GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells.

The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α+ and CD103+ DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.

Slip-Coupled Electroosmosis and Electrophoresis Dictate DNA Translocation Speed in Solid-State Nanopores.

Controlling the DNA translocation speed is critical in nanopore sequencing, but remains rather challenging in practice, as attributable to a complex coupling between nanoscale fluidics and electrically mediated migration of DNA in a dynamically evolving manner. One important factor influencing the translocation speed is the DNA-liquid slippage stemming from the hydrophobic nature of the oligonucleotide, an aspect that has been widely ignored in the reported literature. In an effort to circumvent this conceptual deficit, here we first develop an analytical model to bring out the slip-mediated coupling between the electroosmosis and DNA-electrophoresis in a solid-state nanopore at low surface charge limits, ignoring the end effects. Subsequently, we compare these results with the numerical simulation data on electrokinetically modulated DNA translocation in such a nanopore, albeit of finite length with due accommodation of the end effects, connecting two end reservoirs by deploying a fully coupled Poisson-Nernst-Plank-Stokes flow model. Both the numerical and analytical results indicate that the DNA translocation speed is a linearly increasing function of the slip length, with more than four-fold increase being observed for a slip length as minimal as 0.5 nm as compared to the no-slip scenario. Considering specific strategies on demand for arresting high translocation speeds for accurate DNA sequencing, the above results establish a theoretical proposition for the same, premised on an analytical expression of the DNA-hydrophobicity modulated enhancement in the translocation speed for designing a nanopore-based sequencing platform─a paradigm that remained to be underemphasized thus far.

Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance.

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate-glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83-13.94] and HR: 2.44, [CI 95%: 1.10-5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.

Evaluation of diagnostic accuracy of CBCT and intraoral radiography for proximal caries detection in the presence of different dental restoration materials.

PURPOSE: This study aimed to assess the diagnostic accuracy of cone-beam computed tomography (CBCT) and digital intraoral radiography for the detection of proximal caries adjacent to amalgam, e.max porcelain, and metal-ceramic restorations (MCRs). MATERIALS AND METHODS: Parallel intraoral radiographs were obtained from 40 posterior teeth using PSP sensors. To obtain CBCT scans, the teeth were first radiographed alone, and were then positioned next to a tooth with an amalgam restoration, MCR, and e.max porcelain crown, and radiographed again. Two blinded observers scored radiographs using a four-point scale (0: absence of proximal caries, 1: enamel caries, 2: carious lesion extending to the outer half of dentin, 3: carious lesion extending to the inner half of dentin). Tooth sections were made, and the grade of caries was determined under a light microscope at x12 magnification. The sensitivity, specificity, and accuracy of CBCT and intraoral radiographs were then calculated. RESULTS: Artifact-free CBCT scans and intraoral radiographs had the highest diagnostic accuracy (0.826 and 0.657, respectively) while CBCT images of the teeth next to the amalgam restorations (0.526) had the lowest accuracy. The diagnostic accuracy of CBCT images of the teeth next to the porcelain crowns and MCRs was 0.613 and 0.601, respectively. CONCLUSION: Artifact-free CBCT images had higher diagnostic accuracy than intraoral radiography for the detection of all grades of proximal caries. The diagnostic accuracy of CBCT images of teeth adjacent to amalgam, porcelain, and MCRs was lower compared to intraoral radiographs and artifact-free CBCT images.

The effect of dentin surface pretreatment using dimethyl sulfoxide on the bond strength of a universal bonding agent to dentin.

