Early Activation Research Articles

Assessing infectiousness and the impact of effective treatment to guide isolation recommendations for people with pulmonary tuberculosis.

Determining the extent and duration of infectiousness of individuals with pulmonary tuberculosis (TB) is critical for various aspects of TB care, including decisions regarding isolation. Studies suggest considerable heterogeneity in infectiousness of people with pulmonary TB. Pre-treatment, measures of bacillary burden including sputum smear microscopy, culture time-to-positivity, and Xpert MTB/RIF cycle threshold (Ct) value, predict the risk of transmission to contacts. Index patients with smear negative disease pose lower infectious risk than those who have smear-positive disease, and household contact infection is more likely with index patients who have lower Xpert Ct values. Newer tools that enable detection of Mycobacterium tuberculosis complex (Mtb complex) from cough aerosol sampling and face mask sampling may be better predictors of contact infection risk. Clinical factors such as cough strength and frequency, and presence of cavitation on chest imaging, may also assist with risk prediction. Post-treatment, smear and culture status are poor predictors of infectiousness. While the exact duration of infectiousness post treatment initiation remains uncertain, data from human-to-guinea pig transmission studies and clinical studies suggest effective treatment results in a rapid decline in infectiousness, irrespective of smear or culture conversion. This is largely supported by early bactericidal activity and transcriptomic studies, and cough aerosol sampling studies, although a subset of patients may have persistent cough aerosol positivity. These findings can enable a more nuanced approach to isolation decision making, while further research studies are awaited.

B cell mechanosensing regulates ER remodeling at the immune synapse.

Engagement of the B-cell receptor with immobilized antigens triggers the formation of an immune synapse (IS), a complex cellular platform where B-cells recruit signaling molecules and reposition lysosomes to promote antigen uptake and processing. Calcium efflux from the endoplasmic reticulum (ER) released upon BCR stimulation is necessary to promote B-cell survival and differentiation. Whether the spatial organization of the ER within the B-cell synapse can tune IS function and B-cell activation remains unaddressed. Here, we characterized ER structure and interaction with the microtubule network during BCR activation and evaluated how mechanical cues arising from antigen presenting surfaces affect this process. B-cells were cultured on surfaces of varying stiffness coated with BCR ligands, fixed, and stained for the ER and microtubule network. Imaging analysis was used to assess the distribution of the ER and microtubules at the IS. Upon BCR activation, the ER is redistributed towards the IS independently of peripheral microtubules and accumulates around the microtubule-organization center. Furthermore, this remodeling is also dependent on substrate stiffness, where greater stiffness triggers enhanced redistribution of the ER. Our results highlight how spatial reorganization of the ER is coupled to the context of antigen recognition and could tune B-cell responses. Additionally, we provide novel evidence that the structural maturation of the ER in plasma cells is initiated during early activation of B-cells.

12212 A Rare Case Of Central Precocious Puberty In A Male Infant With Adrenal Hypoplasia Congenita

Abstract Disclosure: A. Mastoropoulou: None. A.H. Lane: None. Introduction: We describe a male with Adrenal Hypoplasia Congenita (AHC) caused by a novel mutation in NR0B1, who was noted at 9 months of age to have central precocious puberty (CPP). Clinical case: A 3 week-old full-term male presented with hypothermia and lethargy, and a 0.3 kg weight loss since birth. Labs were consistent with adrenal crisis: Na 109 mmol/L, K 10.4 mmol/L, Ca 12.2 mg/dL, glucose 43 mg/dL. He was stabilized with stress dose hydrocortisone (HC), insulin and antibiotics, and was admitted. Subsequent labs revealed cortisol 3.5 ug/dL (4.6-23), ACTH 1,123 pg/mL (7.2-63), 17OHP 181 ng/dL (<199), and a renin of 180 ng/mL/h (1.7-11.2) with aldosterone 14.9 ng/dL (6-179). Abdominal ultrasound was remarkable for non-visualization of the adrenal glands. The patient was discharged with HC, fludrocortisone and sodium supplementation with good tolerance and interval weight gain and normal electrolytes. Genetic testing identified a novel pathogenic c.707G>A [p.Trp236Ter] nonsense variant in the DNA-binding domain of NR0B1 (DAX-1). At 9 months of age, penile enlargement with prepubertal testes was noted. Testosterone was 318 ng/dL (Tanner stage I: 0-18), LH 3.2 mIU/mL (prepubertal: 0-0.3), DHEA-S 2 ug/dL (0-33), FSH 1.1 mIU/mL (prepubertal: 0-1), consistent with hypothalamic pituitary gonadal (HPG) axis activation. Given previous reports of prolonged but self-resolving “mini-puberty of infancy” in AHC, observation was initially chosen. At 12 months of age the bone age was consistent with the Greulich and Pyle 17 months standard. At 13 months of age testosterone remained elevated, therefore based on others’ reported experiences we increased HC from 8 to 15 mg/m2/day and noted a decrease in testosterone to 104 ng/dL within 5 days. HC was further increased to 18 mg/m2/day for 15 days, however testosterone increased to 270 ng/dL, therefore decision was made to treat with Lupron Depot. Conclusions: Historically, hypogonadotropic hypogonadism has been observed in 76% of adolescent patients with AHC who have alterations in NR0B1. CPP has been infrequently described in AHC, and the natural history and management of CPP in this setting is not established. CPP in AHC does not seem to correlate with any particular functional domain of DAX1, because previously reported NR0B1 variants associated with CPP, and this case’s, are dispersed across the gene. The course of our patient suggests multiple underlying mechanisms, including early HPG axis activation as well as the possibility of ACTH dependent precocious puberty. Our observations may contribute to the understanding of factors influencing normal and abnormal puberty in infants. Increased awareness of the possibility of CPP in AHC will aid clinicians in the earlier clinical and laboratory detection of this complication. Presentation: 6/1/2024

