH in the Asia-Pacific region, especially in the context of delayed diagnosis, causing advanced HIV disease. Immune reconstitution through early diagnosis and ART administration remains a priority in Asian PLWH.

Recommendations for Adult Immunization by the Korean Society of Infectious Diseases, 2023: Minor Revisions to the 3rd Edition.

The Korean Society of Infectious Diseases has been regularly developing guidelines for adult immunization since 2007. In 2023, the guidelines for the following seven vaccines were revised: influenza, herpes zoster, pneumococcal, tetanus-diphtheria-pertussis (Tdap), human papillomavirus (HPV), meningococcal, and rabies vaccines. For the influenza vaccine, a recommendation for enhanced vaccines for the elderly was added. For the herpes zoster vaccine, a recommendation for the recombinant zoster vaccine was added. For the pneumococcal vaccine, the current status of the 15-valent pneumococcal conjugate vaccine and 20-valent PCV was described. For the Tdap vaccine, the possibility of using Tdap instead of tetanus-diphtheria vaccine was described. For the HPV vaccine, the expansion of the eligible age for vaccination was described. For the meningococcal vaccine, a recommendation for the meningococcal B vaccine was added. For the rabies vaccine, the number of pre-exposure prophylaxis doses was changed. This manuscript documents the summary and rationale of the revisions for the seven vaccines. For the vaccines not mentioned in this manuscript, the recommendations in the 3rd edition of the Vaccinations for Adults textbook shall remain in effect.

Nationwide Analysis of Antimicrobial Prescription in Korean Hospitals between 2018 and 2021: The 2023 KONAS Report.

BACKGROUND: Data on antimicrobial use at the national level are crucial for establishing domestic antimicrobial stewardship policies and enabling medical institutions to benchmark each other. This study aimed to analyze antimicrobial use in Korean hospitals. MATERIALS AND METHODS: We investigated antimicrobials prescribed in Korean hospitals between 2018 and 2021 using data from the Health Insurance Review and Assessment. Primary care hospitals (PCHs), secondary care hospitals (SCHs), and tertiary care hospitals (TCHs) were included in this analysis. Antimicrobials were categorized according to the Korea National Antimicrobial Use Analysis System (KONAS) classification, which is suitable for measuring antimicrobial use in Korean hospitals. RESULTS: Among over 1,900 hospitals, PCHs constituted the highest proportion, whereas TCHs had the lowest representation. The most frequently prescribed antimicrobials in 2021 were piperacillin/ß-lactamase inhibitor (9.3%) in TCHs, ceftriaxone (11.0%) in SCHs, and cefazedone (18.9%) in PCHs. Between 2018 and 2021, the most used antimicrobial classes according to the KONAS classification were 'broad-spectrum antibacterial agents predominantly used for community-acquired infections' in SCHs and TCHs and 'narrow spectrum beta-lactam agents' in PCHs. Total consumption of antimicrobials decreased from 951.7 to 929.9 days of therapy (DOT)/1,000 patient-days in TCHs and 817.8 to 752.2 DOT/1,000 patient-days in SCHs during study period; however, no reduction was noted in PCHs (from 504.3 to 527.2 DOT/1,000 patient-days). Moreover, in 2021, the use of reserve antimicrobials decreased from 13.6 to 10.7 DOT/1,000 patient-days in TCHs and from 4.6 to 3.3 DOT/1,000 patient-days in SCHs. However, in PCHs, the use increased from 0.7 to 0.8 DOT/1,000 patient-days. CONCLUSION: This study confirmed that antimicrobial use differed according to hospital type in Korea. Recent increases in the use of total and reserve antimicrobials in PCHs reflect the challenges that must be addressed.

Unraveling the interplay of temperature with molecular aggregation and miscibility in TEA-water mixtures.

In the phase diagram of binary liquid mixtures, a miscibility gap is found with the concomitant liquid-liquid phase separation, wherein temperature is a key parameter in modulating the phase behavior. This includes critical temperatures such as the lower critical solution temperature (LCST) and upper critical solution temperature (UCST). Using a comprehensive approach including molecular dynamics (MD) simulation, graph theoretical analysis and spatial inhomogeneity measurement in an LCST-type mixture, we attempt to establish the relationship between the molecular aggregation pattern and phase behavior in TEA-water mixtures. At lower temperatures of binary liquid mixtures, TEA molecules tend to aggregate while simultaneously interacting with water forming a homogeneous solution. As the temperature increases, these TEA aggregates tend to self-associate by minimizing the interaction with water, which facilitates formation of two distinct liquid phases in the binary liquid. The spatial distribution analysis also reveals that the TEA aggregates compatible with water promote uniform distribution of water molecules, maintaining a homogeneous solution, while the water-incompatible ones generate isolation of water H-bond aggregates, leading to liquid-liquid phase separation in the binary system. This current study on temperature-induced molecular aggregation behavior is anticipated to contribute to a critical understanding of the phase behavior in binary liquid mixtures, including UCST, LCST, and reentrant phase behavior.

