Miracle-dz/UniFAR-FTUs huggingface dataset:
Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug miltefosine is capable of immunomodulation and induction of Th1 cytokines. ABSTRACT Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug miltefosine is capable of immunomodulation and induction of Th1 cytokines. A better understanding of the immunomodulatory effects of miltefosine is central to providing a rationale regarding synergistic mechanisms of activity to combine miltefosine optimally with other conventional and future antileishmanials that are currently under development. Therefore, a systematic literature search was performed to evaluate to what extent and how miltefosine influences the host Th1 response. Miltefosine’s effects observed in both a preclinical and a clinical context associated with immunomodulation in the treatment of leishmaniasis are evaluated in this review. A total of 27 studies were included in the analysis. Based on the current evidence, miltefosine is not only capable of inducing direct parasite killing but also of modulating the host immunity. Our findings suggest that miltefosine-induced activation of Th1 cytokines, particularly represented by increased gamma interferon (IFN-γ) and interleukin 12 (IL-12), is essential to prevail over the Leishmania-driven Th2 response. Differences in miltefosine-induced host-mediated effects between in vitro, ex vivo, animal model, and human studies are further discussed. All things considered, an effective treatment with miltefosine is acquired by enhanced functional Th1 cytokine responses and may further be enhanced in combination with immunostimulatory agents.
Microparticles for controlled growth differentiation factor 6 delivery to direct adipose stem cell‐based nucleus pulposus regeneration

Currently, there is no effective long‐term treatment for intervertebral disc (IVD) degeneration, making it an attractive candidate for regenerative therapies. Hydrogel delivery of adipose stem cells (ASCs) in combination with controlled release of bioactive molecules is a promising approach to halt IVD degeneration and promote regeneration. Growth differentiation factor 6 (GDF6) can induce ASC differentiation into anabolic nucleus pulposus (NP) cells and hence holds promise for IVD regeneration. Here, we optimised design of novel poly(DL‐lactic acid‐co‐glycolic acid) (PLGA)–polyethylene glycol–PLGA microparticles to control GDF6 delivery and investigated effect of released GDF6 on human ASCs differentiation to NP cells. Recombinant human (rh)GDF6 was loaded into microparticles and total protein and rhGDF6 release assessed. The effect of microparticle loading density on distribution and gel formation was investigated through scanning electron microscopy. ASC differentiation to NP cells was examined after 14 days in hydrogel culture by quantitative polymerase chain reaction, histological, and immunohistochemical staining in normoxic and IVD‐like hypoxic conditions. RhGDF6 microparticles were distributed throughout gels without disrupting gelation and controlled rhGDF6 release over 14 days. Released GDF6 significantly induced NP differentiation of ASCs, with expression comparable with or exceeding media supplemented rhGDF6. Microparticle‐delivered rhGDF6 also up‐regulated sulphated glycosaminoglycan and aggrecan secretion in comparison with controls. In hypoxia, microparticle‐delivered rhGDF6 continued to effectively induce NP gene expression and aggrecan production. This study demonstrates the effective encapsulation and controlled delivery of rhGDF6, which maintained its activity and induced ASC differentiation to NP cells and synthesis of an NP‐like matrix suggesting suitability of microparticles for controlled growth factor release in regenerative strategies for treatment of IVD degeneration.
A Formally Verified Protocol for Secure Vertical Handovers in 4G Heterogeneous Networks

In this paper, we propose a formally verified protocol to securely manage vertical handovers heterogeneous networks (HetNets), even when dierent cryptographic algorithms are used in the infrastructure. The protocol presentation goes with a review of the current propositions of security mechanisms and procedures dedicated to manage vertical handovers. From a critical analysis, the HetNets are positioned in the context of wireless security to describe the possible attacks that aict this new kind of infrastructure. From this analysis, it is revealed that the dierent entities involved in the management of handovers are surrounded by new security challenges. This challenges and the positioning of HetNets helps to deliver a new suited protection. Securing vertical handovers means to deal with the dierent cryptographic algorithms from the security architecture of the dierent technologies that protect the sessions of communications.
Hyperglycemia in non‐obese patients with type 2 diabetes is associated with low muscle mass: The Multicenter Study for Clarifying Evidence for Sarcopenia in Patients with Diabetes Mellitus

Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes.
Stunting trajectories from post-infancy to adolescence in Ethiopia, India, Peru, and Vietnam.

