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Musculoskeletal modeling, typically implemented using marker-based systems in laboratory environments, is commonly used for noninvasive estimations of loads. Inertial measurement units (IMUs) have become an alternative for the evaluation of kinematics. However, estimates of spine joint contact forces using IMUs have yet to be thoroughly evaluated. Dynamics tasks and static postures from activities of daily living were captured on 11 healthy subjects using both systems simultaneously. Spine kinematics obtained from IMU- and marker-based systems and L4–L5 joint contact forces were compared. Lateral bending resulted in a weak agreement with significant differences between the 2 systems (P =.02, average root mean-squared error = 4.81), whereas flexion–extension and axial rotation exhibited the highest agreement with no significant differences (P <.05, average root mean-squared error = 5.51 and P <.31, average root mean-squared error = 5.08, respectively). All tasks showed excellent correlations (R2 =.76–.99) in estimated loads between systems. Differences in predicted loads at the L4–L5 were only observed during flexion–extension (1041 N vs 947 N, P =.0004) and walking with weights (814 N vs 727 N, P =.004). Different joint reaction force outcomes were obtained in 2 of the 8 tasks between systems, suggesting that IMUs can be robust tools allowing for convenient and less expensive evaluations and for longitudinal assessments inside and outside the laboratory setting. [ABSTRACT FROM AUTHOR]

Many studies have shown that personalized exergames have a positive effect on promoting regular and proper exercise. However, there is no consensus on the design characteristics and evaluation of exergames. This systematic review of published research literature aimed to explore the general characteristics, personalization characteristics, and evaluation of personalized exergames for middle-aged and older people. We screened published studies in the Web of Science, Scopus, PubMed, ACM, and IEEE Xplore databases, extracted data, and performed a thematic analysis according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. Three main themes and nine subthemes were generated from 24 included papers. Moreover, a personalization model (FACTS) and evaluation system (PMSS) of exergames were developed. Personalized exergames had potential positive effects on motivating middle-aged and older people to exercise and improve their health, particularly physical, mental, and social health. However, more fine-grained studies on personalized exergames are necessary in the future. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of continuous perioperative clopidogrel treatment on the osseointegration of titanium implants. Materials and Methods: A total of 32 New Zealand rabbits were randomly divided between two groups: a clopidogrel group (n = 16) and a control group (n = 16). For 1 week prior to the surgical placement of a titanium implant in their medial femoral condyle, rabbits in the clopidogrel group received 3 mg/kg of clopidogrel daily, and the control group received only the vehicle. This treatment was continued for another 6 weeks postoperatively. At 6 weeks, the rabbits were euthanized and postmortem histologic and histomorphometric evaluation of the implants was performed. Results: The surgical procedures and postoperative period were uneventful and well tolerated by all animals without any surgical wound dehiscence, signs of infection, or other complication. No implant failure was observed in any of the groups. Histomorphometric analysis showed that bone-to-implant contact (BIC) was 48.77% for the clopidogrel group and 34.65% for the control group, with statistically significant difference between them (P < .001). Moreover, clopidogrel group had significantly greater bone tissue density (40.52% vs 28.74%, respectively; P <.001) and mean trabecular thickness (284.7 μm vs 180.7 μm, respectively; P < .001) in proximity to the implant surface than the control group, while the mean trabecular number had no difference between groups (1.56 vs 1.60, respectively; P = .961). Conclusions: The present study showed that continuous clopidogrel treatment does not negatively affect osseointegration, but rather promotes it in terms of BIC and bone density around the titanium implants. Further studies on the effect of the P2Y12 receptor and its antagonists on peri-implant bone homeostasis may provide useful information or applications for long-term success of dental implant therapy. [ABSTRACT FROM AUTHOR]

This canine in vivo study assessed the effect of recombinant human platelet-derived growth factor (rhPDGF) on the healing of periapical tissues following apical surgery. From a total of 96 premolar teeth, 64 teeth from six beagle dogs (2 years old) were classified as experimental and were randomly assigned to four experimental groups (16 teeth per group). After having the pulp extirpated, leaving teeth open to the oral cavity for 1 week, and sealing with an immediate restorative material for 8 weeks, nonsurgical endodontic treatment was performed. A split-mouth design was used, and intra-animal randomization of treatment sides was applied to the groups as follows: apical curettage + 1.5-mm root-end resection (Group 1); apicoectomy + mineral trioxide aggregate (MTA) root-end filling (Group 2); apicoectomy + MTA root-end filling + rhPDGF (Group 3); and apical curettage + rhPDGF (Group 4). The animals were sacrificed 24 months after apical surgery, and histologic and µCT analyses were performed for bone volume loss (BVL). Group 1 showed partial resolution of the periapical lesions without signs of tissue regeneration (BVL: 49.09 ± 10.97 mm3). Group 2 had minimal bone regeneration and showed cementum reformation in 9 teeth, with no direct attachment to the MTA (BVL: 35.34 ± 10.97 mm3). Group 3 showed regeneration of all damaged apical tissues without direct contact between the cementum and MTA (BLV: 4.51 ± 1.55 mm3). Group 4 showed regeneration of PDL, bone, and cementum and attachment of functional cementum fibers (BVL: 2.82 ± 2.3 mm3). The difference in BVL was statistically significant only for Groups 1 and 2 (P < .05). rhPDGF may help regenerate apical tissue structures following apical surgery. [ABSTRACT FROM AUTHOR]

Purpose: To review experimental peri-implantitis studies using rat models and summarize different peri-implantitis induction techniques and evaluate their effectiveness. Materials and Methods: Electronic searches were conducted by two independent examiners to address the following issues. Meta-analyses explored the marginal bone loss (MBL) of four types of peri-implantitis induction methods in rats. The detailed induction tactics--such as the implant design, implant size, surgical process, time cost, induction methods, and endpoint measurements--were summarized. Results: Of the 18 included studies, 38.9% of the studies placed implants at the maxillary first molar, and 44.4% placed them at the alveolar ridge region anterior to the maxillary first molar. As for the induction method, the numbers of published studies on ligature methods, bacterial inoculation, and bacterial lipopolysaccharide inoculation were equally high among all selected studies. The total implant survival rate at the end was 160 out of 213 implants (75.11%). Eight studies with high pooled heterogeneity (I2 = 98, P < .01) in the meta-analysis reported an overall MBL (µ-CT) of 0.47 mm (95% CI = 0.14 to 0.81). A subgroup analysis estimated an MBL of 0.31 mm (95% CI = 0.12 to 0.50) for bacterial inoculation and 0.66 mm (95% CI = 0.07 to 1.26) for the ligature method. Histopathologic analysis revealed that peri-implantitis in rats was similar to peri-implantitis lesions in humans. Conclusions: Implant placement at the maxillary first molar with bacterial inoculation and the silk ligature method to build peri-implantitis rat models is reliable to use for research on peri-implantitis. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of supraphysiologic administration of testosterone in an early and late model of implant osseointegration in rat tibiae. Materials and Methods: A total of 40 rats were randomly allocated into four groups (n = 10/group), which were divided according to the type of experiment and time of osseointegration: (1) vehicle (14 days), (2) testosterone (14 days), (3) vehicle (42 days), and (4) testosterone (42 days). Testosterone cypionate (7.5 mg/kg) administration started 4 weeks before implant placement, and the injections were performed daily until euthanasia. Machined-surface titanium implants (2.2 mm in diameter and 4 mm high) were placed bilaterally in the tibia of animals 28 days after the first testosterone injection. At days 14 and 42 after implant placement, euthanasia was performed and the tibiae were harvested to perform biomechanical evaluation and histomorphometric analysis of bone-to-implant contact (BIC%) and bone between the threads (BBT%). Results: There was no statistical difference in the removal torque of the implants between the groups treated with the vehicle (control group) or testosterone (P > .05). At 14 days of osseointegration, the BIC% and BBT% did not differ between vehicle or testosterone groups (P > .05), while at 42 days, both the BIC% and BBT% were significantly reduced by testosterone compared to the vehicle group (P < .05). Conclusions: Testosterone cypionate in supraphysiologic dose impaired late-phase osseointegration in rat tibiae. [ABSTRACT FROM AUTHOR]