Interactive Deformable Colored Sound Display Achieved with Electrostrictive Fluoropolymer and Halide Perovskite.

The association of color and sound helps human cognition through a synergetic effect like intersensory facilitation. Although soft human-machine interfaces (HMIs) providing unisensory expression have been widely developed, achieving synchronized optic and acoustic expression in one device system has been relatively less explored. It is because their operating principles are different in terms of materials, and implementation has mainly been attempted through structural approaches. Here, a deformable sound display is developed that generates multiple colored lights with large sound at low input voltage. The device is based on alternating-current electroluminescence (ACEL) covered with perovskite composite films. A sound wave is created by a polymer matrix of the ACEL, while simultaneously, various colors are produced by the perovskite films and the blue electroluminescence (EL) emitted from the phosphors in the ACEL. By patterning different colored perovskite films onto the ACELs, associating the color and the sound is successfully demonstrated by a piano keyboard and a wearable interactive device.

Screening and purification of antimicrobial materials from coelomic fluid of sea urchin, Heliocidaris crassispina.

Marine organisms, such as sea urchins like Heliocidaris crassispina, produce bioactive substances with antimicrobial activity to protect themselves from the high density of microorganisms in their habitats. One such substance, Echinochrome A (Ech A), has been isolated from various sea urchins' shells and spines using strong acidic solutions and organic solvents. Ech A, however, has not been reported from the coelomic fluid of H. crassispina. In this study, we report the antimicrobial activity of H. crassispina coelomic fluid extract against various microbes, evaluating its potential for purifying potent antimicrobial materials. Upon confirming the extract as a promising source of antimicrobial materials, we isolated antimicrobial compounds from the extract. A series of HPLC steps were taken to purify antimicrobial materials from the H. crassispina coelomic fluid extract, resulting in the isolation of two single absorbance peaks showing antimicrobial activity against Staphylococcus aureus. One peak consisted of a single antimicrobial compound with a molecular weight (MW) corresponding to Ech A, while the other peak comprised five MWs inferred to be those of Ech A and its oxidative products. The elution of Ech A in two separate peaks may be attributable to the presence of Ech A's isomer, as reported in several previous studies. The use of the environmentally friendly extraction method in procurement of Ech A from the coelomic fluid would contribute to the implementation of risk-reducing extraction method for researchers studying Ech A from sea urchins.

Fermentation Characteristics of Unripe Citrus unshiu Vinegar Production Using Acetic Acid Bacteria Isolated from Traditional Fermented Vinegars.

Here, we aimed to isolate an acetic acid bacterium that is suitable for the production of unripe Citrus unshiu vinegar from traditional fermented vinegars. We compared the halo sizes of isolates to select a strain with superior acetic acid production capabilities and selected Komagataeibacter kakiaceti P6 (P6) as the final strain. Using Acetobacter pasteurianus CY (CY) and A. pasteurianus KACC 17058 (KACC 17058) as controls, we analyzed the total phenolic compounds, total flavonoid content, antioxidant activities, and organic acids of the selected strain to verify its suitability for acetic acid fermentation. On the 30th day of the fermentation period, P6 showed a total acidity of 4.86%, which was higher than that of control groups (CY, 4.16%; KACC 17058, 4.01%). The total phenolic compounds, total flavonoid content, 1,1-diphenyl-2-picrylhydrazyl scavenging activity, and ferric ion reducing antioxidant power values significantly increased during fermentation with P6 compared with the initial C. unshiu wine, and no significant differences were observed from the vinegars produced by CY and KACC 17058. Moreover, organic acid analysis revealed that the unripe C. unshiu vinegar produced with P6 had an acetic acid content of 26.15 mg/mL, which was significantly higher than those produced with CY and KACC 17058, indicating that the P6 strain effectively produces acetic acid without adversely affecting other quality aspects during fermentation. In conclusion, the novel P6 strain is expected to be used as a starter for fermenting unripe C. unshiu vinegar, and its excellent acetic acid production capabilities suggest potential applications for other vinegars.

Analysis of the spatial and morphological characteristics of oligodendrocytes from images of in vitro culture.

