Successful Targeting Research Articles

Analysis of sports policy in Papua in the formation of the Papuan contingent at the XX National Sports Week (PON)

Analyzing sports policy in Papua in the formation of the XX PON contingent is something that must be done because the achievements of Papua Province at the national level at the national sports week (PON) event, which is held every 4 years, will be increasingly competitive. This study aims to analyze sports policy in Papua in the formation of the Papua contingent at the XX national sports week (PON). Using qualitative methods with data collection techniques interviews, observation and documentation. With the policy analysis methodology used in problem solving: problem formulation, forecasting, recommendations, monitoring, and evaluation. The participants were the Indonesian National Sports Committee (KONI) Papua, the Papua Sports and Youth Office (DISORDA), the Papua Provincial Sports Branch Management, coaches and athletes totaling 22 people. The results of this analysis found that the policies taken by Papua Province in the formation of the XX PON contingent related to the recruitment of Papuan domiciled athletes, recruitment of athletes domiciled outside Papua (contract athletes) and training centers inside and outside Papua aim to determine the medal acquisition target, improve achievement and become a good host. The results of the study concluded that the province of Papua has a policy, namely the Papua Governor Regulation Number 29 of 2020 concerning the Description of Duties and Functions of the Papua Provincial Sports and Youth Office and in the stage of drafting a Special Regional Regulation (PERDASUS) of Sports and the use of athlete mutation regulations in the framework of PON contained in KONI Decree Number 56 of 2010 as an attitude of primordialism to achieve the successful achievement target of the host of the XX Papua PON. Through this research can provide positive input for the Papua provincial government to realize the Sports PERDASUS so that the selection of potential athletes in Papua is managed with a planned, systematic, measurable and sustainable sports coaching pattern. Keywords: Sports Policy, Papua Contingent, PON XX

γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome.

Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides. Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-β were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404.

Targeted removal of the FA2 site on human albumin prevents fatty acid–mediated inhibition of Zn2+ binding

Zinc is required for virtually all biological processes. In plasma, Zn2+ is predominantly transported by human serum albumin (HSA), which possesses two Zn2+-binding sites of differing affinities (sites A and B). Fatty acids (FAs) are also transported by HSA, with seven structurally characterized FA-binding sites (named FA1-FA7) known. FA binding inhibits Zn2+-HSA interactions, in a manner that can impact upon hemostasis and cellular zinc uptake, but the degree to which binding at specific FA sites contributes to this inhibition is unclear. Wild-type HSA and H9A, H67A, H247A, and Y150F/R257A/S287A (FA2-KO) mutant albumins were expressed in Pichia pastoris. Isothermal titration calorimetry studies revealed that the Zn2+-binding capacity at the high-affinity Zn2+ site (site A) was reduced in H67A and H247A mutants, with site B less affected. The H9A mutation decreased Zn2+ binding at the lower-affinity site, establishing His9 as a site B ligand. Zn2+ binding to HSA and H9A was compromised by palmitate, consistent with FA binding affecting site A. 13C-NMR experiments confirmed that the FA2-KO mutations prohibited FA binding at site FA2. Zn2+ binding to the FA2-KO mutant was unaffected by myristate, suggesting binding at FA2 is solely responsible for inhibition. Molecular dynamics studies identified the steric obstruction exerted by bound FA in site FA2, which impedes the conformational change from open (FA-loaded) to closed (FA-free) states, required for Zn2+ to bind at site A. The successful targeting of the FA2 site will aid functional studies exploring the interplay between circulating FA levels and plasma Zn2+ speciation in health and disease.

Tumor versus Tumor Cell Targeting in Metal-Based Nanoparticles for Cancer Theranostics.

The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of "tumor targeting" and "tumor cell targeting" are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where 'smart design' refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.