BACKGROUND: This study aimed to evaluate the effect of dentin pretreatment by Dimethyl Sulfoxide (DMSO) on the bond strength and microleakage of a universal bonding agent to dentin. METHODS: Fifty-six dentinal discs (thickness = 2 mm) were obtained from the crowns of the human third molars. The disks were assigned into 4 groups and treated as follows; self-etch-control group: G-Premio universal adhesive was used in self-etch mode, total-etch-control: G-Premio universal adhesive was used in total-etch mode, self-etch-DMSO: Water-based DMSO (50% volume) was applied on the samples for 60 s followed by application of G-Premio universal adhesive in self-etch mode, and Total-etch-DMSO: The samples were etched, and then, water-based DMSO was applied on them for 60 s followed by the application of G-Premio universal adhesive in total-etch mode. Afterward, resin composite was placed on all samples and light-cured. The samples were kept in distilled water and subjected to 5000 thermal cycles. Microshear bond strength was measured using the universal testing machine and failure modes were analyzed using a stereomicroscope. Forty-eight human third molars were used for microleakage evaluation and a standardized class five cavity was prepared on the buccal surface of each tooth. The teeth were assigned into 4 groups and received aforementioned surface treatment and the cavities were filled with resin composite. After storing in water for 24 h, the samples were subjected to 5000 cycles of thermocycling and the microleakage level of the samples was evaluated using silver nitrate uptake at the bonded interface. Two-way ANOVA test was used to analyze the effect of bonding technique (self-etch/ total-etch) and DMSO pretreatment on the microshear bond strength and microleakage of G-Premio adhesive to dentin. RESULTS: Bonding technique had no effect on the bond strength values (p = 0.17) while DMSO pretreatment significantly decreased the microshear bond strength of the samples (p = 0.001). DMSO application increased microleakage significantly in total-etch (P-value = 0.02) while it had no effect in self-etch mode (P-value = 0.44). CONCLUSIONS: Pretreatment of dentin using 50% DMSO significantly reduced the bond strength of G-Premio Bond in both self-etch and total-etch modes. DMSO effect on microleakage depended on the etching technique; DMSO increased the microleakage level when the adhesive was used in total-etch mode while did not affect the microleakage in self-etch mode.

Incorporation of white tea extract in nano-liposomes: optimization, characterization, and stability.

BACKGROUND: In the present study, an extraction method affected by sonication intensity (40%, 70% and 100%), sonication time (5, 10 and 15 min) and different solvents (ethanol, methanol and a combination of ethanol/methanol) was optimized to extract the white tea with the greatest polyphenolic compounds using a response surface methodology. To prepare the nano-liposomal vesicles, phospholipids and cholesterol in various proportions (60:0, 40:20, 30:30 and 20:40) were applied based on thin-film hydration and ultrasound method. The nano-capsules enriched in bioactive compounds were examined through particle characteristics, encapsulation efficiency, morphological analysis, thermal properties and Fourier transform infrared spectroscopy. RESULTS: The observations showed that the extraction yield highly depended on the type of solvent with varying permeability, sonication time and power. The highest total phenolic content (68.38 mg GA g-1 ) and free radical scavenging activity (77.65%) were observed for the following optimal conditions: 70% for sonication intensity, 15 min for sonication time and methanol as solvent. Characteristics of nanoliposomes within a compositional ratio of lecithin/cholesterol (40:20) and with a zeta potential of -56 ± 0.01 mV, as well as white tea extract (WTE) samples with an average particle diameter of 82.20 ± 0.08, microencapsulation efficiency of 76.5% ± 0.081, polydispersity index of 0.06 ± 0.02 and span value of 0.69 ± 0.03. are used as the optimal formulation for microencapsulation of antioxidant WTE. The results demonstrated an increment in thermal stability of liposomal WTE samples compared to other samples. CONCLUSION: The findings of the present study indicated that nano-liposomes comprise an effective technology for coating the WTE, as well as to increasing its stability and thermal properties. © 2021 Society of Chemical Industry.

Vickers micro-hardness study of the effect of fluoride mouthwash on two types of CAD/CAM ceramic materials erosion.

BACKGROUND: The aim of this study was to evaluate the protective effects of fluoride mouthwash on the surface micro-hardness of two types of CAD/CAM ceramics after exposure to acidic solutions. METHODS: 40 samples (5 × 5 × 3 mm3) were prepared from two different ceramics: Vitabloc Mark II CAD, and IPS e.max CAD. The samples were randomly divided into 5 groups in each ceramic (n = 8) immersed in different solutions: Gs: saliva: GGA: gastric acid, GAA: acetic acid, GFGA: sodium fluoride + gastric acid, GFAA: sodium fluoride + acetic acid. The microhardness of samples was measured before and after immersion in different solutions by Vickers microhardness tester. By subtracting the microhardness values after and before immersion, the microhardness changes of the samples were obtained. Data were analyzed by Two-way analysis of variance, one-way analysis of variance, and Tukey test (α = 0.05). RESULTS: Immersion in different solutions reduced the microhardness. Microhardness loss was significantly affected in G FAA and G FGA groups in both types of ceramics (P < 0.05). For Vitabloc Mark II groups, the microhardness loss was significantly higher in GFAA and GFGA compared to IPS e.max CAD P < 0.001). CONCLUSION: Fluoride mouthwash in conjunction with acidic solutions may adversely affect microhardness of Vitabloc Mark II CAD, and IPS e.max CAD that may consequently compromise the clinical service. Vitabloc Mark II CAD was significantly more affected than IPS e.max CAD.

Serotype-dependent recombinant adeno-associated vector (AAV) infection of Epstein-Barr virus-positive B-cells, towards recombinant AAV-based therapy of focal EBV + lymphoproliferative disorders.

