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ABSTRACTThe visceral form of leishmaniasis (VL), due to infection by Leishmania infantum, is a neglected tropical disease. The accessible therapeutic options are limited. Artemisinin is an efficient antileishmanial product with poor biological availability that requires high repetition of therapeutic doses in VL. Solid lipid nanoparticles (SLNs) provide targeted delivery, increase bioavailability and reduce toxicity of the traditional therapeutic strategy. The spherical shape artemisinin-loaded SLNs were prepared in a particle diameter of 222.0 ± 14.0 nm. The SLNs showed no particular toxic effect on the parasites, whereas the native artemisinin demonstrated a significant toxicity rate of 31% in viability of the promastigotes at the 250 µg/ml concentration. The therapeutic efficacy of the artemisinin-loaded SLNs was demonstrated in the experimental VL, using the L. infantum-infected BALB/c mice, in the present study. The 10 and 20 mg/kg doses of artemisinin-loaded SLNs showed higher level of antileishmanial efficacy compared with the free artemisinin. There was a significant diminishing of the parasite burden in liver (84.7 ± 4.9%) and spleen (85.0 ± 3.1%) and hepatosplenomegaly by the artemisinin-loaded SLNs treated at 20 mg/kg compared to the free artemisinin. Therefore, the present study supports the superior efficacy of artemisinin-loaded SLNs over the free artemisinin and could be considered as a new therapeutic strategy in the treatment of leishmaniasis.

Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteripopulations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.

AbstractReal-world studies have demonstrated impressive effectiveness of the BNT162b2 COVID-19 vaccine in preventing symptomatic and asymptomatic SARS-CoV-2 infection. We describe an outbreak of SARS-CoV-2 infections in a hospital with high vaccine uptake. We found a low secondary attack rate (7%), suggesting low infectivity of vaccinated persons with vaccine breakthrough SARS-CoV-2 infections.

In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient’s body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.

A subset of megathrust earthquakes produce anomalously large tsunamis for their magnitude. All of these recorded ‘tsunami earthquakes’ in the past 50 years had extensional aftershocks in the upper plate. These include the two largest and most destructive earthquakes of that period, the 2004 Sumatra–Andaman and the 2011 Tohoku events. Evidence from the region of Tohoku indicates that normal fault slip in the upper plate during the earthquake may have contributed to the tsunami size. Here we present a numerical model that shows how a reduction of the dip of a subducting slab, on a timescale of millions of years, can result in an extensional fault failure above a megathrust earthquake on timescales of seconds to months. Slab dip reduction bends the upper plate so that the shallow part fails in extension when a megathrust rupture relieves compressional stress. This results in a distribution of extensional aftershocks comparable to that seen above the Tohoku megathrust. Volcanic arc migration and uplift data for Tohoku and several other tsunami earthquakes is consistent with slab dip reduction. The collection of more such data might identify other areas of tsunami hazard related to slab dip reduction.

AbstractClinical Enterobacteriacae isolates with a colistin minimum inhibitory concentration (MIC) ≥4 mg/L from a United States hospital were screened for the mcr-1gene using real-time polymerase chain reaction (RT-PCR) and confirmed by whole-genome sequencing. Four colistin-resistant Escherichia coli isolates contained mcr-1. Two isolates belonged to the same sequence type (ST-632). All subjects had prior international travel and antimicrobial exposure.

Cutaneous wound healing is a complex orchestrated process influenced by many endogenous and exogenous imbalances. The main goal of tissue regeneration in wound healing is to increase wound contraction and reduce scar formation, effectively to regenerate a new healthy epidermis and prevent scar contracture. Additionally, prevention, control and treatment of wound infections, particularly in burn wounds, is a vital strategy in the healing process. It was previously supposed that local application of sugar-based materials increases the chance of wound infection and delays wound healing. This review shows that topical application of sugar-based compounds has no negative effects on different wound types. Whereas, hyperglycaemia created by diabetes, stress or certain medications can act to impair wound healing. Therefore, this work was designed to review the recent studies that evaluated the role of sugar-based compounds on wound healing and to demonstrate in various cutaneous wound models how these compounds may be involved in healing. It also deals with different physio-pharmacologic conditions resulting in hyperglycaemia in different models of cutaneous wound healing in order to illustrate the role of endogenous glucose in wound healing and remodelling.