It is not currently possible to directly and noninvasively measure in vivo patellofemoral joint contact force during dynamic movement; therefore, indirect methods are required. Simple models may be inaccurate because patellofemoral contact forces vary for the same knee flexion angle, and the patellofemoral joint has substantial out-of-plane motion. More sophisticated models use 3-dimensional kinematics and kinetics coupled to a subject-specific anatomical model to predict contact forces; however, these models are time consuming and expensive. We applied a principal component analysis prediction and regression method to predict patellofemoral joint contact forces derived from a robust musculoskeletal model using exclusively optical motion capture kinematics (external approach), and with both patellofemoral and optical motion capture kinematics (internal approach). We tested this on a heterogeneous population of asymptomatic subjects (n = 8) during ground-level walking (n = 12). We developed equations that successfully capture subject-specific gait characteristics with the internal approach outperforming the external. These approaches were compared with a knee-flexion based model in literature (Brechter model). Both outperformed the Brechter model in interquartile range, limits of agreement, and the coefficient of determination. The equations generated by these approaches are less computationally demanding than a musculoskeletal model and may act as an effective tool in future rapid gait analysis and biofeedback applications. [ABSTRACT FROM AUTHOR]

In this narrative review, we explore developments in the field of computational musculoskeletal model personalization using the Physiome and Musculoskeletal Atlas Projects. Model geometry personalization; statistical shape modeling; and its impact on segmentation, classification, and model creation are explored. Examples include the trapeziometacarpal and tibiofemoral joints, Achilles tendon, gastrocnemius muscle, and pediatric lower limb bones. Finally, a more general approach to model personalization is discussed based on the idea of multiscale personalization called scaffolds. [ABSTRACT FROM AUTHOR]

Purpose: To compare bone substitutes composed of glycated collagen with synthetic micro-sized (1 to 10 µm) hydroxyapatite (OB) vs non-cross-linked collagen matrix with large-particle (250 to 1,000 µm) bovine-derived hydroxyapatite (BOC). Materials and Methods: The P1 to P4 premolars were bilaterally extracted from the mandibles of 19 Beagle dogs. After 21 days, osteotomies were created in each dog that received OB or BOC and were covered with a collagen membrane or were left untreated. The animals were randomly divided into three groups based on sacrifice time (4, 12, or 24 weeks). The right and left hemimandibles were trimmed to facilitate imaging and histology, and all tissues were placed in 10% neutral-buffered formalin. Microcomputed tomography (MicroCT 40 Scanner, Scanco) was used to analyze bone sections. Bone volume, residual material volume, and bone mineral density were determined for each treatment site (OB and BOC) based on a volume of interest that encompassed the original defect. Additionally, blinded histopathologic assessment (based on the ISO 10993-6 scoring system) and histomorphometry were performed on sections ground to < 100 µm thick and stained with Stevenel's blue. Results: No clinical side effects were noted. No statistical differences were observed for OB vs BOC regarding the mineral volume percentage. Compared to OB, BOC had significantly higher mean mineralization densities at 12 weeks (P < .01), but this difference did not extend to 24 weeks. For residual grafting material, bone maturation, alveolar ridge restoration, and inflammatory response, OB showed a residual amount of bone graft and no statistical differences compared to BOC. Conclusion: Both OB and BOC represent valid treatment options for critically sized bone defects. Both bone fillers outperformed the sham-operated, ungrafted (empty) control, demonstrating statistically improved bone growth and ridge restoration. [ABSTRACT FROM AUTHOR]

Stochastic differential equations (SDE) are a powerful tool to model biological regulatory processes with intrinsic and extrinsic noise. However, numerical simulations of SDE models may be problematic if the values of noise terms are negative and large, which is not realistic for biological systems since the molecular copy numbers or protein concentrations should be non-negative. To address this issue, we propose the composite Patankar-Euler methods to obtain positive simulations of SDE models. A SDE model is separated into three parts, namely, the positive-valued drift terms, negative-valued drift terms, and diffusion terms. We first propose the deterministic Patankar-Euler method to avoid negative solutions generated from the negative-valued drift terms. The stochastic Patankar-Euler method is designed to avoid negative solutions generated from both the negative-valued drift terms and diffusion terms. These Patankar-Euler methods have the strong convergence order of a half. The composite Patankar-Euler methods are the combinations of the explicit Euler method, deterministic Patankar-Euler method, and stochastic Patankar-Euler method. Three SDE system models are used to examine the effectiveness, accuracy, and convergence properties of the composite Patankar-Euler methods. Numerical results suggest that the composite Patankar-Euler methods are effective methods to ensure positive simulations when any appropriate stepsize is used. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of BMP-2 on the volumetric and histometric changes in peri-implant defect treatments in animal models. Materials and Methods: An electronic search of four databases and a manual search of peer-reviewed journals for relevant articles were performed. Animal studies with data that compared the volumetric and/or histometric outcomes of peri-implant defect treatment with and without the use of BMP-2 were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables. Results: After completing the search process, 21 randomized controlled trials were included. The results of the metaanalyses showed that the WMD of bone-to-implant contact (%BIC) with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.50% (95% CI = 3.28% to 27.72%, P = .01) and 16.17% (95% CI = 11.17% to 21.16%, P < .00001), respectively, favoring the BMP-2 group. The WMD for the percentage of defect fill with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.88% (95% CI = 3.90% to 27.86%, P = .009) and 10.48% (95% CI = 0.95% to 20.02%, P = .03), respectively, favoring the BMP-2 group. The WMD for the vertical bone gain with 8 to 16 weeks of follow-up was 1.63 mm (95% CI = 0.58 to 2.67 mm, P = .002), also favoring the BMP-2 group. Conclusion: This review demonstrated that the use of BMP-2 in treating periimplant defects showed better clinical and histometric outcomes than defects not treated with BMP-2 in animal models. [ABSTRACT FROM AUTHOR]

Background: Studies have reported that polyphyllin I (PPI) had effective anti-tumor activity against hepatocellular carcinoma (HCC). However, the precise molecular mechanism of this action and the direct target remain unclear. The aim of this study was to discover the molecular targets and the exact mechanism of PPI in the treatment of HCC. Methods: Various HCC cells and Zebrafish xenotransplantation models were used to examine the efficacy of PPI against HCC. A proteome microarray, surface plasmon resonance (SPR) analysis, small molecule transfection, and molecular docking were conducted to confirm the direct binding targets of PPI. Transcriptome and Western blotting were then used to determine the exact responding mechanism. Finally, the anticancer effect and its precise mechanism, as well as the safety of PPI, were verified using a mouse tumor xenograft study. Results: The results demonstrated that PPI had significant anticancer activity against HCC in both in vitro studies of two cells and the zebrafish model. Notably, PPI selectively enhanced the action of the Zinc finger and BTB domain-containing 16 (ZBTB16) protein by directly binding to it. Furthermore, specific knockdown of ZBTB16 markedly attenuated PPI-dependent inhibition of HCC cell proliferation and migration caused by overexpression of the gene. The transcriptome and Western blotting also confirmed that the interaction between ZBTB16 and PPI also activated the PPARγ/RXRα pathway. Finally, the mouse experiments confirmed the efficacy and safety of PPI to treat HCC. Conclusions: Our results indicate that ZBTB16 is a promising drug target for HCC and that PPI as a potent ZBTB16 agonist has potential as a therapeutic agent against HCC by regulating the ZBTB16/PPARγ/RXRα signaling axis. [ABSTRACT FROM AUTHOR]