7269 Interim Analysis of Gonadotropin-Releasing Hormone Agonist (GnRHa) Treatment in Children with Central Precocious Puberty: Focus on FMV Urinary LH Levels and Clinical Outcomes

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) refers to early activation of the hypothalamic–pituitary–gonadal (HPG) axis in children. There is an urgent need to understand the treatment pattern and clinical outcomes among children suffering from CPP. Studies have reported that first morning voided (FMV) urinary Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) have substantial association with CPP tested in GnRH stimulation test and can be useful in diagnosis and management of CPP in children. Gonadotropin-releasing hormone agonists (GnRHa) such as Leuprolide acetate (LA) are the recommended treatment for children suffering from CPP. The current study aimed to provide the information on level of LH and FSH in FMV urine when CPP diagnosis at baseline and the present results may also revealed trend of FMV-LH and FMV-FSH change during LA intervention in children with CPP. Here we present interim results from this study. Methods: This is an open-label, multicentre, single arm, prospective study that enrolled 31 subjects with CPP. Individuals were administered LA depot 11.25 mg, subcutaneously every 12 weeks. The study comprises a screening period; a 6-month treatment period: 24 weeks; and a post-treatment follow-up period: 12 weeks. The FMV urinary LH and FSH were diagnosed by Clopper-Pearson method with a 95% confidence interval. Results: Due to the data collection time point for the interim analysis, only 8 female subjects reached the 12-week visit time point and had a 12-week visit for FMV urinary Gn testing. Therefore, for this interim analysis, only FMV Gn decline at week 12 of the 8 subjects who had a 12-week visit will be presented. At baseline, the mean value of FMV urinary LH and FSH is 0.58 IU/L and 2.27 IU/L respectively. The FMV Gn urinary LH was demonstrated a decrease in 87.5% (95% CI: 47.35,99.68) of the children after LA intervention. Additionally, urinary FSH value of FMV urinary Gn was found to decrease in 75.00% of the children (95% CI: 34.91,96.81) compared to baseline FSH value. Conclusion: The present study reveals a decreasing trend in FMV Gn urinary LH and FSH levels in CPP children treated with LA during interim analysis. LA was shown to be safe and effective in ameliorating the level of LH and FSH in children suffering from CPP. From the study, it can be concluded that urinary LH and FSH may act as a potential biomarker for diagnosis and management of CPP. Presentation: 6/3/2024

7128 Efficacy and Safety of Leuprolide Acetate 3M Depot in Chinese Children with Central Precocious Puberty: Interim Analysis of Multicenter, Single-Arm, Prospective Study