Abstract:Adlerian parenting study groups, a prevalent format in many Western countries, aim to impart democratic practices to parents. As part of the learning process in these groups, instructors try to model how to conduct democratic-deliberative discourse in the family. As a case study for a global format for parenting study groups, the present study examines an Adlerian parenting group in Israel. Specifically, it examines how discussions in these groups meet the objective of conducting democratic discourse. The study reveals that many principles of deliberative exchange were only partially implemented, indicating a clear gap between the group's objective and actual implementation of that objective. Overall, the study elucidates the need to teach parent educators deliberative principles.

Several studies have reported the beneficial effects of Lawsonia inermison wound healing, but the mechanism of action is still unknown. This study aimed to investigate the effectiveness of a new ointment formulation of hydroethanolic extract leaves of L. inermison wound healing by gene expression of glucose transporter‐1 (Glut‐1) and insulin‐like growth factor I (Igf‐1) in Wistar rats. The animals were topically treated with different doses of L. inermis. An experimentally induced circular excisional wound model of 314 mm2surface area was surgically created. The percentage of wound contraction and histopathological changes was assessed at different time points following wound induction. The expression of Glut‐1 and Igf‐1 was evaluated by reverse‐transcription PCR. Topical administration of L. inermis, dose dependently, shortened inflammatory phase, accelerated cellular proliferation, and enhanced wound contraction ratio. It also improved revascularization, collagen deposition, and re‐epithelialization rate and promoted intracytoplasmic carbohydrate storage (P< 0.05). Moreover, the mRNA levels of Igf‐1 and Glut‐1 were significantly higher in the L. inermis‐treated groups than the control group (P< 0.05). Topical administration of L. inermispromoted the healing process by reducing tissue inflammation and increasing glucose uptake, which was mediated by up‐regulating the expression of Igf‐1 and Glut‐1.

The Australian allodapine bee, Exoneura robusta,is an important pollinator of native flowering plants in Australian wet forests. In this study, the karyotype of E. robustais illustrated and described using an air-drying technique. The metaphase analysis of the females revealed a diploid chromosome number of 26 (2n = 26). We then discuss parameters affecting the quality of chromosomal spreads including humidity which is not included or examined in existing insect karyotyping protocols. It is further discussed that this might be a reason why current bee chromosomal preparation protocols cannot be easily adapted to different bee species.

Curcumin is a naturally derived active agent of the perennial herb Curcuma longawith anti-inflammatory, antimicrobial, antioxidant and wound healing properties. Because curcumin has very low aqueous solubility and quick degradation, its use is difficult. Incorporation of curcumin nanoparticles (CNs) into a biocompatible scaffold conquers this difficulty and improves the topical drug delivery and therapeutic efficacy of curcumin. In this study, the authors synthesized and characterized three scaffolds made with CNs and using biocompatible polymers, namely, collagen (C) and chitosan (Ch), with ratios of 2:1 (C2Ch1), 1:1 (C1Ch1) and 1:2 (C1Ch2). Then, the scaffolds were applied as wound dressing to enhance the cutaneous wound healing. Since C1Ch2 and CN-incorporated C1Ch2 (CN-C1Ch2) scaffolds demonstrated the best physicochemical characteristics, these samples were used for further biological evaluations through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide detection of viable cells and evaluation of wound healing activity by excision wound model using male Wistar rats. The in vivo and in vitro wound healing studies presented a greater closure of wounds with enhanced histological parameters in the wounds treated with CN-C1Ch2 scaffolds compared to the other samples. The obtained results indicated that the CN-incorporated C1Ch2 scaffolds could significantly improve the wound healing activity.