Our investigation has unveiled a series of pyridine-based SARM1 inhibitors, with the lead compound TH-408 exhibiting remarkable potency, achieving an IC50 value of 0.46 μM. This exceptional inhibitory effect significantly curtailed SARM1-mediated cell death across diverse biological models. This finding highlights the promising therapeutic potential for neurodegenerative disorders by disrupting SARM1 activation and advances our understanding of molecular interventions in these complex disorders, including the regulation of NAD+ metabolism. [ABSTRACT FROM AUTHOR]

Many organisms in nature thrive in intricate habitats through their unique bio-adhesive surfaces, facilitating tasks such as capturing prey and reproduction. It's important to note that the remarkable adhesion properties found in these natural biological surfaces primarily arise from their distinct micro- and nanostructures and/or chemical compositions. To create artificial surfaces with superior adhesion capabilities, researchers delve deeper into the underlying mechanisms of these captivating adhesion phenomena to draw inspiration. This article provides a systematic overview of various biological surfaces with different adhesion mechanisms, focusing on surface micro- and nanostructures and/or chemistry, offering design principles for their artificial counterparts. Here, the basic interactions and adhesion models of natural biological surfaces are introduced first. This will be followed by an exploration of research advancements in natural and artificial adhesive surfaces including both dry adhesive surfaces and wet/underwater adhesive surfaces, along with relevant adhesion characterization techniques. Special attention is paid to stimulus-responsive smart artificial adhesive surfaces with tunable adhesive properties. The goal is to spotlight recent advancements, identify common themes, and explore fundamental distinctions to pinpoint the present challenges and prospects in this field. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a precursor to the development of many diseases (atherosclerosis, diabetes, etc.). It is marked by disruptions in glucose and lipid metabolism, along with hypertension. Numerous types of risk factors contribute to the development of the MetS, inflammation and insulin resistance are present throughout the metabolic abnormalities. Chrysanthemum indicum L. is a traditional Chinese plant used for both tea and medicine, known for its high content of total flavonoids, which are important secondary metabolites. Our research led to the extraction of a Buddleoside-Rich Chrysanthemum indicum L. extract (BUDE) which has demonstrated anti-inflammatory properties. Nonetheless, the specific role and mechanism of BUDE in preventing MetS remain unclear. Methods: The study initially evaluated the role of BUDE in preventing MetS. Subsequently, it investigated the anti-inflammatory properties of BUDE in the liver and pancreas in response to unhealthy diets. It then examined the level of insulin resistance and pancreatic β-cell function induced by inflammation. Additionally, an lipopolysaccharide (LPS)-induced macrophage inflammation model was used to further investigate the ameliorative effects of BUDE in inflammation. Results: BUDE has hypotensive, hypoglycemic and hypolipidemic effects. It can also resolve the imbalance between macrophage subpopulations, impede the triggering of the NF-κB signaling pathway, reduce the secretion of inflammatory mediators, ameliorate insulin resistance, and safeguard organs such as the liver and pancreas from inflammatory damage. These effects collectively contribute to preventing the development of MetS. Discussion: BUDE has the ability to modulate macrophage-mediated inflammation, leading to improved insulin resistance. Additionally, it delivers antihypertensive, hypoglycemic, and hypolipidemic effects, offering a potential for preventing MetS. [ABSTRACT FROM AUTHOR]

Background: A retrotransposon HORT1 in the promoter of the anthocyanin activator gene PeMYB11, microRNA858 (miR858) that targets PeMYB11, and a repressor PeMYBx have been implicated in pigmentation patterning diversity of harlequin Phalaenopsis orchids. However, the interrelationship among them remains to be elucidated. Results: To understand how these factors interact to generate anthocyanin spots in Phalaenopsis, we successfully developed a mathematical model based on the known reaction–diffusion system to simulate their interplay and refined the conceptual biological model. Intriguingly, the expression of both PeMYBx and PeMYB11 were in phase for purple spot formation, even though they showed adverse effects on anthocyanin accumulations. An increase in the self-activation rate of PeMYB11 resulted in the increased size of purple spots, but no effects on spot fusion. Decreased degradation rate of miR858 in the purple regions, led to disruption of the formation of spotted pigmentation patterning and a full-red pigmentation pattern. Significantly, the reduced miR858 level promotes the fusion of large dark purple dots induced by the solo-LTR of HORT1, eventually generating the purple patches. In addition, the spatially heterogeneous insertion of HORT1 caused by the remnant solo-LTR of HORT1 derived from random homologous unequal recombination of HORT1 in individual cells of floral organs could explain the diverse pigmentation patterning of harlequin Phalaenopsis. Conclusions: This devised model explains how HORT1 and miR858 regulate the formation of the pigmentation patterning and holds great promise for developing efficient and innovative approaches to breeding harlequin Phalaenopsis orchids. [ABSTRACT FROM AUTHOR]

AbstractPolygonati rhizoma (Huangjing in Chinese) is a common clinical tonic with the traditional effects of tonifying Qi, nourishing Yin. However, the lack of precise control of processing parameters has led to the uneven quality of processed Huangjing. A prediction model using the CRITIC method optimizes processing by correlating method, component contents, and biological activity, ensuring consistent quality and efficacy. [ABSTRACT FROM AUTHOR]

Recently, the area devoted to fractional calculus has given much attention by researchers. The reason behind such huge attention is the significant applications of the mentioned area in various disciplines. Different problems of real world processes have been investigated by using the concepts of fractional calculus and important and applicable outcomes were obtained. Because, there has been a lot of interest in fractional differential equations. It is brought on by both the extensive development of fractional calculus theory and its applications. The use of linear and quadratic perturbations of nonlinear differential equations in mathematical models of a variety of real-world problems has received a lot of interest. Therefore, motivated by the mentioned importance, this research work is devoted to analyze in detailed, a class of fractal hybrid fractional differential equation under Atangana- Baleanu- Caputo ABC derivative. The qualitative theory of the problem is examined by using tools of non-linear functional analysis. The Ulam-Hyer's (U-H) type stability criteria is also applied to the consider problem. Further, the numerical solution of the model is developed by using powerful numerical technique. Lastly, the Wazewska-Czyzewska and Lasota Model, a well-known biological model, verifies the results. Several graphical representations by using different fractals fractional orders values are presented. The detailed discussion and explanations are given at the end. [ABSTRACT FROM AUTHOR]

Loss of function (LoF) mutations affecting the histone methyl transferase SETD1A are implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model of Setd1a haploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, male Setd1a+/- mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young male Setd1a+/- mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes in Setd1a+/ samples. In adulthood, we found enhanced acoustic startle responding in male Setd1a+/- mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and female Setd1a+/- mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety, Setd1a haplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes. [ABSTRACT FROM AUTHOR]