Analysis of Contribution and Effectiveness of Local Taxes and Levies on Southeast Sulawesi Revenue

The research aims to assess the contribution of local taxes and levies to Southeast Sulawesi Province's original income and evaluate their effectiveness. Utilizing quantitative descriptive research, findings indicate a consistent high contribution of local taxes from 2018 to 2022, ranging between 98.99% to 99.25%. This demonstrates their significant role in surpassing the 90% mark, thus positively impacting the province's Original Income. Conversely, levies exhibit unsatisfactory performance during this period, with contributions declining notably, hitting a low of 0.01% in 2022. In terms of effectiveness, local taxes consistently surpassed the 100% mark from 2018 to 2021, showcasing successful revenue targets attainment. Although a slight dip occurred in 2022 to 95.81%, local taxes remained effective. Conversely, levies demonstrated exceptional effectiveness in 2018 and 2019, exceeding 120%, indicating proficient management and surpassing revenue targets. The reciprocal relationship between the government and the people, as per stakeholder theory, underscores how effective tax management influences the province's welfare. The positive correlation between local taxes, levies, and regional income stems from improved tax collection principles enforced by stakeholders. In conclusion, while local taxes significantly contribute to regional income, effective levy management is crucial. This study underscores the importance of leveraging tax resources for societal welfare, highlighting the need for continuous evaluation and improvement in tax management strategies.

Harnessing extracellular vesicle membrane for gene therapy: EVs-biomimetic nanoparticles

One of the main concerns in oligonucleotide-based therapeutics is achieving a successful cell targeting while avoiding drug degradation and clearance. Nanoparticulated drug delivery systems have emerged as a way of overcoming these issues. Among them, membrane-coated nanoparticles are of increasing relevance mainly due to their enhanced cellular uptake, immune evasion and biocompatibility. In this study, we designed and elaborated a simple and highly tuneable biomimetic drug delivery nanosystem based on a polymeric core surrounded by extracellular vesicles (EVs)-derived membranes. This strategy should allow the nanosystems to benefit from the properties conferred by the membrane proteins present in EVs membrane, key paracrine mediators. The developed systems were able to successfully encapsulate the required oligonucleotides. Also, their characterisation through already well standardised methods (dynamic light scattering, transmission electron microscopy and nanoparticle tracking analysis) and by fluorescence cross-correlation spectroscopy (FCCS) showed the desired core-shell structure. The cellular uptake using different cell types further confirmed the coating though an enhancement in cell internalisation of the developed biomimetic nanoparticles. This study brings up new possibilities for GapmeR delivery as it might be a base for the development of new delivery systems for gene therapy.

Stronger control of eating 3 months after sleeve gastrectomy predicts successful weight loss outcomes at one year

BackgroundWeight loss response to sleeve gastrectomy (SG) is variable and predicting the effectiveness of surgery is challenging and elusive. The aim of our study was to assess and quantify the association between eating control and weight loss outcomes and identify the control of eating (CoE) attributes during the early postoperative period that might predict good vs. poor response to SG at one year. MethodsA prospective longitudinal cohort study using the Control of Eating Questionnaire (CoEQ) was designed as a series before and at 3-, 6-, and 12-months post-SG. Primary outcomes were changes in CoE attributes and percent of total weight loss (%TWL) 12-months post-surgery. Subjects were categorized based on %TWL as good (GR, ≥25 %) or poor responders (PR, <25 %). A receiver operating characteristic and logistic regression analyses were performed. ResultsWe included 41 participants (80.5% females, 51.2% Hispanic, mean age 41.7±10.6, median baseline body mass index (BMI) 43.6 kg/m2 [range 35.2–66.3]) who completed the CoEQ at all four timepoints. The “Difficulty to control eating” score at 3 months revealed the highest area under the curve (AUC) (AUC 0.711; 95%CI 0.524–0.898; p=0.032). In a trade-off between a high Youden index and high sensitivity, the “Difficulty to control eating” score of 7 at 3 months was identified as the optimal cut-off for distinguishing between GRs and PRs. Score ≤7 at 3 months was strongly independently associated with a successful weight loss target of 25%TWL at one-year post-SG (Relative Risk 4.43; 95%CI 1.06–18.54; p=0.042). Conclusion“Difficulty to control eating” score at 3 months post-SG is an independent early predictor of optimal response (achieving a successful TWL target of ≥25 % at one-year post-SG). Our results support the utility of this easy-to-administer validated tool for predicting the effectiveness of SG and may assist in identifying individuals with suboptimal response early and helping them with interventions to attain optimal weight loss targets.