Many interventions focus on preventing stunting in the first 1,000 days of life. We take a broader perspective on childhood growth to assess the proportions of children who suffer persistent stunting, recover, and falter and become newly stunted between birth and adolescence. We use longitudinal data collected on 7,128 children in Ethiopia, India, Peru, and Vietnam. Data were collected in five survey waves between the ages of 1 to 15 years. We use descriptive and graphical approaches to compare the trajectories of children first stunted by age 1, first stunted by age 5, and those remained not stunted until age 5. On average, 29.6% of children were first stunted by age 1, 12.9% of children were first stunted by the age 5, and 68.7% of children were not stunted at either age 1 or age 5. A larger percentage of children stunted by age 1 remained stunted at age 15 (40.7%) compared with those who were first stunted by age 5 (32.3%); 33.7% of children first stunted by age 1 and 31.1% of children first stunted by age 5 go on to recover, but then falter during later childhood. 13.1% of children who were not stunted at age 1 or age 5 become newly stunted between the ages of 8 and 15. Our results show that children both become stunted and recover from stunting into adolescence. More attention should be paid to interventions to support healthy growth throughout childhood.
Hyperglycemia‐Triggered Sphingosine‐1‐Phosphate and Sphingosine‐1‐Phosphate Receptor 3 Signaling Worsens Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization

Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine‐1‐phosphate (S1P) and sphingosine‐1‐phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia‐related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)–induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow–derived macrophages (BMDMs) were differentiated in high‐glucose (HG; 30 mM) or low‐glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia‐related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ‐induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia‐related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. Dual‐immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia‐modulated M1/M2 polarization. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia‐modulated M1/M2 polarization and attenuated inflammation. In conclusion, our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.
Development of an Enzyme-Linked Immunosorbent Assay for Rapid Detection of Dengue Virus (DENV) NS1 and Differentiation of DENV Serotypes during Early Infection

Dengue fever, caused by infections with the dengue virus (DENV), affects nearly 400 million people globally every year. Early diagnosis and management can reduce the morbidity and mortality rates of severe forms of dengue disease as well as decrease the risk of wider outbreaks. ABSTRACT Dengue fever, caused by infections with the dengue virus (DENV), affects nearly 400 million people globally every year. Early diagnosis and management can reduce the morbidity and mortality rates of severe forms of dengue disease as well as decrease the risk of wider outbreaks. Although the early diagnosis of dengue can be achieved using a number of commercial NS1 detection kits, none of these can differentiate among the four dengue virus serotypes. In this study, we developed an enzyme-linked immunosorbent assay (ELISA) for the detection of dengue virus (DENV) NS1 by pairing a serotype-cross-reactive monoclonal antibody (MAb) with one of four serotype-specific MAbs in order to facilitate the rapid detection of NS1 antigens and the simultaneous differentiation of DENV serotypes. A total of 146 serum samples obtained from patients suspected to be in the acute phase of DENV infection were used to evaluate the clinical application of our novel test for the detection and serotyping of DENV. The overall sensitivity rate of our test was 84.85%, and the sensitivity rates for serotyping were as follows: 88.2% (15/17) for DENV serotype 1 (DENV1), 94.7% (18/19) for DENV2, 75% (12/16) for DENV3, and 66.6% (6/9) for DENV4. Moreover, there was no cross-reactivity among serotypes, and no cross-reactivity was observed in sera from nondengue patients. Thus, our test not only enables the rapid detection of the dengue virus but also can distinguish among the specific serotypes during the early stages of infection. These results indicate that our ELISA for DENV NS1 is a convenient tool that may help elucidate the epidemiology of DENV outbreaks and facilitate the clinical management of DENV infections.
Neuroprotective effects of an engineered commensal bacterium in the 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine Parkinson disease mouse model via producing glucagon‐like peptide‐1

While glucagon‐like peptide‐1 (GLP‐1) was reported to have a positive impact on Parkinson disease, it is extremely short half‐life greatly hindered its clinical use. In this study, the mouse strain MG1363‐pMG36e‐GLP‐1 was engineered to continuously express GLP‐1 to treat Parkinson disease in a 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP)‐treated Parkinson disease model. In our study, oral supplementation with MG1363‐pMG36e‐GLP‐1 significantly (p < 0.05) reduced MPTP‐induced locomotor impairments, increased tyrosine hydroxylase‐positive neurons, suppressed microglia and astrocyte activation, and down‐regulated expression of several inflammation‐related molecules. In addition, MG1363‐pMG36e‐GLP‐1 significantly (p < 0.01) reduced intestinal pathogen Enterobacteriaceae and markedly enhanced the number of probiotic Lactobacillus and Akkermansia. These data suggest that MG1363‐pMG36e‐GLP‐1 could be a novel therapeutic means for Parkinson disease.
Development of a Photoswitchable Lithium-Sensitive Probe to Analyze Nonselective Cation Channel Activity in Migrating Cancer Cells