Background: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. Methods: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. Results: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P <.05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P <.01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. Conclusion: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans. [ABSTRACT FROM AUTHOR]

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is far from over as new strains are emerging all over the world. Selenium as a micronutrient is important for immunity and also has anti-viral activity. Objective: The study evaluated the activity of a Selenium enriched garlic powder (SeGP or SelenoForce®) against SARS-CoV-2 viral replication in vitro and explored its possible mechanism of action. Methods: The anti-SARS-CoV-2 activity assay was carried out in Vero E6 cells in vitro. Human lung carcinoma A549 cells were used to study the antioxidant activity, expression of angiotensin converting enzyme (ACE), transmembrane protease, serine 2 (TMPRSS2) and the activity of proprotein convertase, and furin. Anti-inflammatory activity was evaluated in lipopolysaccharide-activated RAW 264.7 cells. Results: SeGP inhibited the replication of SARS-CoV-2 in Vero E6 cells with an IC50 of 19.59 μg/ml. It exhibited significant antioxidant activity in vitro with IC50 value determined as 43.45 μg/ml. The Selenium enriched product inhibited the expression of ACE and TMPRSS2 and also showed inhibition of furin protease activity. In the presence of SeGP, the secretion of nitric oxide, interleukin −6 and TNF-α were reduced in activated RAW 264.7 macrophages. Conclusion: The results of the study suggest that Selenium enriched garlic powder could inhibit SARS-CoV-2 multiplication in vitro, reduce oxidative stress and inflammatory mediators suggesting that it could be developed as an effective supplement or adjunct therapy to combat viral infections. [ABSTRACT FROM AUTHOR]

Background: Dental caries is a common disease in the oral cavity, and the microorganisms in the cavity are colonized in the form of dental plaque biofilm. Streptococcus mutans is the main pathogen causing dental caries. Using probiotics to inhibit the growth and colonization of pathogenic bacteria, regulate mucosal immunity and improve oral microecological balance is an effective way to prevent or treat dental caries. The aim of this study was to evaluate the caries-prevention of probiotics in vitro and in rat caries models. Methods: The probiotics used in this study are a combination of 4 strains of bacteria. After the fermentation of 4 strains (L. plantarum, L. salivarius, L. rhamnosus, and L. paracasei) was completed, they were mixed in equal volume proportions and used as samples to be tested. The mixture was then assessed the ability to inhibit the growth of S. mutans in vitro and in vivo. SPSS Statistics 22.0 (SPSS, Inc., Chicago, IL, USA) was used for analysis. Results: In vitro the probiotics mixture could inhibit the growth of S. mutans and was able to remove biofilms formed by S. mutans. In a 42-day in vivo experiment, the probiotics group significantly reduced the level of S. mutans on the tooth surface of rats, reducing more than half the bacterial quantities compared with the caries model group (P < 0.05). The amount of S. mutans in the antagonist group was low and highly significant compared with the caries model group. Moreover, the mixture of 4 strains significantly reduced the caries scores (modified Keyes scoring method) in both the probiotic and antagonist groups (p < 0.05). Conclusions: The study showed that the combination of the four strains can reduce the cavity scores, and the four strains can be used as products in oral care products. At the same time, the study also suggests that probiotic therapy can be an effective way to prevent dental caries. [ABSTRACT FROM AUTHOR]

A good theory of mathematical beauty is more practical than any current observation, as new predictions about physical reality can be self-consistently verified. This belief applies to the current status of understanding deep neural networks including large language models and even the biological intelligence. Toy models provide a metaphor of physical reality, allowing mathematically formulating the reality (i.e., the so-called theory), which can be updated as more conjectures are justified or refuted. One does not need to present all details in a model, but rather, more abstract models are constructed, as complex systems such as the brains or deep networks have many sloppy dimensions but much less sti dimensions that strongly impact macroscopic observables. This type of bottom-up mechanistic modeling is still promising in the modern era of understanding the natural or artificial intelligence. Here, we shed light on eight challenges in developing theory of intelligence following this theoretical paradigm. Theses challenges are representation learning, generalization, adversarial robustness, continual learning, causal learning, internal model of the brain, next-token prediction, and the mechanics of subjective experience. [ABSTRACT FROM AUTHOR]

Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo, toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alphasynuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of lonicerin on an osteoarthritis model in vitro and determine its mechanism of action. We induced SW1353 cells with interleukin-1β to construct a cell model of osteoarthritis. The effects of lonicerin on cell viability were observed using cell counting kit-8 assays. Quantitative polymerase chain reaction, immunoblot, and enzyme-linked immune-sorbent assays revealed the effects of lonicerin on inflammation. Additionally, quantitative polymerase chain reaction and immunoblot assays showed the degree of extracellular matrix degradation. Immunoblot assays were further performed to confirm the mechanism of action of lonicerin. Lonicerin contributed to interleukin-1β-stimulated SW1353 cell viability. Furthermore, lonicerin restrained the inflammatory response of interleukin-1β-stimulated SW1353 cells, suppressed the extracellular matrix degradation of interleukin-1β-stimulated SW1353 cells, and increased collagen II expression. Mechanically, lonicerin suppressed the nuclear factor-kappa B pathway and prevented osteoarthritis progression. Lonicerin alleviates interleukin-1β-stimulated cartilage extracellular matrix and inflammation. [ABSTRACT FROM AUTHOR]

Progress in biotechnology is critically dependent on continued access to new biological "components" (genes, proteins, organisms) from nature. Over recent decades, the way that researchers access and use these components has changed dramatically in response to similarly dramatic developments in technology and regulation. The net effect of these changes has been to severely restrict the availability of high-quality genetic data from biodiversity. This bottleneck limits the potential of machine learning (AI) in biotechnology and is a threat to progress across the industry. We suggest that the inevitable demand for high-quality genetic data to train the next generation of biological AI models has the potential to align the economic and technical interests of the bioeconomy with those of biodiverse "provider" countries and communities. The impending era of big data in biotechnology will therefore require the industry to break its dependence on "digital biopiracy" and embrace sustainable partnership-based data supply chains. [ABSTRACT FROM AUTHOR]

Purpose: The traditional Chinese herbal medicine Suaeda salsa (L.) Pall (S. salsa) with a digesting food effect was taken as the research object, and its chemical composition and action mechanism were explored. Methods: The chemical constituents of S. salsa were isolated and purified by column chromatography, and their structures were characterized by nuclear magnetic resonance. The food accumulation model in mice was established, and the changes of the aqueous extract of S. salsa in gastric emptying and intestinal propulsion rate, colonic tissue lesions, serum brain-gut peptide hormone, colonic tissue protein expression, and gut microbiota structure were compared. Results: Ten compounds were isolated from S. salsa named as naringenin (1), hesperetin (2), baicalein (3), luteolin (4), isorhamnetin (5), taxifolin (6), isorhamnetin-3-O-β-d-glucoside (7), luteolin-3′-d-glucuronide (8), luteolin-7-O-β-d-glucuronide (9), and quercetin-3-O-β-d-glucuronide (10), respectively. The aqueous extract of S. salsa can improve the pathological changes of the mice colon and intestinal peristalsis by increasing the rate of gastric emptying and intestinal propulsion. By adjusting the levels of 5-HT, CCK, NT, SS, VIP, GT-17, CHE, MTL, and ghrelin, it can upregulate the levels of c-kit, SCF, and GHRL protein, and restore the imbalanced structure of gut microbiota, further achieve the purpose of treating the syndrome of indigestion. The effect is better with the increase of dose. Conclusion: S. salsa has a certain therapeutic effect on mice with the syndrome of indigestion. From the perspective of "brain-gut-gut microbiota", the mechanism of digestion and accumulation of S. salsa was discussed for the first time, which provided an experimental basis for further exploring the material basis of S. salsa. [ABSTRACT FROM AUTHOR]