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) due to early activation of the hypothalamic-pituitary-gonadal axis leads to early puberty. CPP has a negative impact on adult height. Leuprolide acetate (LA), a gonadotropin-releasing hormone agonist (GnRHa) is the standard treatment for CPP. As CPP requires prolonged treatment, a 3-month (3M) depot formulation would increase patient compliance and reduce the injection burden. This interim analysis presents the effect of LA 3M depot on the gonadotropic axis and assesses safety in children with CPP. Methods: In this open-label, multicenter, single-arm, and prospective study, 31 children with CPP were included. Key inclusion criteria were the appearance of secondary sexual characteristics below the age of eight years in girls and nine years in boys with a confirmed diagnosis of CPP. Children treated with prior GnRHa and/or having underlying medical conditions were excluded. Eligible children were treated with LA 11.25 mg subcutaneously every 12 weeks. The primary endpoint of this interim analysis was the proportion of children achieving inhibition of peak LH defined as peak LH ≤ 3.0 IU/L in the GnRH stimulation test at weeks 24. The secondary endpoint was safety analysis in the children receiving at least one dose of LA 3M depot. Results: At baseline, 30 girls and one boy were enrolled. The median (95% CI) chronological age (CA) of the girls was 8.0 (7.0, 9.0) years and the boy was 10 years old. Girls had a median height of 136.95 (131.5, 139.7) cm, weight of 30 (27, 34) kg, and BMI of 16.4 (15.1, 17.9) kg/m2. Baseline bone (BA) age was 11 (10, 11) years, and BA/CA was 1.24 (1.2, 1.3). Boy’s characteristics at baseline differed in CA (10 years), height (144 cm), and BMI (17.4 kg/m2) from girls of this cohort. Due to the data collection time points for the interim analysis, 8 out of the 31 enrolled subjects had a visit at week 24, and 30 subjects reached the week 12 visit time point and had a visit at week 12. The percentage of children achieving inhibition of peak LH (≤ 3.0 IU/L) in the GnRH stimulation test at week 12 was 100 (88.4, 100) %. At week 24, all of them achieved inhibition of LH in the GnRH stimulation test 100 (63, 100) %. Decreases in BA/CA from baseline at weeks 12 and 24 are 93 (77.9, 99.2) % and 50 (15.7, 84.3) % respectively. No progression of the Tanner stage was observed in 96.7 (82.8, 99.9) % and 100 (63, 100) % at weeks 12 and 24. At the data cut-off, 4 (13.33%) patients experienced a total of 5 treatment-emergent adverse events (TEAEs) in the safety population of 30 subjects. No grade ≥3 AE or serious AE was reported. The incidence of injection site reaction was 3.33%. Conclusion: LA at 11.25mg/3M depot effectively suppresses the gonadotropic axis at weeks 12 and 24, normalizing growth and reversibly slowing the early onset of puberty in children with CPP. LA in a 3-month injecting frequency is a safe and convenient treatment option to improve patient compliance. Presentation: 6/3/2024

Analysis of immunopathogenesis of psoriasis in the dynamics of treatment

Оbjective — to analyze the parameters of the immune system of the organism in patients with psoriasis before and after treatment. Materials and methods. The parameters of cellular immunity in an organism estimated after the change of relative and absolute amount of T- (CD3+) and B- (CD19+) of lymphocytes and subpopulations (CD4+, CD8+, CD16+, CD25+, CD71+, CD30+, CD95+). To identify of surface structures of lymphocytes the method of direct immune fluorescence was used where fluorescent label was attached to anti-CD of mononuclear antibodies of series Leu of the firm «Becton Dikinson» (USA). Calculations were conducted on the laser instantaneous cytofluorometer of the firm «Baston» (USA). Results and discussions. The most positive influence on the parameters of the cellular link of the immune system of the organism was found in patients with psoriasis who received immunobiological therapy with the medication etanercept in combination with narrowband (311 nm) phototherapy. After treatment in patients of this group, due to a significant decrease in the production of TNF and its serum concentration, the pro-inflammatory changes in the cellular link of the immune system decreased, the number of lymphocytes with the an early activation marker, which initiated a further cytokine cascade of development and prolongation of inflammation decreased significantly. In addition, the established reduction in the number of CD30+ lymphocytes is an indirect factor indicating the switching of the Tx2 response (autoimmune manifestations) to Tx1, and hence the achievement of the clinical and immunological remission of the psoriatic process. It is extremely important for the functioning of the immune system the decrease in the content of activated lymphocytes that express the Fas-receptor as due to the increased lymphocyte apoptosis, namely, T-cytotoxic lymphocytes, and autoimmune and proliferative changes took place inherent in the exacerbation of the psoriatic process. Conclusions. It was established that all our schemes of psoriasis treatment have immunorehabiting properties but their degree of severity was different. The most effective treatment scheme is the combined use of etanercept and UVB therapy, thus proliferative and inflammatory changes in the skin reduced, antigenic loading decreased, the level of CICs, autosensibilization and autoimmune disorders also decreased.