A ratiometric fluorescent probe with dual-targeting capability for heat shock imaging

HSO3− is an important reactive sulfur species that maintains the normal physiological activities of living organisms and participates in a variety of redox homeostatic processes. It has been found that changes in HSO3− levels is closely related to the heat stroke phenomenon of the organism. Heat stroke causes damage to normal cells, which in turn causes damage to the body and even death. It is crucial to accurately monitor and track the physiological behavior of HSO3− during heat stroke. Herein, a ratiometric multifunctional fluorescent probe DRM-SO2 with dual-targeting ability to rapidly and precisely recognize HSO3− being constructed based on the FRET mechanism. DRM-SO2 has extra Large Stokes shift (216 nm), very high sensitivity (DL = 12.2 nM), fast response time and good specificity. When DRM-SO2 undergoes Michael addition with HSO3−, the fluorescence emission peak was blue-shifted from 616 nm to 472 nm, and a clear ratiometric signal appeared. The interaction between lysosomes and mitochondria in maintaining cellular homeostasis was investigated by the dual-targeting ability of the probe using HSO3− as a mediator. DRM-SO2 achieved successful targeting and real-time monitoring of exogenous and endogenous HSO3− in the cells. More importantly, imaging experiments in heat stroke mice revealed high HSO3− expression in intestinal tissues. This provides new ideas and research tools for early prevention of heat stroke-induced diseases such as intestinal injuries. In addition, the semi-quantitative monitoring experiments for paper-based visualization of HSO3− make the probe promising for the design of portable detectors.

An Empirical Study of the Impact of NREGA Implementation on Rural Poverty Rates in India

The National Rural Employment Guarantee Act (NREGA), now known as the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA), was implemented in India with the objective of enhancing livelihood security in rural areas by providing at least 100 days of wage employment per year to every household willing to do unskilled manual work. This study empirically examines the impact of NREGA on rural poverty rates in India, utilizing a Difference-in-Differences (DID) approach to analyze data from the National Sample Survey (NSS) and Census of India. The findings reveal a significant reduction in rural poverty rates in districts where NREGA was implemented compared to non-NREGA districts. The program has been particularly effective in regions with higher initial poverty levels, indicating successful targeting of the most vulnerable populations. Additionally, the study highlights regional variations in the impact of NREGA, with some areas experiencing greater benefits than others. The results suggest that while NREGA has substantially contributed to poverty reduction, its effectiveness is influenced by local governance and administrative capacities. Policy recommendations include improving administrative efficiency, enhancing the quality and sustainability of created assets, and complementing NREGA with other skill development and capacity-building initiatives. Addressing regional disparities and ensuring robust monitoring and evaluation mechanisms are also crucial for maximizing the program’s impact.

Towards a More Efficient Breast Cancer Therapy Using Active Human Cell Membrane-Coated Metal–Organic Frameworks

The recent description of well-defined molecular subtypes of breast cancer has led to the clinical development of a number of successful molecular targets. Particularly, triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with historically poor outcomes, mainly due to the lack of effective targeted therapies. Recent progresses in materials science have demonstrated the impressive properties of metal–organic framework nanoparticles (NPs) as antitumoral drug delivery systems. Here, in a way to achieve efficient bio-interfaces with cancer cells and improve their internalization, benchmarked MIL-100(Fe) NPs were coated with cell membranes (CMs) derived from the human TNBC cell line MDA-MB-468. The prepared CMs-coated metal–organic framework (CMs_MIL-100(Fe)) showed enhanced colloidal stability, cellular uptake, and cytotoxicity in MDA-MB-468 cells compared to non-coated NPs, paving the way for these human CMs-coated MIL-100(Fe) NPs as effective targeted therapies against the challenging TNBC.