Oligodendrocytes (OLs) are glial cells responsible for the formation of myelin sheaths in the central nervous system. The characteristic features of the oligodendrocyte lineage, ranging from proliferative and migratory oligodendrocyte progenitor cells (OPC) to myelinating mature OLs, can be observed in vitro cultures of OL lineage cells. Here, we introduce a method for analyzing the spatial distribution of OPCs, which reflects their capacity for proliferation and migration, and the morphological complexity of mature OLs, which reflects their capacity for myelin formation, from immunostaining images of in vitro OL cultures. Through the methods described, we have demonstrated the tendency for OPCs to cluster in an environment with epidermal growth factor (EGF), and the differing morphological complexity of mature OLs according to culture medium and duration of differentiation.•The proliferative and migratory characteristics of OPCs can be evaluated by analyzing their spatial distribution.•The myelin-forming capacity of mature OLs can be measured by analyzing their morphological complexity.•Image-based analyses may be a substitute for more convoluted experiments to assess OL function.

An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1.

In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1ß and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions.

Dialkyl Carbonate Synthesis Using Atmospheric Pressure of CO2.

Dialkyl carbonates (DRCs) are valuable compounds widely used in the industry. The synthesis of DRC from CO2 has attracted interest as an alternative to the current method, which uses phosgene. However, the reported approaches for DRC synthesis from CO2 requires high-pressure and high-concentration CO2, resulting in elevated costs associated with CO2 purification and manufacturing facilities. In this report, we present an environmentally friendly method for producing DRC from low-concentration and low-pressure CO2 via a dehydration condensation approach without the use of halogenated alkylating agents. This method involves the formation of monoalkyl carbonate [BASE-H][ROC(O)O] using a strong organic base and alcohols, tetraalkyl orthosilicates as dehydrating agents, and CeO2 as the catalyst. Using the method, 39 and 30% of diethyl carbonate yields were accomplished with only 100 and 15 vol % CO2 (CO2/N2 = 15:85) gas bubbling at atmospheric pressure, even under reaction conditions with no large excess of either CO2, alcohol, or dehydration agent.

Study on Pyridine-Boryl Radical-Promoted, Ketyl Radical-Mediated Carbon-Carbon Bond-Forming Reactions.

Ketyl radicals are synthetically versatile reactive species, but their applications have been hampered by harsh generation conditions employing highly reducing metals. Recently, the pyridine-boryl radical received wide attention as a promising organic reductant because of its mildness as well as convenience in handling. While probing the utility of the pyridine-boryl radical, our group observed facile pinacol coupling reactivity that had not been known at that time. This serendipitous finding was successfully rendered into a practical synthesis of tetraaryl-1,2-diols in up to 99% yield within 1 h. Subsequently, upon examinations of various reaction manifolds, a diastereoselective ketyl-olefin cyclization was accomplished to produce cycloalkanols such as trans-2-alkyl-1-indanols. Compared to the previous methods, the stereocontrolling ability was considerably enhanced by taking advantage of the structurally modifiable boryl group that would be present near the bond-forming site. In this full account, our synthetic efforts with the O-boryl ketyl radicals are disclosed in detail, covering the discovery, optimization, scope expansion, and mechanistic analysis, including density functional theory (DFT) calculations.

Comparison of HIV characteristics across 3 datasets: the Korea HIV/AIDS Cohort Study Prospective, Retrospective, and National Reporting System.

Objectives: The Korea HIV/AIDS Cohort Study has been conducted prospectively for 18 years. However, it faces limitations in representing the entire population of patients with HIV in Korea. To address these limitations and validate the study design, we analyzed characteristics across several HIV datasets. Methods: We compared epidemiological and clinical characteristics from 3 datasets: the Korea HIV/AIDS Cohort Study (dataset 1, n=1,562), retrospective cohort data (dataset 2, n=2,665), and the national HIV reporting system of the Korea Disease Control and Prevention Agency (KDCA) (dataset 3, n=17,403). Results: The demographic characteristics of age, sex, and age at HIV diagnosis did not differ significantly across datasets. However, dataset 3 contained a higher percentage of patients diagnosed after 2008 (69.5%) than the other datasets. Regarding transmission routes, same-sex contact accounted for a greater proportion of dataset 1 (59.8%) compared to datasets 2 (20.9%) and 3 (32.6%). The percentage of patients with CD4 T-cell counts below 200/mm3 at HIV diagnosis was higher in datasets 1 (39.4%) and 2 (33.3%) compared to dataset 3 (16.3%). Initial HIV viral load measurements were not obtained for dataset 3. Conclusion: The Korea HIV/AIDS Cohort Study demonstrated representativeness regarding the demographic characteristics of Korean patients. Of the sources, dataset 1 contained the most data on transmission routes. While the KDCA data encompassed all HIV patients, it lacked detailed clinical information. To improve the representativeness of the Korea HIV/AIDS Cohort Study, we propose expanding and revising the cohort design and enrolling more patients who have been recently diagnosed.