Early Rehabilitation Activity and Rehabilitation in ICU Wards in Central China: A Cross-Sectional Survey.

Patients in Intensive Care Units (ICUs) face high risks of physical, functional, cognitive, and mental impairments. Early rehabilitation activities are crucial for reducing mortality and complication rates. This survey investigates the characteristics, current implementation, and detailed status of early rehabilitation activities in ICUs across Central China. A cross-sectional survey was conducted involving 158hospitals, with 131 responding. Data on institutional characteristics and early rehabilitation activities were collected through questionnaires. Descriptive statistical analysis described the current status, and a univariate regression model identified factors associated with the implementation of early rehabilitation measures. A total of 131 ICUs completed the survey, with a response rate of 82.91% (131/158). Results indicated that 82.44% (108/131) of ICUs implemented early rehabilitation activities, but only 65 (49.62%) had explicit early rehabilitation exercise protocols or standards/procedures. Before implementing early rehabilitation activities, approximately 89.97% (110/131) of ICUs conducted assessments, and 46.56% (61/131) regularly held structured interdisciplinary rounds to discuss early activity measures and goals. More than half of the participating adult ICUs reported screening patients for swallowing function (64.89%; 85/131), and 55.73% (73/131) of adult ICUs reported having a nutrition therapy specialist conduct regular consultations/visits. Only 26.72% (35/131) of adult ICUs reported having a speech therapist conduct consultations/visits. A total of 81.68% (107/131) of ICUs believed that the current implementation of early rehabilitation activities was insufficient. In the analysis of influencing factors, the presence of rehabilitation therapists in the ICU was a significant factor for the implementation of early rehabilitation activities (P<0.05). The majority of ICUs in hospitals in central China have implemented early rehabilitation activities; however, less than half have explicit early rehabilitation exercise protocols or standards/procedures. The presence of professional rehabilitation therapists in the ICU is a key factor in the implementation of early rehabilitation activities in ICUs in hospitals in Central China.

Spatial Contextual Information Modulates Affordance Processing and Early Electrophysiological Markers of Scene Perception.

Scene perception allows humans to extract information from their environment and plan navigation efficiently. The automatic extraction of potential paths in a scene, also referred to as navigational affordances, is supported by scene-selective regions (SSRs) that enable efficient human navigation. Recent evidence suggests that the activity of these SSRs can be influenced by information from adjacent spatial memory areas. However, it remains unexplored how these contextual information could influence the extraction of bottom-up information, such as navigational affordances, from a scene and the underlying neural dynamics. Therefore, we analyzed ERPs in 26 young adults performing scene and spatial memory tasks in artificially generated rooms with varying numbers and locations of available doorways. We found that increasing the number of navigational affordances only impaired performance in the spatial memory task. ERP results showed a similar pattern of activity for both tasks, but with increased P2 amplitude in the spatial memory task compared with the scene memory. Finally, we reported no modulation of the P2 component by the number of affordances in either task. This modulation of early markers of visual processing suggests that the dynamics of SSR activity are influenced by a priori knowledge, with increased amplitude when participants have more contextual information about the perceived scene. Overall, our results suggest that prior spatial knowledge about the scene, such as the location of a goal, modulates early cortical activity associated with SSRs, and that this information may interact with bottom-up processing of scene content, such as navigational affordances.

Triiodothyronine (T3) suppresses hepatic tumorigenesis and development by inhibiting the phosphorylation of ERK.

The effect of triiodothyronine (T3) on the phosphorylation of ERK and the occurrence and development of hepatocellular carcinoma (HCC) is controversial and remains to be clarified. In the present study, both in vitro (hepatoma cell lines) and in vivo (wild-type mice [WT] and mouse models of HCC [HrasG12Vand KrasG12Dtransgenic mice (Hras-Tg and Kras-Tg)]) systems were used to investigate the effect of T3 on p-ERK and hepatocarcinogenesis. The results showed that, in vitro, T3 treatment elevated the levels of p-ERK in hepatoma cells within 30 min. However, p-ERK levels returned to normal after 1 h with no significant effects on cellular proliferation or apoptosis. Interestingly, in vivo, T3 induced early rapid and transient activation of ERK and later persistent downregulation of p-ERK in liver tissues of WT. In Hras-Tg, liver weight, liver/body weight ratio, hepatic tumor numbers and sizes were significantly reduced withT3treatment compared with the untreated group. Furthermore, the levels of albumin, HrasG12V, and p-ERK in hepatic precancerous and tumor tissues were all significantly downregulated with T3 treatment; however, the levels of endogenous Hras were not affected. In WT, T3 also induced downregulation of Albumin in liver tissues, but without influence on the expression of endogenous Hras and p-MEK. Especially, the inhibitory effect of T3 on p-ERK and hepatic tumorigenesis and development without influence on the levels of KrasG12D and p-MEK was further confirmed in Kras-Tg. In conclusion, T3 suppresses hepatic tumorigenesis and development by independently and substantially inhibiting the phosphorylation of ERK in vivo.