Targeted lung therapy with rosmarinic acid encapsulated in PLGA microspheres for radiation-induced pulmonary fibrosis

Radiation-induced pulmonary fibrosis (RIPF) is a frequent complication among individuals affected by nuclear accidents and patients undergoing chest radiation therapy for tumors. However, the availability of effective drugs for prevention and treatment of RIPF remains limited. Rosmarinic acid (RA), which displays inhibitory properties against RIPF, suffers from poor targeting in previous drug studies. To overcome this issue and achieve optimal therapeutic effects, continuous administration over several days is usually employed. In this study, we developed PLGA microspheres with an average size of 17 μm and drug loading efficiency of 24.97 % (±0.97 %), loaded with RA (RA/PLGAMS) using the membrane emulsification method. By controlling the size of microspheres in the pulmonary capillaries, we achieved lung targeting of microspheres, and based on the release of drugs as PLGA degrades, the residence time of drugs in the body is prolonged. And it was confirmed by in vivo imaging and SEM imaging that PLGAMS could exist in the lungs for at least 7 days. Our results demonstrated successful targeting of the lungs in a mouse model and sustained release of RA encapsulated in the PLGA microspheres. Notably, under the same administration conditions, the therapeutic efficacy of PLGA-encapsulated RA surpassed that of ordinary RA. We observed decreased expression of inflammatory factors, reduced M2 macrophage polarization, and weakened epithelial mesenchymal transformation following our treatment, which might explain the radiation damage alleviating effect of RA. After treatment, it was shown that the deep inspiratory capacity of the mice improved by 57.8 %, and WB showed a decrease of 52.4 % and 28.3 % in the expression of epithelial mesenchymal transition related proteins (TGF-β1 and α-SMA). In summary, PLGA microspheres offer a promising drug delivery system and treatment strategy for radiation-induced pulmonary fibrosis.

Enhancing surgical outcomes: accurate identification and removal of prostate cancer with B7-H3-targeted NIR-II molecular imaging.

One of the main reasons for prostate cancer (PCa) recurrence is the difficulty in identifying and removing cancerous lesions during surgery. Accurately localizing and excising cancerous tissue remains a significant challenge. The second near-infrared window (NIR-II, 1000-1700nm) fluorescence offers enhanced resolution, a high signal-to-noise ratio, and the potential for deeper tissue penetration. However, this technology is not currently employed for intraoperative imaging of PCa. This study aims to construct a new NIR-II probe targeting B7-H3 (AbB7-H3-800CW) for accurate intraoperative identification and resection of PCa. Based on the differential expression of B7-H3 in PCa, we designed a novel imaging probe to accurately identify and guide the resection of preclinical PCa models and ex vivo human PCa tissues using NIR-II fluorescence imaging technology. Analyzing tissue samples from 60 clinical cases of PCa, along with benign prostatic hyperplasia and normal prostate tissue from 22 cases, we observed a significant difference in B7-H3 protein expression levels (P < 0.001). Subcutaneous and orthotopic mouse models of PCa were imaged using NIR-II fluorescence after AbB7-H3-800CW injection, showing promising results with successful tumor targeting and high-contrast images achieved within 24-48h post-injection. The imaging also enabled the detection of occult PCa lesions approximately 1mm in diameter. In addition, imaging analysis of human PCa and adjacent tissues using AbB7-H3-800CW incubation revealed that cancer tissues exhibited a significantly higher fluorescence intensity than adjacent tissues (P < 0.05), which was conducive to the evaluation of tumor resection margin in vitro. The findings revealed that B7-H3 was a compelling imaging target for PCa. The AbB7-H3-800CW molecular imaging probe is capable of accurately identifying PCa lesions and guiding their removal. This approach can potentially reduce the rate of surgical margins under NIR-II fluorescence guidance.

Targeting KRAS Diversity: Covalent Modulation of G12X and Beyond in Cancer Therapy.