BACKGROUND: B-cell proliferative disorders, such as post-transplant lymphoproliferative disease (PTLD), are increased among persons afflicted by T-cell compromise. Most are Epstein-Barr virus (EBV) + and can first present with a focal lesion. Direct introduction of oncolytic viruses into localized tumors provides theoretical advantages over chemotherapy, immunotherapy and radiation therapy by reducing systemic toxicity. Despite extensive study as a vehicle for gene therapy, adeno-associated viruses (AAV) have rarely been applied to human cancer research due to technical and theoretical obstacles. Moreover, human B-cells have historically been described as resistant to AAV infection. Nonetheless, advances using different recombinant (r)AAV serotypes with unique tropisms to deliver cytotoxic therapy suggested a localized anti-tumor approach was feasible. METHODS: As a prelude to the development of a therapeutic vehicle, the ability of fifteen distinct EGFP-bearing rAAV serotypes to transduce human B-cells, including primary, immortalized, and B-cell tumor lines ± EBV was assessed by confocal microscopy, flow cytometry and subsequently cell viability assay. RESULTS: Rank order analysis revealed augmented transduction by rAAV6.2 and closely related virions. EBV infection of EBV-negative B-cell tumor lines and EBV immortalization of primary B-cells increased susceptibility to rAAV6.2 transduction. As a proof of concept, transduction by rAAV6.2 encoding herpes simplex virus type 1 (HSV1)-thymidine kinase (TK) eliminated TK-negative rhabdomyosarcoma cells and diminished viability of transduced B-cell lines upon incubation with ganciclovir. CONCLUSIONS: rAAV serotypes differentially transduce human B-cell lines reversing the dogma that human B-cells are refractory to AAV infection. EBV + B-cells display increased susceptibility to rAAV6.2 infection, uncovering a new method for improved nucleic acid transfer into transfection-resistant B-cell lines. The introduction of a functional suicide gene into the rAAV6.2 genome identifies a candidate vector for the development of rAAV-based oncolytic therapy targeting focal EBV-bearing B-lymphoproliferative disorders.

Immune Response of Gamma-Irradiated Inactivated Bivalent Polio Vaccine Prepared plus Trehalose as a Protein Stabilizer in a Mouse Model.

INTRODUCTION: Poliovirus causes paralysis by infecting the nervous system. Currently, 2 types of polio vaccine are given in many countries in polio eradication program including inactivated polio vaccine (IPV) and oral polio vaccine (OPV). Because of OPV-related paralysis, OPV should be replaced by IPV. METHODS: The aim of this study was to prepare the gamma-irradiated IPV and determine its effectiveness compared with the commercial vaccine (OPV) in the mouse model. The virus titration of OPV was determined and then inactivated by the appropriate dose of gamma radiation into an irradiated vaccine formula. The vaccine was inoculated in BALB/c mice in 2 different formulations of intramuscular injection with 2-week intervals. The level of anti-polio-neutralizing antibody and polio-specific splenocyte proliferation assay were evaluated by collecting the blood samples and spleens of the vaccinated groups with conventional vaccine and irradiated vaccine. RESULTS: There was a significant increase in the neutralizing antibody titration between all of the vaccinated groups and negative control group (A) (p < 0.05). And it shows that the IPV by gamma irradiation has the highest antibody titration. Also, the increasing of stimulation index value in the B* group, F group, and G group was the most against other groups. Furthermore, the neutralizing anti-serum titer and splenic lymphocyte proliferation assay show humoral and cellular immunity were significantly increased in the irradiated vaccine group as compared with conventional group. CONCLUSION: According to the results, gamma-irradiated IPV could induce humoral and cellular immunity in vaccinated mouse groups, so the irradiated poliovirus could be recommended as a good candidate vaccine to prevent the transport of poliovirus to the central nervous system and thus protect against paralysis.

Comparison the effect of charcoal-containing, hydrogen peroxide-containing, and abrasive whitening toothpastes on color stability of a resin composite; an in vitro study.