Elucidating the Mechanism of Large-Diameter Titanium Dioxide Nanotubes in Protecting Osteoblasts Under Oxidative Stress Environment: The Role of Fibronectin and Albumin Adsorption.

Large-diameter titanium dioxide nanotubes (TNTs) have shown promise in preserving osteoblast function under oxidative stress (OS) in vitro. However, their ability to enhance osteogenesis in vivo under OS conditions and the underlying mechanisms remain unclear. This study aimed to evaluate the osteogenic potential of 110 nm TNTs (TNT110) compared to 30 nm TNTs (TNT30) in an aging rat model exhibiting OS, and to investigate the mechanisms involved. Surface properties of TNTs were characterized, and in vitro and in vivo experiments were conducted to assess their osteoinductive effects under OS. Transcriptomic, proteomic analyses, and Western blotting were performed to investigate the protective mechanisms of TNT110 on osteoblasts. Protein adsorption studies focused on the roles of fibronectin (FN) and albumin (BSA) in modulating osteoblast behavior on TNT110. In both in vitro and in vivo experiments, TNT110 significantly improved new bone formation and supported osteoblast survival under OS conditions. Subsequent ribonucleic acid sequencing results indicated that TNT110 tended to attenuate inflammatory responses and reactive oxygen species (ROS) expression while promoting endoplasmic reticulum (ER) stress and extracellular matrix receptor interactions, all of which are crucial for osteoblast survival and functionality. Further confirmation indicated that the cellular behavior changes of osteoblasts in the TNT110 group could only occur in the presence of serum. Moreover, proteomic analysis under OS conditions revealed the pivotal roles of FN and BSA in augmenting TNT110's resistance to OS. Surface pretreatment of TNT110 with FN/BSA alone could beneficially influence the early adhesion, spreading, ER activity, and ROS expression of osteoblasts, a trend not observed with TNT30. TNT110 effectively protects osteoblast function in the OS microenvironment by modulating protein adsorption, with FN and BSA synergistically enhancing osteogenesis. These findings suggest TNT110's potential for use in implants for elderly patients.

Analysis of fuel storage tanks under internal deflagrations with different venting technologies: an experimental and numerical study

This study investigates small-scale fuel storage tanks subjected to internal methane-air explosions, focusing on three depressurization technologies using roof ventilation to mitigate overpressure and damage. Tests with low methane-air concentrations were conducted to generate a pseudo-static internal pressure. This approach minimized scale effects and aligned internal pressure frequency with real-scale tank behavior during deflagrations. The first prototype features a tank with a frangible roof activated by localized brittle failure of stitch welds around the roof-to-shell junction. This confirms that stitched weld patterns ensure controlled brittle failure with activation pressure estimated by a simplified equation. The second technology employs a sequential ventilation strategy, starting with a small hinged panel followed by stitch weld failure, managing low to medium-intensity explosions with the small vent alone, and allowing rapid operational recovery. In severe explosions, the hinged door facilitates earlier activation of the frangible roof, reducing the initial pressure rise rate and controlling the roof opening direction. Lastly, the study explores tanks with commercial explosion vent panels as an alternative to traditional frangible roofs, offering a practical solution for retrofitting existing tanks. Each technology enhances safety in fuel storage facilities by effectively managing internal pressures during explosive events.

Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy.

Partial hepatectomy (PH) is commonly used to treat patients with hepatocellular carcinoma. The recovery of patients from PH depends on the initiation of liver regeneration, a process that mainly relies on liver cell proliferation. As sex affects the human liver regeneration progress, we investigated sex disparity in PH-induced liver regeneration in adult zebrafish. We found that, after PH, males began liver regeneration earlier than females in terms of liver cell proliferation and liver mass recovery, and this was associated with earlier activation of Yap1 signaling in male than female livers. We also found that androgen receptors regulated the sex-biased liver regeneration in a Yap1-dependent manner and that activated estrogen receptors are responsible for the later onset of female hepatocyte proliferation. Furthermore, we identified that S100A1, a calcium-binding protein, regulates the sex disparity in liver regeneration, as heterozygous S100A1 knockout inhibited Yap1 activity in male livers and delayed hepatocyte proliferation in males following PH. Thus, multiple pathways and/or their interplays contribute to the sex disparity in liver regeneration, suggesting that sex-biased therapeutic strategies are required for patients who have received PH-based therapies.