In addition to lipid-lowering properties, statins have been suggested to affect bone turnover by increasing the osteoblastic bone formation and blocking the osteoclastogenesis. However, there are many controversial reports regarding the beneficial effect of statins on osteoporosis. In this study, we investigated the therapeutic effects of the most important lipophilic statins administered orally for 60 days to the ovariectomized (OVX) female Sprague–Dawley rats and compared the effects on different harvested trabecular and compact bones. Thirty female rats were divided into five equal groups including the normal rats, untreated OVX rats (negative control), and the OVX rats treated with atorvastatin (20 mg/kg/day), simvastatin (25 mg/kg/day), and lovastatin (20 mg/kg/day). The osteoporotic animals were treated daily for 60 days and euthanized at the end of experiments. The effectiveness of these treatments was evaluated by biomechanical testing, histopathologic, histomorphometric, micro-CT scan, real-time PCR, and serum biochemical analysis. Moreover, the hepatotoxicity and rhabdomyolysis related with these treatments were assessed by biochemistry analysis and histopathological evaluation. The results and statistical analysis showed that systemic delivery of simvastatin and lovastatin significantly increased serum calcium level, expression of osteogenic genes, bone mineral density (BMD), and biomechanical properties in comparison to the untreated OVX rats, especially in trabecular bones (P< 0.05). The results of different analysis also indicated that there was no statistical difference between the atorvastatin-treated animals and the negative control. Among all treatments, only atorvastatin showed an evident hepatotoxicity and myopathy. It was concluded that the lovastatin and simvastatin efficiently ameliorated the OVX-induced osteoporosis. Moreover, the simvastatin-treated animals showed more resemblance to the normal group in terms of BMD, expression of osteogenic genes, serum biochemical parameters, histomorphometric findings, and biomechanical performance with no significant side-effects.

Methane hydrates in fine‐grained continental slope sediments often occupy isolated depth intervals surrounded by hydrate‐free sediments. As they are not connected to deep gas sources, these hydrate deposits have been interpreted as sourced by in situ microbial methane. We investigate here the hypothesis that these isolated hydrate accumulations form preferentially in sediments deposited during Pleistocene glacial lowstands that contain relatively large amounts of labile particulate organic carbon, leading to enhanced microbial methanogenesis. To test this hypothesis, we apply an advection‐diffusion‐reaction model with a time‐dependent organic carbon deposition controlled by glacioeustatic sea level variations. In the model, hydrate forms in sediments with greater organic carbon content deposited during the penultimate glacial cycle (~120–240 ka). The model predictions match hydrate‐bearing intervals detected in three sites drilled on the northern Gulf of Mexico continental slope, supporting the hypothesis of hydrate formation driven by enhanced organic carbon burial during glacial lowstands. Natural methane hydrates, ice‐like compounds of water and methane, are widespread in continental margin sediments. We show here evidence for the hypothesis that methane hydrates form preferentially in sediments deposited during glacial periods, which contain more organic matter that is converted to methane by microbes. Methane hydrates within continental slope sediments often occupy isolated depth intervalsHydrate‐bearing intervals may be formed by enhanced methanogenesis in organic carbon‐rich sediments deposited during glacial lowstandsModeling driven by higher organic carbon deposition during lowstands matches hydrate‐bearing intervals observed in Gulf of Mexico boreholes

The incidence of pneumonia increases with age, and is particularly high in patients who reside in long-term care facilities (LTCFs). Mortality rates for pneumonia in older adults are high and have not decreased in the last decade. Atypical symptoms and exacerbation of underlying illnesses should trigger clinical suspicion of pneumonia. Risk factors for multidrug-resistant organisms are more common in older adults, particularly among LTCF residents, and should be considered when making empiric treatment decisions. Monitoring of clinical stability and underlying comorbid conditions, potential drug–drug interactions, and drug-related adverse events are important factors in managing elderly patients with pneumonia.

Acinetobacter baumanniican cause life-threatening nosocomial infections associated with high rates of morbidity and mortality. In recent years, the increasing number of infections due to extensively drug-resistant Acinetobacterwith limited treatment options has resulted in a need for additional therapeutic agents, and a renaissance of older, neglected antimicrobials. This has led to an increased interest in the use of minocycline to treat these infections. Minocycline has been shown to overcome many resistance mechanisms affecting other tetracyclines in A. baumannii, including tigecycline. Additionally, it has favorable pharmacokinetic and pharmacodynamic properties, as well as excellent in vitro activity against drug-resistant A. baumannii. Available data support therapeutic success with minocycline, while ease of dosing with no need for renal or hepatic dose adjustments and improved safety have made it an appealing therapy. This review will focus on the mechanisms of action and resistance to tetracyclines in A. baumannii, the in vitro activity, pharmacokinetic and pharmacodynamic properties of minocycline against A. baumannii, and finally the clinical experience with minocycline for the treatment of invasive infections due to this pathogen.