BACKGROUND: This study aimed to compare the effects of charcoal-containing, hydrogen peroxide-containing, and abrasive whitening toothpastes on color stability of a resin composite. METHODS: Forty-five specimens were fabricated of spectrum TPH3 composite resin and stored in artificial saliva for 24 h. Baseline color assessment was performed using a spectrophotometer device. Then, the specimens were randomly assigned into 5 experimental groups, namely distilled water (GC), Bencer (GB), colgate optic white (GO), perfect white black (GP) and colgate total whitening (GT) toothpastes. The specimens immersed in coffee solution for 10 min and brushed for 1 min with respective toothpaste and then stored in artificial saliva until the next day. This cycle was repeated for 30 days. After 30 days, the final color assessment was performed using the spectrophotometer. Data were analyzed using one-way ANOVA and Tukey tests. RESULTS: Experimental groups were not significantly different in terms of Δa and ΔE values. However, ΔL and Δb values showed significant difference among the groups. Regarding Δa, GT and GC groups showed red color shift while the other groups showed green color shift. Regarding Δb, all groups showed blue color shift except GT group which showed yellow color shift. CONCLUSION: None of the whitening toothpastes could decrease discoloration caused by the coffee solution to the level below the perceptibility threshold except Colgate Optic White which reduced discoloration within the clinically acceptable perceptibility range.

Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus nasal carriage in the West of Iran: a population-based cross-sectional study.

BACKGROUND: Several reports designate the recent increase in community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) nasal carriage. Because of the scanty information regarding the nasal carriage sate of MRSA in the west of Iran, the purpose of the present study was to determine the frequency of CA-MRSA in Sanandaj city. METHODS: Swabs collected from anterior nares of 600 volunteers were analyzed for the presence of S. aureus. The isolates were further investigated for methicillin resistance by using the cefoxitin disk diffusion test, followed by PCR-amplification of the mecA gene. SCCmec types and the presence of the Panton-Valentine Leukocidin (pvl) encoding genes were determined through PCR. Finally, the antimicrobial susceptibility of the isolates was determined by the agar diffusion method. RESULTS: Nasal screening identified 181 S. aureus, of which 55 isolates were MRSA. SCCmec types IV and V were detected in MRSA at frequencies of 80 and 20%, respectively. The overall frequency of pvl genes among the MRSA isolates was 14.54%. MRSA isolates were highly susceptible (98.18%) to mupirocin, gentamicin, and fusidic acid. CONCLUSIONS: The high prevalence of CA-MRSA carriage in the population could pose a serious public health concern for the region. Additionally, advent of drug-resistant pvl-positive strains demands continuous surveillance on the colonization state of CA-MRSA in order to prevent dissemination of the bacterium in the community.

The first positive serological study on rift valley fever in ruminants of Iran.

BACKGROUND & OBJECTIVES: Rift Valley fever (RVF) is a zoonotic vector-borne disease that primarily affects domestic animals but can also infect humans. The purpose of the present study was to investigate the presence of antibodies against RVF virus (RVFV) in ruminants, viz. cattle, sheep, and goats in Kurdistan Province of western Iran. METHODS: Blood samples were collected from 288 ruminants (118 cattle, 142 sheep and 28 goats) of both sexes, under age groups ≤1, 1-3, 3-5 and ≥5 yr, from January 2016 to December 2016. Clinical symptoms and history of abortion were recorded. The presence of RVFV-specific antibodies was investigated by using ELISA (competitive) and indirect immunofluorescence assay (IIFA) after separation of serum. RESULTS: The results of two tests were positive for five (1.74%) of total 288 animals which included two cattle of 118 (1.7%), and three sheep of 142 (2.11%). The results of IIFA were correlated with the ELISA results. All animals were clinically normal. No significant relationship between the RVFV infection rate and the variable considered, i.e. season, animal's age or sex, and the species of the animal (p ≥ 0.05), although there were four seropositive animals in the age group 1-3 and five seropositive animals in the spring season. INTERPRETATION & CONCLUSION: The results of the study revealed the presence of low-level RVFV circulation among the ruminants of Kurdistan Province in Iran indicating that they are at risk of exposure to the virus during their lifetime. Since the present study was the first serological study on RVF in Iran with positive results, further studies are suggested including other areas of Iran.

Phylogenetic characterization of virulent Newcastle disease viruses isolated during outbreaks in northwestern Iran in 2010.

The northwest of Iran shares long borders with three neighboring countries; therefore, it is considered one of the main entry portals of Newcastle disease virus (NDV) into the country. Ten virulent NDVs were recovered from 19 poultry farms of various prefectures in northwestern Iran during Newcastle disease outbreaks in 2010. The isolates were genotypically analyzed using an F-gene-specific reverse transcription polymerase chain reaction (RT-PCR) assay. The amplified F gene (nucleotides 189-1666) sequences of the NDV isolates were compared phylogenetically with those of previously published strains in GenBank. All of the NDV isolates belonged to genotype VIIb and were closely related to some isolates from Iran, Russia, and Sweden. Therefore, it can be postulated that these isolates evolved from previously reported strains. The velogenic viruses carried the motif (112)R-R-Q-K-R/F(117) at the F0 cleavage site and a unique substitution of (190)L→F which had never been reported in any NDV genotype VIIb isolate. They shared high sequence similarity with each other but were distinct from current NDV vaccines and NDV strains reported from other countries. This information is fundamental for improving the efficacy of controlling strategies and vaccine development for NDV.