Effects of water sprays on hydrogen autoignition in heated air

The effects of water mist with different diameters and mass loadings on hydrogen auto-ignition in air with elevated temperatures and pressures are studied. It is shown that smaller droplets with larger mass loading are the most effective in inhibiting the auto-ignition process. Under elevated initial pressures and temperatures, the role of water mist in impacting auto-ignition is minimal, primarily because the ignition delay is substantially shorter than the droplet evaporation duration. As the initial temperature decreases, there exists a temperature value below which water mist markedly extends the ignition delay time, even escalating it by up to two orders of magnitude or causing a complete suppression of ignition. The rate of production for important radicals was analyzed. The data indicates that the evaporation of the water mist lowers the initial temperature, leading to a reduction in the rate of the temperature-sensitive fast chain branching reaction. In contrast, the third body reaction that generates HO2 is not sensitive to temperature. Meanwhile, the introduction of H2O results in an earlier activation of the third body reactions. Consequently, the production of HO2 is enhanced, emphasizing the role of subsequent slow chain propagation reactions that generate OH, thereby extending the ignition delay. By deactivating the mass transfer between two phases and introducing artificial species, it is evident that water vapor dilution and thermal effects predominantly influence the ignition delay, while its role as a direct reactant is minimal.

소비에트 러시아 초기 프롤레트쿨트의 활동(1918-1921)

This paper sheds light on the early activities of the proletarian cultural enlightenment organization established by the leader of Left Bolsheviks Aleksandr Bogdanov, Proletkult. He was the first Russian Marxist interested in building socialism through the formation of an independent culture of the working class. In general, Marxists believed that the superstructure, such as culture, could be transformed through changes of the base such as relations and means of production in economy. Bogdanov, however, argued that culture should take precedence over politics and economics and that changes of the former affect the latter. He attempted to create a proletarian culture based on collectivism as opposed to bourgeois culture dominated by individualism. The party schools in Capri and Bologna, Italy before the October Revolution and the Proletkult after the Revolution were established in this process. The Proletkult aimed for cultural movement with autonomy and rejected any subordination to party and the state. Founded throughout Soviet Russia, the Proletkult branches helped workers develop a sense of collectivism via literature, art, music, and theater studios. However, Bogdanov and the organization failed without bearing fruit in 1921. The leadership of Lenin and Krupskaia’s attempts to deprive the Proletkult’s autonomy at the end of 1920 struck like a lightening bolt. Left Bolsheviks, including Bogdanov, who were criticized as anti-Marxists left the organization.

Cell wall nanoparticles from hyphae of Alternaria infectoria grown with caspofungin, nikkomycin, or pyroquilon trigger different activation profiles in macrophages.

Alternaria infectoria causes opportunistic human infections and is a source of allergens leading to respiratory allergies. In this work, we prepared cell wall nanoparticles (CWNPs) as a novel approach to study macrophage immunomodulation by fungal hyphal cell walls. A. infectoria was grown in the presence of caspofungin, an inhibitor of β(1,3)-glucan synthesis; nikkomycin Z, an inhibitor of chitin synthases; and pyroquilon, an inhibitor of dihydroxynaphthalene (DHN)-melanin synthesis. Distinct CWNPs were obtained from these cultures, referred to as casCWNPs, nkCWNPs, and pyrCWNPs, respectively. CWNPs are round-shaped particles with a diameter of 70-200 nm diameter particles that when added to macrophages are taken up by membrane ruffling. CWNPs with no DHN-melanin and more glucan (pyrCWNPs) caused early macrophage activation and lowest viability, with the cells exhibiting ultrastructural modifications such as higher vacuolization and formation of autophagy-like structures. CasCWNPs promoted the highest tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) increase, also resulting in the release of partially degraded chitin, an aspect never observed in macrophage-like cells and fungi. After 6 h of interaction with CWNPs, only half were viable, except with control CWNPs. Overall, this work indicates that compounds that modify the fungal cell wall led to CWNPs with new properties that may have implications for the effects of drugs during antifungal therapy. CWNPs provide a new tool to study the interaction of hyphal fungal cell wall components with phagocytic cells and enable to show how the modification of cell wall components in A. infectoria can modulate the response by macrophages.IMPORTANCEAlternaria species are ubiquitous environmental fungi to which the human host can continuously be exposed, through the inhalation of fungal spores but also of fragments of hyphae, from desegregated mycelia. These fungi are involved in hypersensitization and severe respiratory allergies, such as asthma, and can cause opportunistic infections in immunodepressed human host leading to severe disease. The first fungal structures to interact with the host cells are the cell wall components, and their modulation leads to differential immune responses. Here, we show that fungal cells grown with cell wall inhibitors led to cell wall nanoparticles with new properties in their interaction with macrophages. With this strategy, we overcame the limitation of in vitro assays interacting with filamentous fungi and showed that the absence of DNH-melanin leads to higher virulence, while caspofungin leads to cells walls that trigger higher hydrolysis of chitin and higher production of cytokines.