Purpose: Paraprobiotics are a non-viable form of probiotics that are reported to provide significant health benefits. Nevertheless, little is known about the beneficial effects of paraprobiotics on inflammatory bowel disease. Although probiotics show potential as therapeutic agents for a range of diseases, including inflammatory bowel disease (IBD), there are certain risks associated with their use. These risks include toxin production, hemolytic potential, antibiotic resistance, and the need to analyze metabolic activities. Hence Using paraprobiotic with the lower aforementioned risk would therefore be the preferable option. Here, we conducted an in vivo study to evaluate the preventive effect of our native paraprobiotic cocktail against dextran sulfate sodium (DSS)-induced murine colitis by affecting the autophagy signaling pathway. Methods: Four-week-old male C57Bl/6 mice were randomly divided into three groups after a two-week acclimation period with normal standard laboratory food diet. Mice were administered PBS (PBS group as control), PBS along with DSS (DSS group, as a control), and a cocktail of paraprobiotics along with DSS (Para group). The severity of colitis, length and histopathology of the colon were evaluated. In addition, the expression of autophagy was assessed using real-time PCR. Results: The results showed that administration of the paraprobiotic cocktail to DSS-treated mice inhibited the severity of colitis symptoms, as evidenced by the inhibition of weight loss and DAI, as well as histopathological scores in the study colon, as well as shortening of colon length caused by DSS. In contrast to the DSS group, the cocktail was able to modulate inflammation through upregulation of autophagy-related genes (becline 1, atg5, atg7, atg12, and atg13). Conclusion: Although there are some limitations in our investigation, such as the dosage and duration of treatments, our native paraprobiotic blend effectively prevented the advancement of colitis. This suggests that it plays a vital role in regulating inflammation and preventing colitis by promoting the autophagy mechanism in cases where the consumption of probiotics may have negative consequences. [ABSTRACT FROM AUTHOR]

Probiotics are well-known to be directly or indirectly involved in the host immune system. In this study, we analyzed the immune-boosting effects of lactic acid bacteria, including Limosilactobacillus and Lactococcus, in immunocompetent C57BL/6J mice. Three different lactic acid bacteria strains were orally administered to C57BL/6J mice for 8 weeks. Then, liver, spleen, and whole blood were harvested after sacrificing the animals. There were no significant changes in whole-body weight, weight of organs, or complete blood cell count by oral administration of lactic acid bacteria. The frequencies of CD3+, CD4+, and CD8+ T cells were significantly increased in the Limosilactobacillus reuteri MG5462 group compared to control. The frequency of NK1.1+ cells was significantly increased in the Lactococcus lactis MG5474 group compared to control. On the other hand, splenocyte proliferations and natural killer cytotoxicity did not differ between groups. In addition, the MG5462 group had a significant increase in the production of TNF-α compared to the control, which is consistent with the upregulation of T cells in the MG5462 group. Therefore, Limosilactobacillus reuteri could be a functional food additive to boost immunity by positively affecting T cell populations. [ABSTRACT FROM AUTHOR]

With ageing of the population worldwide and discovery of new medications for prevention and management of age-related conditions, there is increasing use of medications by older adults. There are international efforts to increase the representativeness of participants in clinical trials to match the intended real-world users of the medications across a range of characteristics including age, multimorbidity, polypharmacy and frailty. Currently, much of the data on medication-related harm in older adults are from pharmacovigilance studies. New methods in pre-clinical models have allowed for measurement of exposures (such as chronic exposure, polypharmacy and deprescribing) and outcomes (such as health span functional measures and frailty) that are highly relevant to geriatric pharmacotherapy. Here we describe opportunities for design and implementation of pre-clinical models that can better predict drug effects in geriatric patients. This could improve the translation of new drugs from bench to bedside and improve outcomes of pharmacotherapy in older adults. [ABSTRACT FROM AUTHOR]

Increasing SNP density by incorporating sequence information only marginally increases prediction accuracies of breeding values in livestock. To find out why, we used statistical models and simulations to investigate the shape of distribution of estimated SNP effects (a profile) around quantitative trait nucleotides (QTNs) in populations with a small effective population size (Ne). A QTN profile created by averaging SNP effects around each QTN was similar to the shape of expected pairwise linkage disequilibrium (PLD) based on Ne and genetic distance between SNP, with a distinct peak for the QTN. Populations with smaller Ne showed lower but wider QTN profiles. However, adding more genotyped individuals with phenotypes dragged the profile closer to the QTN. The QTN profile was higher and narrower for populations with larger compared to smaller Ne. Assuming the PLD curve for the QTN profile, 80% of the additive genetic variance explained by each QTN was contained in ± 1/Ne Morgan interval around the QTN, corresponding to 2 Mb in cattle and 5 Mb in pigs and chickens. With such large intervals, identifying QTN is difficult even if all of them are in the data and the assumed genetic architecture is simplistic. Additional complexity in QTN detection arises from confounding of QTN profiles with signals due to relationships, overlapping profiles with closely spaced QTN, and spurious signals. However, small Ne allows for accurate predictions with large data even without QTN identification because QTNs are accounted for by QTN profiles if SNP density is sufficient to saturate the segments. [ABSTRACT FROM AUTHOR]

53BP1 plays a crucial role in regulating DNA damage repair pathway choice and checkpoint signaling in somatic cells; however, its role in meiosis has remained enigmatic. In this study, we demonstrate that the Caenorhabditis elegans ortholog of 53BP1, HSR-9 , associates with chromatin in both proliferating and meiotic germ cells. Notably, HSR-9 is enriched on the X chromosome pair in pachytene oogenic germ cells. HSR-9 is also present at kinetochores during both mitotic and meiotic divisions but does not appear to be essential for monitoring microtubule–kinetochore attachments or tension. Using cytological markers of different steps in recombinational repair, we found that HSR-9 influences the processing of a subset of meiotic double-stranded breaks into COSA-1 -marked crossovers. Additionally, HSR-9 plays a role in meiotic X chromosome segregation under conditions where X chromosomes fail to pair, synapse, and recombine. Together, these results highlight that chromatin-associated HSR-9 has both conserved and unique functions in the regulation of meiotic chromosome behavior. [ABSTRACT FROM AUTHOR]

To survive daily damage, the formation of actomyosin ring at the wound edge is required to rapidly close cell wounds. Calcium influx is one of the start signals for these cell wound repair events. Here, we find that the rapid recruitment of all 3 Drosophila calcium-responding and phospholipid-binding Annexin proteins (AnxB9, AnxB10, and AnxB11) to distinct regions around the wound is regulated by the quantity of calcium influx rather than their binding to specific phospholipids. The distinct recruitment patterns of these Annexins regulate the subsequent recruitment of RhoGEF2 and RhoGEF3 through actin stabilization to form a robust actomyosin ring. Surprisingly, while the wound does not close in the absence of calcium influx, we find that reduced calcium influx can still initiate repair processes, albeit leading to severe repair phenotypes. Thus, our results suggest that, in addition to initiating repair events, the quantity of calcium influx is important for precise Annexin spatiotemporal protein recruitment to cell wounds and efficient wound repair. [ABSTRACT FROM AUTHOR]