This is the first work to use a newly designed Li+-selective photoswitchable probe Sabrina Heng Lithium (SHL) in living colon cancer cells to noninvasively monitor cation channel activity in real time by the appearance of lithium hot spots detected by confocal microscopy. Punctate Li+ hot spots are clustered in the lamellipodial leading edges of HT29 human colon cancer cells and are colocalized with aquaporin-1 (AQP1) channels. AQP1 is a dual water and cyclic-nucleotide-gated cation channel located in lamellipodia and is essential for rapid cell migration in a subset of aggressive cancers. Both the Li+ hot spots and cell migration are blocked in HT29 cells by the AQP1 ion channel antagonist AqB011. In contrast, Li+ hot spots are not evident in a poorly migrating colon cancer cell line, SW620, which lacks comparable membrane expression of AQP1. Knockdown of AQP1 by RNA interference in HT29 cells significantly impairs Li+ hot spot activity. The SHL probe loaded in living cells shows signature chemical properties of ionic selectivity and reversibility. Dynamic properties of the Li+ hot spots, turning on and off, are confirmed by time-lapse imaging. SHL is a powerful tool for evaluating cation channel function in living cells in real time, with particular promise for studies of motile cells or interlinked networks not easily analyzed by electrophysiological methods. The ability to reset SHL by photoswitching allows monitoring of dynamic signals over time. Future applications of the Li+ probe could include high-throughput optical screening for discovering new classes of channels, or finding new pharmacological modulators for nonselective cation channels.
Interferon‐Induced Transmembrane Proteins Mediate Viral Evasion in Acute and Chronic Hepatitis C Virus Infection

Although adaptive immune responses against hepatitis C virus (HCV) infection have been studied in great detail, the role of innate immunity in protection against HCV infection and immune evasion is only partially understood. Interferon‐induced transmembrane proteins (IFITMs) are innate effector proteins restricting host cell entry of many enveloped viruses, including HCV. However, the clinical impact of IFITMs on HCV immune escape remains to be determined. Here, we show that IFITMs promote viral escape from the neutralizing antibody (nAb) response in clinical cohorts of HCV‐infected patients. Using pseudoparticles bearing HCV envelope proteins from acutely infected patients, we show that HCV variants isolated preseroconversion are more sensitive to the antiviral activity of IFITMs than variants from patients isolated during chronic infection postseroconversion. Furthermore, HCV variants escaping nAb responses during liver transplantation exhibited a significantly higher resistance to IFITMs than variants that were eliminated posttransplantation. Gain‐of‐function and mechanistic studies revealed that IFITMs markedly enhance the antiviral activity of nAbs and suggest a cooperative effect of human monoclonal antibodies and IFITMs for antibody‐mediated neutralization driving the selection pressure in viral evasion. Perturbation studies with the IFITM antagonist amphotericin B revealed that modulation of membrane properties by IFITM proteins is responsible for the IFITM‐mediated blockade of viral entry and enhancement of antibody‐mediated neutralization. Conclusion: Our results indicate IFITM proteins as drivers of viral immune escape and antibody‐mediated HCV neutralization in acute and chronic HCV infection. These findings are of clinical relevance for the design of urgently needed HCV B‐cell vaccines and might help to increase the efficacy of future vaccine candidates.
The Impact of the Acquisition of Electronic Medical Texts on the Usage of Equivalent Print Books in an Academic Medical Library

Objectives – This study examines whether acquiring a text in electronic format effects the usage of the print version of the text, focusing specifically on medical texts. Studies in the literature dealt specifically with general collections and it was not clear if they were applicable to medical collections. It was also not clear if these studies should play a role in determining whether a medical library should purchase electronic texts or whether reserve collections are still needed for print texts. Methods – Four usage studies were conducted using data from the circulation system and the electronic vendor systems. These were 1) trends of print usage; 2) trends of electronic usage; 3) a comparison of electronic usage with print usage of the same title in the reserve collection; 4) a comparison of electronic usage with print usage of the same title in the general collection. Results – In comparison to print, substantial usage is being made of electronic books. Print is maintaining a level pattern of usage while electronic usage is increasing steadily. There was a noticeable difference in the usage levels of the electronic texts as regards to the package in which they are contained. Usage of print texts both on reserve and in the general collection has decreased over time, however the acquisition of the electronic version of a medical title had little impact on the usage of the equivalent print version. Conclusion – There is a demand for medical texts in medical libraries. Electronic versions can replace print versions of texts in reserve. Further investigation is needed of current patterns of print collection usage, with particular emphasis on trends in reserve collection usage.
A Friendly Guide to Wavelets