Burns are the most extensive forms of soft tissue injuries occasionally resulting in extensive and deep wounds and death. Burns can lead to severe mental and emotional distress, because of excessive scarring and skin contractures. Treatment of burns has always been a difficult medical problem and many different methods have been used to treat such injuries, locally. Biofilms are a collection of microorganisms that delay wound healing. One of the new methods of prevention and treatment of burn wound infections is application of antimicrobials, which act on biofilms and prevent the wound infection. Biofilm initiates a persistent, low-grade, inflammatory response, impairing both the epithelialisation and granulation tissue formation. Skin grafts have been shown to dramatically reduce deaths from infection. However, grafting has considerable limitations. Such injuries are long-lasting and many patients suffer from chronic pain for a long time. Tissue engineering is a new approach in reducing the limitations of conventional treatments and producing a supply of immunologically tolerant artificial tissue, leading to a permanent solution for damaged tissues; such criteria make it a cost-effective and reliable treatment modality. To overcome the present limitations of burn wound healing, knowledge about the latest findings regarding healing mechanisms is important. Here the authors discuss the most important events regarding burn wound healing and review the latest treatment strategies that have been used for burn wounds from in vitro to clinical levels. Finally, we discuss the role of tissue engineering and regenerative medicine in the future of burn wound healing, modelling and remodelling.

The Indo‐Burma subduction zone is a highly oblique subduction system where the Indian plate is converging with the Eurasian plate. How strain is partitioned between the Indo‐Burma interface and upper plate Kabaw Fault, and whether the megathrust is a locked and active zone of convergence that can generate great earthquakes are ongoing debates. Here, we use data from a total of 68 Global Navigation Satellite System (GNSS) stations, including newly installed stations across the Kabaw Fault and compute an updated horizontal and vertical GNSS velocity field. We correct vertical rates for fluctuating seasonal signals by accounting for the elastic response of monsoon water on the crust. We model the geodetic data by inverting for 11,000 planar and non‐planar megathrust fault geometries and two geologically viable structural interpretations of the Kabaw Fault that we construct from field geological data, considering a basin‐scale wedge‐fault and a crustal‐scale reverse fault. We demonstrate that the Indo‐Burma megathrust is locked, converging at a rate of 11.6±5.4$11.6\pm 5.4$mm/yr, and capable of hosting >8.2 Mwmegathrust events. We also show that the Kabaw Fault is locked and accommodating strike‐slip motion at a rate of 8.4±3.0$8.4\pm 3.0$mm/yr and converging at a rate of 5.7±4.1$5.7\pm 4.1$mm/yr. Our interpretation of the geological, geophysical, and geodetic datasets indicates the Kabaw Fault is a crustal‐scale structure that actively absorbs a portion of the convergence previously ascribed to the Indo‐Burma megathrust. This reveals a previously unrecognized seismic hazard associated with the Kabaw Fault and slightly reduces the estimated hazard posed by megathrust earthquakes in the region. Subduction zones are plate boundaries where two tectonic plates converge and can generate large earthquake along its main fault, the megathrust. Earthquakes rupture on faults that remain locked and accumulate strain during the interseismic period, the period of time between great earthquakes. The Indo‐Burma subduction zone, where the Indian plate is converging with the Eurasia plate, is home to more than 200 million people. In spite of its enormous population, it is unclear whether the Indo‐Burma subduction zone can generate large megathrust earthquakes. To evaluate its potential to host great earthquakes, we combine new GPS datasets that record plate motion during the interseismic period with geological analysis of the Kabaw Fault, one of the secondary faults in the Indo‐Burma subduction zone. We demonstrate that Indo‐Burma megathrust and Kabaw Fault are locked and can generate significant earthquakes. For the first time, we show that the Kabaw Fault absorbs a portion of the convergence previously ascribed to the Indo‐Burma megathrust which could explain the long repeat time between great earthquakes on the megathrust. The Indo‐Burma subduction zone is capable of hosting large megathrust earthquakesthe Kabaw Fault accommodates strike‐slip and convergence motion previously ascribed to the Indo‐Burma megathrustWe reveal a previously unrecognized seismic hazard associated with the Kabaw Fault The Indo‐Burma subduction zone is capable of hosting large megathrust earthquakes the Kabaw Fault accommodates strike‐slip and convergence motion previously ascribed to the Indo‐Burma megathrust We reveal a previously unrecognized seismic hazard associated with the Kabaw Fault

Previous study confirmed that the acute treatment with baclofen by inhibition of the l-arginine-nitric oxide (NO) pathway diminished the immobility behavior in the forced swimming test (FST) of mice. Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (KATP), in the present study we investigated the involvement of KATPchannels in antidepressant-like effect of baclofen in the forced swimming test (FST).