Chromosome inversions are of unique importance in the evolution of genomes and species because when heterozygous with a standard arrangement chromosome, they suppress meiotic crossovers within the inversion. In Drosophila species, heterozygous inversions also cause the interchromosomal effect, whereby the presence of a heterozygous inversion induces a dramatic increase in crossover frequencies in the remainder of the genome within a single meiosis. To date, the interchromosomal effect has been studied exclusively in species that also have high frequencies of inversions in wild populations. We took advantage of a recently developed approach for generating inversions in Drosophila simulans , a species that does not have inversions in wild populations, to ask if there is an interchromosomal effect. We used the existing chromosome 3R balancer and generated a new chromosome 2L balancer to assay for the interchromosomal effect genetically and cytologically. We found no evidence of an interchromosomal effect in D. simulans. To gain insights into the underlying mechanistic reasons, we qualitatively analyzed the relationship between meiotic double-stranded break (DSB) formation and synaptonemal complex (SC) assembly. We found that the SC is assembled prior to DSB formation as in D. melanogaster ; however, we show that the SC is assembled prior to localization of the oocyte determination factor Orb, whereas in D. melanogaster , SC formation does not begin until the Orb is localized. Together, our data show no evidence that heterozygous inversions in D. simulans induce an interchromosomal effect and that there are differences in the developmental programming of the early stages of meiosis. [ABSTRACT FROM AUTHOR]

In Caenorhabditis elegans , expanded families of divergent Hedgehog-related and patched-related proteins promote numerous processes ranging from epithelial and sense organ development to pathogen responses to cuticle shedding during the molt cycle. The molecular functions of these proteins have been mysterious since nematodes lack a canonical Hedgehog signaling pathway. Here we show that Hedgehog-related proteins are components of the cuticle and precuticle apical extracellular matrices that coat, shape, and protect external epithelia. Of four Hedgehog-related proteins imaged, two (GRL-2 and GRL-18) stably associated with the cuticles of specific tubes and two (GRL-7 and WRT-10) labeled precuticle substructures such as furrows or alae. We found that wrt-10 mutations disrupt cuticle alae ridges, consistent with a structural role in matrix organization. We hypothesize that most nematode Hedgehog-related proteins are apical extracellular matrix components, a model that could explain many of the reported functions for this family. These results highlight ancient connections between Hedgehog proteins and the extracellular matrix and suggest that any signaling roles of C. elegans Hedgehog-related proteins will be intimately related to their matrix association. [ABSTRACT FROM AUTHOR]

Objective: Decreased bone density and strength increase the risk of fracture and thus the rates of morbidity and mortality. L-carnitine (LC) is a supplement commonly used by individuals who participate in sports, especially to increase muscle mass. The aim of this study was to investigate the effect of LC on bone strength. Materials and Methods: In our main study 10 male Wistar rats per group, a tendon injury model was applied by clamping the left Achilles tendons of rats except the control group. LC (100 mg/kg/day) was administered intraperitoneally every day for 5 weeks in the pre-LC group and for 4 weeks in the post-LC group. LC was not given to the control group. Apart from to our main study, remaining right os femurs of rats were extracted at the end of the experiment to test bone strength to reduce the number of animals used in scientific research. 3-D bending test was performed on the extracted bones using a Zwick Roell Z0.5 mechanical testing machine. Results: There were no significant differences among the groups in the parameters and measurements used to evaluate bone strength (p>0.05). Conclusion: LC supplementation had no beneficial or detrimental effects on bone strength in healthy subjects. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is an aggressive form of bone cancer that spreads quickly and is challenging to treat. Genetic screening in this study discovered that the loss of the Arid1a gene is a crucial factor in the development and progression of osteosarcoma. In vitro and in vivo studies validated that the loss of Arid1a increased proliferation and chemoresistance in human cell lines and led to higher disease penetrance, metastases, and shorter survival in mice. Unbiased pathway analyses suggest that Arid1a may contribute to the aggressiveness of osteosarcoma by dysregulating genomic instability. Osteosarcoma is an aggressive bone malignancy, molecularly characterized by acquired genome complexity and frequent loss of TP53 and RB1. Obtaining a molecular understanding of the initiating mutations of osteosarcomagenesis has been challenged by the difficulty of parsing between passenger and driver mutations in genes. Here, a forward genetic screen in a genetic mouse model of osteosarcomagenesis initiated by Trp53 and Rb1 conditional loss in pre-osteoblasts identified that Arid1a loss contributes to OS progression. Arid1a is a member of the canonical BAF (SWI/SNF) complex and a known tumor suppressor gene in other cancers. We hypothesized that the loss of Arid1a increases the rate of tumor progression and metastasis. Phenotypic evaluation upon in vitro and in vivo deletion of Arid1a validated this hypothesis. Gene expression and pathway analysis revealed a correlation between Arid1a loss and genomic instability, and the subsequent dysregulation of genes involved in DNA DSB or SSB repair pathways. The most significant of these transcriptional changes was a concomitant decrease in DCLRE1C. Our findings suggest that Arid1a plays a role in genomic instability in aggressive osteosarcoma and a better understanding of this correlation can help with clinical prognoses and personalized patient care. [ABSTRACT FROM AUTHOR]

Simple Summary: Exercise is well known to decrease the risk of breast cancer. The cellular processes that contribute to exercise-induced cancer prevention are less known. We conducted an exercise training study in rats given a chemical to induce breast cancer. Exercise increased the length of time to development of breast cancer in rats. However, when we gave the rats an antibody which binds to a certain cellular protein (oncostatin M), exercise-induced protection against breast cancer was not observed. These observations may be useful in future studies as the oncostatin M protein is produced by muscles. Thus, these results support a link between muscle use during exercise and breast cancer prevention. Future studies may examine oncostatin M and other proteins produced by exercising muscles for their potential role in breast cancer prevention. Moderate-to-vigorous-intensity physical activity decreases the risk of breast cancer. The muscle-derived cytokine (myokine), oncostatin M (OSM), has been shown to decrease breast cancer cell proliferation. We hypothesized that OSM is involved in physical activity-induced breast cancer prevention, and that OSM antibody (Anti-OSM) administration would mitigate the effect of physical activity in a rat model of mammary carcinoma. Female Sprague Dawley rats were injected with 50 mg/kg N-methyl-N-nitrosourea to induce mammary carcinogenesis. During the 20-week study, rats were exercise trained (EX) or remained sedentary (SED). Additional groups were treated with Anti-OSM antibody (SED + Anti-OSM and EX + Anti-OSM) to explore the impact of OSM blockade on tumor latency. Exercise training consisted of treadmill acclimation and progressive increases in session duration, speed, and grade, until reaching 30 min/day, 20 m/min at 15% incline. Experimentally naïve, age-matched, female rats also completed an acute exercise test (AET) with time course blood draws to evaluate OSM plasma concentrations. Relative tumor-free survival time was significantly longer in EX animals (1.36 ± 0.39) compared to SED animals (1.00 ± 0.17; p = 0.009), SED + Anti-OSM animals (0.90 ± 0.23; p = 0.019), and EX + Anti-OSM animals (0.93 ± 0.74; p = 0.004). There were no significant differences in relative tumor latency between SED, SED + Anti-OSM, or EX + Anti-OSM animals. Following the AET, OSM plasma levels trended higher compared to baseline OSM levels (p = 0.080). In conclusion, we observed that exercise-induced delay of mammary tumor development was mitigated through Anti-OSM administration. Thus, future studies of the OSM mechanism are required to lay the groundwork for developing novel chemo-prevention strategies in women who are unable or unwilling to exercise. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most prevalent forms of cancer diagnosed in women worldwide. Since the estradiol receptor (ER) is overexpressed in 75% of breast tumors, it is a reasonable target for tumor diagnosis and therapy. This study focuses on the development and preclinical evaluation of readily synthesized 18F-labeled estradiol derivatives with different lipophilicity. The least hydrophilic derivative, 18F-TA-Glyco-EE, showed the highest cellular uptake in ER-positive breast cancer cells. The in vivo PET imaging of breast tumor-bearing mice demonstrated the desired rapid clearance of the tracer from the excretory organ through the liver. The in vitro autoradiography of ER-positive tumor sections confirmed the high specific binding of 18F-TA-Glyco-EE. In conclusion, 18F-TA-Glyco-EE may be a promising candidate for imaging of ER-positive breast cancer. About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER− MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity. Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