Variations in deep-sea methane seepage linked to millennial-scale changes in bottom water temperatures ~ 50–6 ka, NW Svalbard margin

During the last glaciation, the northern hemisphere experienced profound millennial-scale changes (termed Dansgaard-Oeschger (DO) events) in atmospheric and oceanic temperatures. In the North Atlantic, the fluctuations resulted in extremely unstable bottom water conditions with bottom water temperatures (BWT) varying up to > 5 °C. We have studied these changes in a core from 1,300 m water depth at Vestnesa Ridge, northwestern Svalbard margin to investigate a possible connection between BWT and seepage of methane from the seafloor covering the period ~ 50–6 ka. Beneath Vestnesa Ridge, gas hydrates containing vast amounts of methane are kept stable due to the high pressure and low temperatures. Release of gas is shown by numerous pockmarks on the seafloor. The pockmarks at 1,300 m water depth are presently inactive, but they bear witness of earlier activity. Our study shows that from ~ 50–6 ka, the core site experienced repeated increases in BWT and in the emissions of gas, both following the pattern of the DO events. This correspondence in time scale indicates that BWT was the primary forcing factor for the variability in methane release. However, the releases were delayed by up to > 1,000 years compared to the initial increase in BWT.

Validity of the PROMIS® Early Childhood Physical Activity Scale among toddlers

BackgroundThe PROMIS® Early Childhood Physical Activity (PROMIS EC PA) scale is a recently developed PROMIS Early Childhood measure to assess PA among children aged 1–5 years. The purpose of this study was to examine test-retest reliability and convergent validity of the PROMIS EC PA scale among toddlers.MethodAn ancillary study was conducted in the toddler-mother dyad sample of the Child and Mother Physical Activity Study. Mothers completed the 7-item PROMIS EC PA scale twice: during a study visit (test) and on the last day when their child’s wore an ActiGraph accelerometer on the hip for 7 days (retest). The PROMIS EC PA summed score was calculated by totaling scores from items 1–5. Test-retest reliability was assessed using intraclass correlation coefficient (ICC) for test and retest PROMIS EC PA. Convergent validity was assessed using rank correlation coefficients (rho) between PROMIS EC PA scores and accelerometer-measured moderate- and vigorous-intensity PA (MVPA).ResultsAmong 74 participants (56% female; 19 ± 4 months of mean age with range of 12–30 months), average accelerometer-measured MVPA was 76 ± 24 min/day. The median number of days between PROMIS EC PA test and retest was 8 days (IQR = 6 to 8), with an average PROMIS EC PA summed score of 11.0 ± 3.5 at test and 10.5 ± 3.4 at retest. ICC for the test-retest PROMIS EC PA summed scores was 0.72 (95% CI = 0.59–0.82). The rank correlation between the PROMIS EC PA summed score and accelerometer-measured MVPA was 0.13 (95% CI=-0.10 to 0.35; p = 0.28).ConclusionIn a sample of children aged 12–30 months, test-retest reliability for the PROMIS EC PA scale was moderate and its convergent validity against accelerometer-measured MVPA was poor. Prior to a widespread use of the PROMIS EC PA scale in large-scale research and clinical practice, the tool should be further refined and validated to elucidate how young children’s lived PA experience as measured in the PROMIS EC PA scale is relevant to their health and wellbeing outcomes.

Spatial Transcriptomic Profiling of Human Saphenous Vein Exposed to Ex Vivo Arterial Haemodynamics-Implications for Coronary Artery Bypass Graft Patency and Vein Graft Disease.