Background: Previous study confirmed that the acute treatment with baclofen by inhibition of the l-arginine-nitric oxide (NO) pathway diminished the immobility behavior in the forced swimming test (FST) of mice. Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (KATP), in the present study we investigated the involvement of KATPchannels in antidepressant-like effect of baclofen in the forced swimming test (FST). Methods: After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of the antidepressant-like activity of baclofen in mice. Baclofen at different doses (0.1, 0.3, and 1 mg/kg) and fluoxetine (20 mg/kg) were administrated by intraperitoneal (ip) route, 30 min before the FST or OFT. To clarify the probable involvement of KATPchannels, after determination of sub-effective doses of glibenclamide as a KATPchannel blocker and cromakalim, as an opener of these channels, they were co-administrated with the sub-effective and effective doses of baclofen, respectively. Results: Baclofen at dose 1 mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20 mg/kg). Co-administration of gelibenclamide sub-effective dose (1 mg/kg) with baclofen (0.1 mg/kg) showed a synergistic antidepressant-like effect in the FST. Also, sub-effective dose of cromakalim (0.1 mg/kg) inhibited the antidepressant-like effect of baclofen (1 mg/kg) in the FST. All aforementioned treatments had not any impact on the locomotor movement of mice in OFT. Conclusions: Our study for the first time revealed that antidepressant-like effect of baclofen on mice is KATP-dependent, and baclofen seems that exert this effect by blocking the KATPchannels.

The vasodilatory effect of angiotensin 1–7 (Ang 1-7) is exerted in the vascular bed via Mas receptor (MasR) gender dependently. However, the crosstalk between MasR and angiotensin II (Ang II) types 1 and 2 receptors (AT1R and AT2R) may change some actions of Ang 1-7 in renal circulation. In this study by blocking AT1R and AT2R, the role of MasR in kidney hemodynamics was described. In anaesthetized male and female Wistar rats, the effects of saline as vehicle and MasR blockade (A779) were tested on mean arterial pressure (MAP), renal perfusion pressure (RPP), renal blood flow (RBF), and renal vascular resistance (RVR) when both AT1R and AT2R were blocked by losartan and PD123319, respectively. In male rats, when AT1R and AT2R were blocked, there was a tendency for the increase in RBF/wet kidney tissue weight (RBF/KW) to be elevated by A779 as compared with the vehicle (P=0.08), and this was not the case in female rats. The impact of MasR on renal hemodynamics appears not to be sexual dimorphism either when Ang II receptors were blocked. It seems that co-blockade of all AT1R, AT2R, and MasR may alter RBF/ KW in male more than in female rats. These findings support a crosstalk between MasR and Ang II receptors in renal circulation.

The most prevalent primary malignant bone tumor affecting children and adolescents is osteosarcoma. Osteosarcoma is characterized by the formation of immature bone or osteoid tissue by neoplastic cells. They arise predominantly in the long bones, occasionally in the axial bones, and seldom in the soft tissues. Patients with osteosarcoma are currently treated with preoperative (neoadjuvant) chemotherapy followed by tumor resection and further postoperative chemotherapy. Wide margin resection often is necessary and leaves large bone defects. These defects must be reconstructed and repaired using appropriate materials and methods to restore function and structure. Currently, autograft, allograft, prosthetic implant, or a combination is used for defect reconstruction. Despite the available options, reconstruction of large bone defects and improvement in survival rates are still challenging. Tissue engineering and regenerative medicine (TERM) may be promising alternative strategies to regenerate bone and may change conventional treatment strategies in patients with osteosarcoma. TERM in the form of scaffolds, healing promotive factors, or stem cells could be designed to be useful for bone reconstruction and regeneration and also for delivery of anti-cancer therapeutic agents. Combining TERM approaches with immunotherapy, chemoimmunotherapy, radioimmunotherapy, and gene therapy together with advances in diagnostic procedures may change palliative results to curative achievements in the future. This review comprehensively discusses current options, challenges, possible strategies, and future directions in managing patients with osteosarcoma.