The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic RAS mutations disrupt this balance, favoring the active form and promoting proliferative signaling, thus rendering KRAS an appealing target for precision medicine in oncology. In 2013, Shokat and co-workers achieved a groundbreaking feat by covalently targeting a previously undiscovered allosteric pocket (switch II pocket (SWIIP)) of KRASG12C. This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Recent achievements in targeting various KRASG12X mutants, using SWIIP as a key binding pocket, are discussed. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.

Tagraxofusp, a first-in-class CD123-targeted agent: Five-year postapproval comprehensive review of the literature.

Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.

Focal atrial tachycardias originating from the aorta-mitral continuity: Anatomical and electrophysiological characteristics

BackgroundThe aorta-mitral annulus conjunction (AMC) is an uncommon site of origin of focal atrial tachycardias (ATs). Hence, the electrophysiological and ablation target characteristics are poorly described. ObjectiveThe purpose of this study was to describe the characteristics of AMC ATs in detail. MethodsThe study enrolled 650 patients with ATs, 21 (3.2%) of whom had ATs originating from the AMC. A comprehensive evaluation, including electrocardiography, electrophysiology study, computed tomography scan, and intracardiac echocardiography, was performed. ResultsThe majority (19, 90.5%) of ATs occurred spontaneously. The mean age of this group was 48.9 ± 21.6 years, with 12 being female (57.1%). Seventeen patients had a typical biphasic P wave with a prominent positive component. The earliest activation site in the right atrium was near the His bundle, with average activation −10.3 ± 6.0 ms preceding the P wave. The successful ablation targets were distributed as follows: 1 case at 9 o’clock, 6 cases at 10 o’clock, 7 cases at 11 o’clock, 6 cases at 12 o’clock, and 1 case in the left coronary cusp. The local AMC potential differed from the commonly perceived annular potential and was characterized by a prominent A wave and a smaller V wave (atrial-to-ventricular ratio > 1). The angle of encroachment on the left atrial anterior wall, compressed by the left coronary cusp, was significantly smaller in the AMC ATs group than in the control group consisted of 40 patients who underwent coronary artery CT scans because of the chest pain but without atrial arrhythmias were randomly selected, which may have contributed to the arrhythmia substrate (141.7° ± 11.5° vs 155.2° ± 13.9°; P = .026). ConclusionA new strategy for mapping AMC ATs has been introduced. The ablation target should have an atrial-to-ventricular ratio of >1.

Dysexecutive difficulty and subtle everyday functional disabilities: the digital Trail Making Test.

Digital neuropsychological tests reliably capture real-time, process-based behavior that traditional paper/pencil tests cannot detect, enabling earlier detection of neurodegenerative illness. We assessed relations between informant-based subtle and mild functional decline and process-based features extracted from the digital Trail Making Test-Part B (dTMT-B). A total of 321 community-dwelling participants (56.0% female) were assessed with the Functional Activities Questionnaire (FAQ) and the dTMT-B. Three FAQ groups were constructed: FAQ = 0 (unimpaired); FAQ = 1-4 (subtle impairment); FAQ = 5-8 (mild impairment). Compared to the FAQ-unimpaired group, other groups required longer pauses inside target circles (p < 0.050) and produced more total pen strokes to complete the test (p < 0.016). FAQ-subtle participants required more time to complete the entire test (p < 0.002) and drew individual lines connecting successive target circles slower (p < 0.001) than FAQ-unimpaired participants. Lines connecting successive circle targets were less straight among FAQ-mild, compared to FAQ-unimpaired participants (p < 0.044). Using stepwise nominal regression (reference group = FAQ-unimpaired), pauses inside target circles classified other participants into their respective groups (p < 0.015, respectively). Factor analysis using six dTMT-B variables (oblique rotation) yielded a two-factor solution related to impaired motor/cognitive operations (48.96% variance explained) and faster more efficient motor/cognitive operations (28.88% variance explained). Digital assessment technology elegantly quantifies occult, nuanced behavior not previously appreciated, operationally defines critical underlying neurocognitive constructs related to functional abilities, and yields selected process-based scores that outperform traditional paper/pencil test scores for participant classification. When brought to scale, the dTMT-B test could be a sensitive tool to detect subtle-to-mild functional deficits in emergent neurodegenerative illnesses.