Preface. - Suggestions to the Reader. - Symbols, Conventions, and Transforms. - Part I: Basic Wavelet Analysis. Preliminaries: Background and Notation. - Windowed Fourier Transforms. - Continuous Wavelet Transforms. - Generalized Frames: Key to Analysis and Synthesis. - Discrete Time-Frequency Analysis and Sampling. - Discrete Time-Scale Analysis. - Multiresolution Analysis. - Daubechies' Orthonormal Wavelet Bases. - Part II: Physical Wavelets. - Introduction to Wavelet Electromagnetics. - Applications to Radar and Scattering. - Wavelet Acoustics. - References. - Index.
Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals.

DESIGN This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks of Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy. METHODS We enrolled HIV-1-infected individuals on suppressive combination antiretroviral therapy. Safety was assessed throughout the study. The primary outcome was reduction in total CD4 T-cell viral DNA levels. Secondary outcomes included safety, detailed immunological and virological analyses, and time to viral rebound (viral load > 5000 copies/ml) after randomization into an analytical treatment interruption (ATI). RESULTS A total of 12 individuals completed the treatment phase and nine completed the ATI. Adverse events were limited and consistent with previous reports for MGN1703. Although the dosing regimen led to potent T-cell activation and increased HIV-1-specific T-cell responses, there were no cohort-wide changes in persistent virus (total CD4 T cells viral DNA; P = 0.34). No difference in time to rebound was observed between the ATI arms (log rank P = 0.25). One of nine ATI participants, despite harboring a large replication-competent reservoir, controlled viremia for 150 days via both HIV-1-specific cellular and antibody-mediated immune responses. CONCLUSION A period of 24 weeks of MGN1703 treatment was safe and improved innate as well as HIV-1-specific adaptive immunity in HIV-1+ individuals. These findings support the incorporation of TLR9 agonism into combination HIV-1 cure strategies. TRIAL NAME AND REGISTRATION TLR9 Enhancement of antiviral immunity in chronic HIV-1 infection: a phase 1B/2A trial; ClinicalTrials.gov NCT02443935.
The effect of matrix interferences on in situ boron isotope analysis by laser ablation multi-collector inductively coupled plasma mass spectrometry.

RATIONALE Boron isotope analysis of marine carbonates by laser ablation multi-collector inductively coupled plasma mass spectrometry (LA-MC-ICP-MS) offers the potential for rapid sample throughput, and the means to examine micron-scale variations in the δ11 B signatures of fossil skeletons and shells/tests of marine organisms. Existing studies demonstrate an acceptable level of reproducibility is achievable, but also typically show a level of accuracy outside the limits required by most applications. Here we investigate matrix interference effects as a cause of inaccuracy and imprecision. METHODS Analyses were performed on a standard format Thermo Scientific Neptune Plus MC-ICP mass spectrometer coupled to a New Wave Research 193 nm ArF laser ablation system. The effects of matrix interference on δ11 B analysis were investigated through analyses of a set of reference materials with differing B/Ca ratios. Three approaches to correct for matrix-induced effects were trialled: (1) use of matrix-matched standards, (2) utilisation of the relationship between δ11 B inaccuracy and11 B/43 Ca, 11 B/40 ArCa4+ or 11 B/Cainterference from three reference materials with known δ11 B values and varying B/Ca ratios, and (3) direct characterisation of the (sloping) interference itself. RESULTS Matrix interference from scattered Ca ions on 10 B can impede both the accuracy and the reproducibility of δ11 B analysis by LA-MC-ICP-MS. Based on analyses of two in-house reference materials, deep sea coral PS69/3181 and inorganic calcite UWC-1, we find approach 2, following the 11 B/Cainterference relationship, gives the best mean accuracies (within 0.4‰ of solution values) and external reproducibilities (± 0.5‰ 2 SD for PS69/3181). This approach has been applied to analyses of an annual growth cycle of a Siderastrea siderea coral and eight Cibicidoides wuellerstorfi benthic foraminifera. Both coral and foraminifera data match solution MC-ICP-MS analyses within reported uncertainties. CONCLUSIONS LA-MC-ICP-MS can produce accurate and precise δ11 B data to a 0.5‰ (2σ) level on <0.3 ng B after correction for Ca interference effects.