Effect of composite radiopacity and margin location of the restoration on the diagnosis of secondary caries.

This research aimed to evaluate the effect of the radiopacity of a Bulk-Fill composite (X-TraFil, VOCO, Germany) and a Conventional composite (P60, 3M ESPE, USA) and assessment of the margin location in the enamel and dentin on the diagnosis of secondary caries. 76 intact premolars with MOD preparation were divided into two equal groups and filled with the conventional and bulk-fill composite. Four regions were considered to simulate carious lesions (two regions in enamel and two regions in dentin). In each group, half of the regions in the dentin and half in the enamel were randomly selected for secondary caries simulation and filled with a wax-plaster combination while the remaining regions stayed intact. Bitewing imaging was done using the PSP digital sensor. Five examiners reviewed the images, and lesions were recorded. Caries diagnosis indicators and paired-sample t-test were used for statistical analysis. The reproducibility and accuracy of the examiners' responses were evaluated using the kappa and agreement coefficient (α=0.05). The sensitivity, specificity, and accuracy of diagnosing secondary carious lesions in enamel were significantly better under conventional than bulk-fill composite. Similarly, the sensitivity and accuracy of diagnosing secondary caries in dentin were significantly higher under conventional composite than bulk-fill composite (p<0.05). No significant differences were found in the agreement and kappa coefficient between conventional and bulk-fill composites in the enamel and dentin (p>0.05). The diagnostic accuracy of carious lesions was higher under conventional composite than bulk-fill composite. However, the location of the secondary was ineffective in caries diagnosis.

Sex Dimorphism in Pain Threshold and Neuroinflammatory Response: The Protective Effect of Female Sexual Hormones on Behavior and Seizures in an Allergic Rhinitis Model.

Our previous research demonstrated that allergic rhinitis could impact behavior and seizure threshold in male mice. However, due to the complex hormonal cycles and hormonal influences on behavior in female mice, male mice are more commonly used for behavioral tests. In this study, we aimed to determine whether these findings were replicable in female mice and to explore the potential involvement of sexual hormones in regulating neuroinflammation in an allergic model. Our results indicate that pain threshold was decreased in female mice with allergic rhinitis and the levels of IL-23/IL-17A/IL-17R were increased in their Dorsal root ganglia. However, unlike males, female mice with AR did not display neuropsychological symptoms such as learning and memory deficits, depression, and anxiety-like behavior. This was along with decreased levels of DNA methyl transferase 1 (DNMT1) and inflammatory cytokines in their hippocampus. Ovariectomized mice were used to mitigate hormonal effects, and the results showed that they had behavioral changes and neuroinflammation in their hippocampus similar to male mice, as well as increased levels of DNMT1. These findings demonstrate sex differences in how allergic rhinitis affects behavior, pain sensitivity, and seizure thresholds. Furthermore, our data suggest that DNMT1 may be influenced by sexual hormones, which could play a role in modulating inflammation in allergic conditions.

Social interactions and olfactory cues are required for contagious itch in mice.

The phenomenon of contagious itch, observed in both humans and rodents, remains a topic of ongoing debate concerning its modulators and underlying pathways. This study delves into the relationship between contagious itch and familiar olfactory cues, a non-visual factor contributing to this intriguing behavior. Our findings showed that contagious itch in observer mice occurs during physical interaction with the cagemate itch-demonstrator but not with a stranger demonstrator or in a non-physical encounter condition. Notably, itch-experienced observer mice displayed an increased contagious itch behavior, highlighting the relevance of itch-associated memory in this phenomenon. Furthermore, anosmic observer mice, whether itch-naïve or itch-experienced, displayed no contagious itch behavior. These results demonstrate that the familiar olfactory cues, specifically cagemate body odors, are required for contagious itch behaviors in mice. In line with these behavioral findings, our study reveals increased activity in brain regions associated with olfaction, emotion, and memory during contagious itch, including the olfactory bulb, the amygdala, the hypothalamus, and the hippocampus, with this activity diminished in anosmic mice. In conclusion, our study unveils the critical role of familiar olfactory cues in driving contagious itch in mice, shedding light on the interplay between social factors, sensory perception, and memory in this phenomenon.

Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment.

In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.

Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery.

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in "hard-to-penetrate" tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.