Total sleep deprivation effects on the attentional blink.

The Attentional Blink (AB) is a phenomenon that reflects difficulty in detecting or identifying the second of two successive targets (T1 and T2) that are presented in rapid succession, between 200-500ms apart. The AB involves indicators of attentional and temporal integration mechanisms related to the early stages of visual processing. The aim of this study was to identify the effects of 24-h of sleep deprivation (total sleep deprivation, TSD) on the attentional and temporal integration mechanisms of the AB. Twenty-two undergraduate students were recorded during five successive days, in these three conditions: baseline (two days), TSD (one day), and recovery (two days). Each day, at around 12:00h, participants responded to a Rapid Serial Visual Presentation task (RSVP) that presented two targets separated by random intervals from 100 to 1000ms. The attentional mechanisms were assessed by the AB presence, the AB magnitude, and the AB interval, while the temporal integration mechanisms were evaluated by lag-1 sparing and order reversal responses. TSD negatively affected the attentional mechanisms, which is expressed by an overall reduction in performance, an extended AB interval, and a reduced AB magnitude. TSD also negatively affected the temporal integration mechanisms, manifested by an absence of lag-1 sparing and an increase in order reversals. These results suggest that people are still able to respond to two successive stimuli after 24h without sleep. However, it becomes more difficult to respond to both stimuli because the attentional and temporal integration mechanisms of the AB are impaired.

The MDM2-p53 Axis Represents a Therapeutic Vulnerability Unique to Glioma Stem Cells.

The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.

Educator Professionalism in The Independent Curriculum Through Digital Literacy Training for Teachers

This training aims to train teachers in Sukoharjo Regency in the independent curriculum by applying digital literacy as professional educators. The training method involves socialization, training, mentoring, and evaluation stages. The success target in this training is 40%. The training results show that the training stages are carried out in four stages: providing material, implementing an application in digital literacy learning, assisting teachers in creating and operating digital literacy, and evaluating this training. This training was carried out on February 6, 2023, with the results showing that 49 teachers in Sukoharjo Regency stated that they were very satisfied with the delivery of material by the presenters, a total of 27 people (55.1%). The benefits of this digital literacy training were in the very useful category for 34 teachers or 69.4%. Furthermore, in the continuation of this training, it was categorized from the data above as follows: 12 teachers felt it was very actionable, 31 teachers felt it could be followed up, and six teachers felt it was quite actionable. The evaluation data above stated that there was success in implementing this training, which reached above 40%.

Protein profiling and immunoinformatic analysis of the secretome of a metal-resistant environmental isolate Pseudomonas aeruginosa S-8.

The bacterial secretome represents a comprehensive catalog of proteins released extracellularly that have multiple important roles in virulence and intercellular communication. This study aimed to characterize the secretome of an environmental isolate Pseudomonas aeruginosa S-8 by analyzing trypsin-digested culture supernatant proteins using nano-LC-MS/MS tool. Using a combined approach of bioinformatics and mass spectrometry, 1088 proteins in the secretome were analyzed by PREDLIPO, SecretomeP 2.0, SignalP 4.1, and PSORTb tool for their subcellular localization and further categorization of secretome proteins according to signal peptides. Using the gene ontology tool, secretome proteins were categorized into different functional categories. KEGG pathway analysis identified the secreted proteins into different metabolic functional pathways. Moreover, our LC-MS/MS data revealed the secretion of various CAZymes into the extracellular milieu, which suggests its strong biotechnological applications to breakdown complex carbohydrate polymers. The identified immunodominant epitopes from the secretome of P. aeruginosa showed the characteristic of being non-allergenic, highly antigenic, nontoxic, and having a low risk of triggering autoimmune responses, which highlights their potential as successful vaccine targets. Overall, the identification of secreted proteins of P. aeruginosa could be important for both diagnostic purposes and the development of an effective candidate vaccine.