Nature provides us with a wealth of inspiration for the design of bionic functional surfaces. Numerous types of plant leaves with exceptional wettability, anisotropy, and adhesion are extensively employed in many engineering applications. Inspired by the wettability, anisotropy, and adhesion of indocalamus leaves, bionic upper and lower surfaces (BUSs and BLSs) of the indocalamus leaf were successfully prepared using a facile approach combining laser scanning and chemical modification. The results demonstrated the BUSs and BLSs obtained similar structural features to the upper and lower surfaces of the indocalamus leaf and exhibited enhanced and more-controllable wettability, anisotropy, and adhesion. More importantly, we conducted a detailed comparative analysis of the wettability, anisotropy, and adhesion between BUSs and BLSs. Finally, BUSs and BLSs were also explored for the corresponding potential applications, including self-cleaning, liquid manipulation, and fog collection, thereby broadening their practical utility. We believe that this study can contribute to the enrichment of the research on novel biological models and provide significant insights into the development of multifunctional bionic surfaces. [ABSTRACT FROM AUTHOR]

Background: Exposure to stress during childhood and adolescence is a risk factor for alcohol use disorder (AUD) and comorbid conditions, including posttraumatic stress disorder (PTSD). We previously established an adolescent social isolation (SI) model that leads to the emergence of a wide range of behavioral risk factors for AUD, including increased anxiety‐like behavior, locomotor activity, and ethanol consumption in male and female rats. Here, we sought to test the hypothesis that SI may increase vulnerability to single prolonged stress (SPS), a rodent model of PTSD. Methods: Female Long Evans rats (n = 8/group) were either single‐housed or group‐housed (GH) (4/cage) on postnatal day 21. One week later, rats underwent testing in the open field test (OFT), elevated plus‐maze (EPM), and successive alleys test (SAT). Following initial behavioral testing, a subset of SI/GH rats were exposed to SPS. All rats were then tested on the novelty‐suppressed feeding test (NSFT) followed by fear conditioning and home cage two‐bottle choice to assess ethanol consumption. Results: SI significantly increased activity in the OFT and anxiety‐like behavior on the SAT, but not the EPM. While SI and SPS alone had no effect on the NSFT, exposure to both stressors significantly increased approach latency. Complex effects of stress history were observed across a 3‐day fear conditioning paradigm and no group differences were observed with home cage ethanol consumption, regardless of prior ethanol exposure. Conclusions: The results from this study provide novel evidence that SI interacts with SPS in female rats to influence behavior in assays of unconditioned anxiety‐like behavior (NSFT) and conditioned fear. Surprisingly, stress exposure had no effect on home cage ethanol consumption. Ultimately, these models provide useful avenues to examine the interaction between stressful experiences, alcohol exposure, biological sex, and the neurobiological adaptations underlying potential risk factors for psychiatric conditions. [ABSTRACT FROM AUTHOR]

Background: Alcohol is commonly consumed by adolescents in a binge‐like pattern, which can lead to long‐lasting cognitive deficits, including reduced behavioral flexibility. We and others have determined that adolescent intermittent ethanol (AIE) exposure leads to increased number of perineuronal net (PNN) numbers in brain regions that are important for behavioral flexibility. However, whether altered neurochemistry stemming from AIE exposure plays a significant role in reduced behavioral flexibility is unknown. Methods: We measured the number and size of parvalbumin expressing (PV+) interneurons and associated PNNs within the orbitofrontal cortex (OFC), prelimbic cortex (PrL), infralimbic cortex (IL), and anterior insular cortex (AIC) of female and male rats following AIE or control exposure and subsequent training on an attentional set‐shift task (ASST). We then ran analyses to determine whether AIE‐induced changes in PV and PNN measures statistically mediated the AIE‐induced behavioral deficit in reversal learning. Results: We demonstrate that AIE exposure impaired behavioral flexibility on reversal two of the ASST (i.e., recalling the initial learned associations), and led to smaller PV+ cells and increased PNN numbers in the AIC. Interestingly, PNN size and number were not altered in the PrL or IL following AIE exposure, in contrast to prior reports. Mediation analyses suggest that AIE alters behavioral flexibility, at least in part through changes in PV and PNN fluorescent measures in the AIC. Conclusions: This study reveals a significant link between AIE exposure, neural alterations, and diminished behavioral flexibility in rats, and highlights a potential novel mechanism comprising changes in PV and PNN measures within the AIC. Future studies should explore the impact of PNN degradation within the AIC on behavioral flexibility. [ABSTRACT FROM AUTHOR]

Context.--: Conventional karyotype analysis, which provides comprehensive cytogenetic information, plays a significant role in the diagnosis and risk stratification of hematologic neoplasms. The main limitations of this approach include long turnaround time and laboriousness. Therefore, we developed an integral R-banded karyotype analysis system for bone marrow metaphases, based on deep learning. Objective.--: To evaluate the performance of the internal models and the entire karyotype analysis system for R-banded bone marrow metaphase. Design.--: A total of 4442 sets of R-banded normal bone marrow metaphases and karyograms were collected. Accordingly, 4 deep learning-based models for different analytic stages of karyotyping, including denoising, segmentation, classification, and polarity recognition, were developed and integrated as an R-banded bone marrow karyotype analysis system. Five-fold cross validation was performed on each model. The whole system was implemented by 2 strategies of automatic and semiautomatic workflows. A test set of 885 metaphases was used to assess the entire system. Results.--: The denoising model achieved an intersection-over-union (IoU) of 99.20% and a Dice similarity coefficient (DSC) of 99.58% for metaphase acquisition. The segmentation model achieved an IoU of 91.95% and a DSC of 95.79% for chromosome segmentation. The accuracies of the segmentation, classification, and polarity recognition models were 96.77%, 98.77%, and 99.93%, respectively. The whole system achieved an accuracy of 93.33% with the automatic strategy and an accuracy of 99.06% with the semiautomatic strategy. Conclusions.--: The performance of both the internal models and the entire system is desirable. This deep learning-based karyotype analysis system has potential in a clinical application. [ABSTRACT FROM AUTHOR]