Vein graft disease is the process by which saphenous vein grafts, utilised for revascularisation during coronary artery bypass graft surgery, undergo an inflammation-driven intimal hyperplasia and accelerated atherosclerosis process in subsequent years after implantation. The role of the arterial circulation, particularly the haemodynamic properties' impact on graft patency, have been investigated but have not to date been explored in depth at the transcriptomic level. We have undertaken the first-in-man spatial transcriptomic analysis of the long saphenous vein in response to ex vivo acute arterial haemodynamic stimulation, utilising a combination of a custom 3D-printed perfusion bioreactor and the 10X Genomics Visium Spatial Gene Expression technology. We identify a total of 413 significant genes (372 upregulated and 41 downregulated) differentially expressed in response to arterial haemodynamic conditions. These genes were associated with pathways including NFkB, TNF, MAPK, and PI3K/Akt, among others. These are established pathways involved in the initiation of an early pro-inflammatory response, leukocyte activation and adhesion signalling, tissue remodelling, and cellular differentiation. Utilising unsupervised clustering analysis, we have been able to classify subsets of the expression based on cell type and with spatial resolution. These findings allow for further characterisation of the early saphenous vein graft transcriptional landscape during the earliest stage of implantation that contributes to vein graft disease, in particular validation of pathways and druggable targets that could contribute towards the therapeutic inhibition of processes underpinning vein graft disease.

Higher resolution pooled genome-wide CRISPR knockout screening in Drosophila cells using Integration and Anti-CRISPR (IntAC).

CRISPR screens enable systematic, scalable genotype-to-phenotype mapping. We previously developed a pooled CRISPR screening method for Drosophila melanogaster and mosquito cell lines using plasmid transfection and site-specific integration to introduce single guide (sgRNA) libraries, followed by PCR and sequencing of integrated sgRNAs. While effective, the method relies on early constitutive Cas9 activity that potentially can lead to discrepancies between genome edits and sgRNAs detected by PCR, reducing screen accuracy. To address this issue, we introduce a new method to co-transfect a plasmid expressing the anti-CRISPR protein AcrIIa4 to suppress Cas9 activity during early sgRNA expression, which we term "IntAC" (integrase with anti-CRISPR). IntAC allowed us to construct a new CRISPR screening approach driven by the high strength dU6:3 promoter. This new library dramatically improved precision-recall of fitness genes across the genome, retrieving 90-95% of essential gene groups within 5% error, allowing us to generate the most comprehensive list of cell fitness genes yet assembled for Drosophila. Our analysis determined that elevated sgRNA levels, made permissible by the IntAC approach, drove much of the improvement. The Drosophila fitness genes show strong correlation with human fitness genes and underscore the effects of paralogs on gene essentiality. We further demonstrate that IntAC combined with a targeted sgRNA sub-library enabled precise positive selection of a transporter under solute overload. IntAC represents a straightforward enhancement to existing Drosophila CRISPR screening methods, dramatically increasing accuracy, and might also be broadly applicable to virus-free CRISPR screens in other cell types, including mosquito, lepidopteran, tick, and mammalian cells.

Human-connected wild lands: How network analysis can inform invasive species management

Wild landscapes are critical strongholds for biodiversity, yet even in the remotest parts of the globe, increasing human use and development are leading to an influx of biodiversity threats including invasive species. Natural resource management agencies, and those that rely on public lands, need a better understanding of the long-distance dispersal pathways in which invasive species are introduced to remote locations. Pathway information is essential for targeting prevention and early detection across vast landscapes, but it is often challenged by information gaps and high surveillance costs. Data-driven approaches centered around a participating public can help resource managers and biosecurity professionals to better prioritize prevention and early detection activities to minimize incipient and secondary invasions. This study employed surveys with resource users to integrate and analyze multiple human-mediated dispersal networks for aquatic invasive species (AIS) across Alaska's part of the North American Boreal Forest. Specifically, it applied network analysis to further inform management priorities that so far were only based on a single pathway and different metrics. Results underline the vulnerability of remote wild freshwater systems to the introduction of AIS and provide a waterbody-specific tool for prioritizing monitoring and inform pathway-specific interventions that were unavailable through past research. The study compares the prioritization of waterbodies under newly derived network topology metrics accounting for multiple generic pathways with the existing single- species and single-pathway prediction model. Advantages of a more comprehensive multi-pathway network topology are discussed in the context of various invasion stages, multiple invasive taxa, and resource constraint conservation management systems.