Shifting perspectives: From "Epilepsy" to "Cerebroelectric Disorder".

BACKGROUND & OBJECTIVE: Epilepsy has long been associated with stigma and misconceptions. In response, the Korean Epilepsy Society initiated the Epilepsy Renaming project in 2008 to replace the stigmatizing term with a neutral and scientifically grounded name, "cerebroelectric disorder". This study explores the impact of changing terminology on the public discourse surrounding epilepsy. METHODS: Online news articles from distinct time periods (2001-2003, 2011-2014, 2017-2018, and 2020-2022) were analyzed using text data analysis techniques, including Latent Dirichlet Allocation topic modeling, frequency analysis, and sentiment analysis. The inclusion of data from 2017 to 2018 allowed for an examination of discourse trends independent of the COVID-19 pandemic's influence. Correlation of words in each period was visualized via network maps. Migraine was set as control term to highlight changes in perception devoid of significant stigma intervention efforts. RESULTS: The analysis revealed a significant shift in terminology preference, with cerebroelectric disorder gradually replacing epilepsy in news articles. The discourse surrounding epilepsy evolved over time from focusing on healthcare and economic aspects to patient-centered discussions, emphasizing the daily lives of individuals with epilepsy. This shift towards more empathetic and less stigmatized language was contrasted against the discourse on migraine, highlighting the specific impact of the terminological change on epilepsy's perception. CONCLUSION: The adoption of the neutral term "cerebroelectric disorder" in South Korea has influenced the discourse surrounding epilepsy, leading to more patient-centered discussions and a reduction in stigma. This study highlights the importance of terminology in shaping public perceptions of diseases and suggests that changing terminology can positively impact the understanding and destigmatization of epilepsy.

Highly sensitive and label-free protein immunoassay-based biosensor comprising infrared metamaterial absorber inducing strong coupling.

A mid-infrared label-free immunoassay-based biosensor is an effective device to help identify and quantify biomolecules. This biosensor employs a surface-enhanced infrared absorption spectroscopy, which is a highly potent sensing technique for detecting minute quantities of analytes. In this study, a biosensor was constructed using a metamaterial absorber, which facilitated strong coupling effects. For maximum coupling effect, it is necessary to enhance the near-field intensity and the spatial and spectral overlap between the optical cavity resonance and the vibrational mode of the analyte. Due to significant peak splitting, conventional baseline correction methods fail to adequately analyze such a coupling system. Therefore, we employed a coupled harmonic oscillation model to analyze the spectral distortion resulting from the peak splitting induced by the strong coupling effect. The proposed biosensor with a thrombin-binding aptamer-based immunoassay could achieve a limit of detection of 267.4 pM, paving the way for more efficient protein detection in clinical practice.

Joint preserving procedures for Takakura stage IIIB varus ankle osteoarthritis.

A man in his early 70s with right Takakura stage IIIB varus ankle osteoarthritis underwent medial opening wedge supramalleolar osteotomy with inframalleolar correction as joint preserving procedure. We also performed anteroinferior tibiofibular ligament (AITFL) resection with fibular shortening valgisation osteotomy to enhance the talar tilt correction. Postoperative decrease in talar tilt with dramatic symptom improvement was achieved. Performing the AITFL resection with fibular shortening valgisation osteotomy plus concomitant supramalleolar osteotomy and inframalleolar correction for Takakura stage IIIB varus ankle osteoarthritis resulted in successful improvement in talar tilt by making room for the valgus deviation of the talus.

Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway.

Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.

Design, Synthesis, and Biological Evaluation of New 2,6,7-Substituted Purine Derivatives as Toll-like Receptor 7 Agonists for Intranasal Vaccine Adjuvants.

TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and cancer. Despite the structural similarity of TLR7/8, their immune stimulation mechanisms and time-course responses significantly differ. In this study, a new series of TLR7-selective agonists was synthesized utilizing the economical building block 2,6-dichloropurine. Compound 27b showed the most potent activity on hTLR7 with an EC50 of 17.53 nM and demonstrated high hTLR7 selectivity (224 folds against TLR8). 27b effectively stimulated the secretion of proinflammatory cytokines in mouse macrophages and enhanced intranasal vaccine efficacy against influenza A virus in vivo. Assessment of humoral and mucosal antibody titers confirmed that 27b elevates IgG and IgA levels, protecting against both homologous and heterologous influenza viral infections. These findings suggest that 27b is a promising candidate as a vaccine adjuvant to prevent viral infections or as a robust immunomodulator with prolonged activity for treating immune-suppressed diseases.