Background: Lesion durability and transmurality are crucial for successful radiofrequency (RF) ablation. This study provides a model of real‐time RF lesion visualization and insights into the role of underlying parameters, as local impedance (LI). Methods: A force‐sensing, LI‐sensing catheter was used for lesion creation in an ex vivo model involving cross‐sections of porcine cardiac preparations. During 60 s of RF application, one measurement per second was performed regarding lesion size and available ablation parameters. In total, 1847 measurements from n = 36 lesions were performed. Power (20–50 W) and contact force (1–5 g, 10–15 g, 20–25 g) were systematically alternated. Results: Lesion formation was most prominent in the first seconds of RF application during which nonlinear lesion growth was observed (max. 1.08 mm/s for lesion depth and 2.71 mm/s for lesion diameter). Power levels determined the extent of lesion formation in the early phase. After 20 s, lesion size growth velocity approaches 0.1 mm/s at all power levels. LI changes were also highest in the first seconds (up to – 12 Ω/s) and decreased to less than – 0.1Ω/s after prolonged application. Conclusion: Lesion formation in irrigated RF ablation is a nonlinear process. Final lesion size resulting from an RF application is mainly influenced by high rates of lesion growth in the first seconds of ablation. LI seems to be a good surrogate for differentiating changes in lesion formation. [ABSTRACT FROM AUTHOR]

Cell-derived sheets are of global interest for regenerative therapy. Transplanting a sheet for abdominal organs requires a device for laparoscopic delivery to minimize invasiveness. Here, using a porcine model, we aimed to confirm the feasibility of a device developed to deliver sheets to the thoracic cavity in a laparoscopic transplantation procedure. We used the device to transplant human skeletal myoblast cell sheets onto the liver and measured extra-corporeal, intra-abdominal, and total procedure times for sheet transplantation. Tissues, including the liver and the sheet, were collected two days after transplantation and analyzed histologically. In all experiments (n = 27), all sheets were successfully placed at target locations. The mean (± standard deviation) extra-corporeal, intra-abdominal, and total procedure times were 44 ± 29, 33 ± 12, and 77 ± 36 s, respectively. We found no difference between the two surgeons in procedure times. Histological analyses showed no liver damage with the transplantation and that sheets were transplanted closely onto the liver tissue without gaps. We confirmed the feasibility of a simple universal device to transplant cell-derived sheets via laparoscopic surgery. This device could support a minimally invasive procedure for sheet transplantation. [ABSTRACT FROM AUTHOR]

Background: Limited literature exists on the feasibility and effectiveness of integrating stereotactic ablative radiotherapy (SABR) techniques with hyperfractionated regimens for patients with lung cancer. This study aims to assess whether the SABR technique with hyperfractionation can potentially reduce lung toxicity. Methods: We utilized the linear‐quadratic model to find the optimal fraction to maximize the tumor biological equivalent dose (BED) to normal‐tissue BED ratio. Validation was performed by comparing the SABR plans with 50 Gy/5 fractions and hyperfractionationed plans with 88.8 Gy/74 fractions with the same tumor BED and planning criteria for 10 patients with early‐stage lung cancer. Mean lung BED, Lyman–Kutcher–Burman (LKB) normal tissue complication probability (NTCP), critical volume (CV) criteria (volume below BED of 22.92 and 25.65 Gy, and mean BED for lowest 1000 and 1500 cc) and the percentage of the lung receiving 20Gy or more (V20) were compared using the Wilcoxon signed‐rank test. Results: The transition point occurs when the tumor‐to‐normal tissue ratio (TNR) of the physical dose equals the TNR of α/β in the BED dose‐volume histogram of the lung. Compared with the hypofractionated regimen, the hyperfractionated regimen is superior in the dose range above but inferior below the transition point. The hyperfractionated regimen showed a lower mean lung BED (6.40 Gy vs. 7.73 Gy) and NTCP (3.50% vs. 4.21%), with inferior results concerning CV criteria and higher V20 (7.37% vs. 7.03%) in comparison with the hypofractionated regimen (p < 0.01 for all). Conclusions: The hyperfractionated regimen has an advantage in the high‐dose region of the lung but a disadvantage in the low‐dose region. Further research is needed to determine the superiority between hypo‐ and hyperfractionation. [ABSTRACT FROM AUTHOR]

Background: Preserving sufficient oxygen supply to the tissue is fundamental for maintaining organ function. However, our ability to identify those at risk and promptly recognize tissue hypoperfusion during abdominal surgery is limited. To address this problem, we aimed to develop a new method of perfusion monitoring that can be used during surgical procedures and aid surgeons' decision-making. Methods: In this experimental porcine study, thirteen subjects were randomly assigned one organ of interest [stomach (n = 3), ascending colon (n = 3), rectum (n = 3), and spleen (n = 3)]. After baseline perfusion recordings, using high-frequency, low-dose bolus injections with weight-adjusted (0.008 mg/kg) ICG, organ-supplying arteries were manually and completely occluded leading to hypoperfusion of the target organ. Continuous organ perfusion monitoring was performed throughout the experimental conditions. Results: After manual occlusion of pre-selected organ-supplying arteries, occlusion of the peripheral arterial supply translated in an immediate decrease in oscillation signal in most organs (3/3 ventricle, 3/3 ascending colon, 3/3 rectum, 2/3 spleen). Occlusion of the central arterial supply resulted in a further decrease or complete disappearance of the oscillation curves in the ventricle (3/3), ascending colon (3/3), rectum (3/3), and spleen (1/3). Conclusion: Continuous organ-perfusion monitoring using a high-frequency, low-dose ICG bolus regimen can detect organ hypoperfusion in real-time. [ABSTRACT FROM AUTHOR]

Background: Implementing a robotic system for minimally invasive surgical procedures necessitates a comprehensive training regimen. This involves not only mastering the technological aspects of the robotic system but also enhancing surgical proficiency in manipulating robotic instruments. Furthermore, procedural expertise in specific surgeries is critical. Minimally invasive inguinal hernia repair is particularly suitable as an initial procedure for human application. The development of a comprehensive training model for this type of repair is a crucial element of such an educational pathway. Method: Anatomical dissections were carried out on pigs to assess both the similarities and differences between pig and human anatomy. A structured minimally invasive inguinal hernia repair was performed to determine the suitability of the porcine inguinal region for training purposes. Results: A detailed anatomical description of the porcine inguinal region is outlined, to provide a framework for assessing the critical view of the porcine myopectineal orifice. By integrating the human 'ten golden rules' for safe and effective minimally invasive inguinal hernia repair, the standardized porcine integrated robotic inguinal hernia training (SPIRIT) model describes a step-by-step approach to practice surgical techniques in a realistic setting. Conclusion: The SPIRIT model is designed to be a well-structured training model for minimally invasive inguinal hernia repair and incorporates the specific surgical steps as encountered in a human patient. [ABSTRACT FROM AUTHOR]

Little is known about gender differences in the symptom burden of people living with HIV/AIDS (PLWHA) on antiretroviral therapy in China. This study was conducted based on a biopsychosocial-medical model to describe gender differences in symptom burden among 1035 PLWHA in Yunnan Province, China. After propensity score matching, 798 PLWHA were included in this analysis. Feeling stressed, poor sleep, and memory loss were the most burdensome symptoms among men, while feeling stressed, memory loss, and dizziness were the most burdensome symptoms among women. Among men PLWHA, factors associated with symptom burden were being of the ethnic minority, CD4 count ≥ 500 cells/mm3, physical functioning, and social support. Among women PLWHA, factors associated with symptom burden were being an inpatient, physical functioning, psychological functioning, and social support. Our findings suggest that healthcare providers need to take into account gender differences when developing optimal prevention, treatment, and care programs that provide individualized care to reduce patients' symptom burden. [ABSTRACT FROM AUTHOR]