Target Level Research Articles

Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease.

Therapeutic drug monitoring (TDM) and dose optimization have been shown to improve clinical outcomes with antitumor necrosis factor and recent studies in adults suggest an exposure-response relationship with drug levels associated with improved clinical outcomes. However, these levels are not universally recognized as therapeutic targets for vedolizumab dosing. We aimed to assess the impact of a TDM quality improvement (QI) initiative on 52-week clinical outcomes and describe proactively obtained vedolizumab levels during the induction period in children with inflammatory bowel disease (IBD). A QI initiative to proactively obtain TDM levels at Week 6 was implemented in 2019. A retrospective review of pediatric patients with IBD treated with vedolizumab from 2018 to 2022 was performed. Baseline demographic data, medication dosing details, disease characteristics, lab results, and 12-month clinical outcomes were recorded. For this study, we defined therapeutic target levels (>20 μg/mL at Week 6 and >12 μg/mL during maintenance) based on existing data correlating these levels with improved clinical outcomes. Fifty-nine patients (31 Crohn disease [CD], 28 ulcerative colitis [UC]/indeterminate colitis [IC]) were included in the study. In total, 68% (40/59) of patients had vedolizumab levels at Week 6and 90% (53/59) had levels drawn at Week 6 or 14. Thirty-five percent of Week 6 trough levels were below our defined target of 20 μg/mL. Fifty-two of 59 patients had available data at 52 weeks. Over 80% (42/52) of patients remained on vedolizumab 52 weeks after initiation (CD 79% [23/29], UC/IC 83% [19/23]). Sixty-two percent (26/42) of patients that remained on vedolizumab at 52 weeks were treated with an intensified dosing interval of <8 weeks. Thirty-one of these 42 (74%) were in clinical remission (CR)rate at 52 weeks with 29/42 (69%) in corticosteroid-free remission. The CR rate for the entire cohort including those who discontinued therapy due to a lack of efficacy before 52 weeks was 60% (31/52). Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.

Contrasting Phosphorus Build-up and Drawdown Dynamics in Soils Receiving Dairy Processing Sludge and Mineral Fertilisers

Sustainable utilisation of waste from the food industry is required to transition to a circular economy. The dairy industry relies on high phosphorus (P) inputs and produces large quantities of P-rich dairy processing sludge (DPS). Recycling DPS into P fertilisers provides an opportunity to decrease the reliance on chemical P fertilisers. However, current soil nutrient management planning (NMP) is based on chemical P and does not account for recycled alternatives. A pot trial using a novel isotope pool dilution technique was used to describe build-up and drawdown cycles of P in soils fertilised with DPS. Changes in available, exchangeable, and Mehlich3 P (M3-P) pools were recorded over 36 weeks of grass growth. Results demonstrated that in the period of high P demand (12 weeks), these P pools were depleted. As crop growth and demand decreased, available P recovered through mobilisation of P from exchangeable P and M3-P reserves. DPS allowed available P to recover and build up to agronomic target levels after 24 weeks. Using DPS, build-up of available and exchangeable P was slower but P use efficiency was higher at stages of slow growth. Dairy waste created a more stable P pool which could be utilised by crops over a growing season indicating that NMP needs to account for this in the decision support for growers. Isotope studies revealed that extractive agronomic tests do not capture drawdown in P reserves.

P770 Proactive Infliximab monitoring improves the rates of transmural remission in Crohn’s disease – a propensity score matched analysis

Abstract Background Few patients can reach transmural remission in Crohn’s disease (CD) with currently available therapies. Proactive optimization of Infliximab (IFX) based on trough levels may potentially improve these results. Methods Retrospective cohort study including consecutive CD patients starting treatment with IFX. Rates of transmural remission were compared between patients with and without therapeutic drug monitoring (target level: 5-7 µg/mL). A propensity score matched analysis was performed to adjust for potential confounders (figure). Results 195 CD patients were included, 57.9% receiving proactive therapeutic drug monitoring. The rates of transmural remission were higher in patients under proactive therapeutic drug monitoring (37.2% vs 18.3%, P=0.004) with similar results in the propensity score matched analysis (34.2% vs 17.1%, P=0.025). In multivariate analysis, proactive therapeutic drug monitoring was independently associated with transmural remission: OR 2.95 95%CI(1.44-6.06), P=0.003. Conclusion Proactive optimization of IFX based on trough levels increases the rates of transmural remission in CD.

The daily calcium profile in patients with chronic hypoparathyroidism depending on different 25(OH) vitamin D level

BACKGROUND: Chronic hypoparathyroidism is a relatively rare disease, which usually treated active forms of vitamin D and oral calcium supplements. Supplementation with native vitamin D can be useful both for achieving «non-skeletal» effects of vitamin D and for a more stable serum calcium profile.AIM: The aim of this study was to estimate the daily serum calcium and 24-hour urine calcium levels depending on different 25(OH) vitamin D values in patients with chronic hypoparathyroidism on treatment of active forms of vitamin D and calcium supplements.MATERIALS AND METHODS: Forty patients with chronic hypoparathyroidism were involved in the study. All patients were divided in two groups, matched on sex and age, according to the median level of 25(OH) vitamin D in the total group.RESULTS: There were no significant differences between groups by total, albumin-adjusted serum calcium levels and urine calcium excretion. Patients with serum 25(ОН) vitamin D level ≥ 35 ng/ml had significant tendency to achieve more often the target levels of total serum calcium during the day (128 vs. 149 measurements during the day, p=0.049, χ2). However, this tendency disappeared for albumin-adjusted serum calcium levels (p=0.517, χ2). There frequency of hypercalcemia by albumin-adjusted serum calcium in the group of patients with 25(ОН) vitamin D ≥ 35 ng/ml (p=0.006, χ2) was significantly lower, but not for total serum calcium (a trend, p=0.042, χ2). As regards hypocalcemia, there were no significant differences by albumin-adjusted serum calcium (p=0.581, χ2) and it tends to lower frequency by total serum calcium (p=0.023, χ2).CONCLUSION: The additional administration of native vitamin D in patients with chronic hypoparathyroidism may have some advantages, related to the general concept of worldwide vitamin D deficiency and better disease control.

Sex Differences in the Primary Prevention of Cardiovascular Diseases in a Dutch Primary Care Setting.

Sex differences in the primary prevention of cardiovascular diseases (CVD) have been shown, but the evidence is mixed and fragmented. In this study, we assessed sex differences in cardiovascular risk factors assessment, risk factor levels, treatment, and meeting of treatment targets, within a Dutch primary care setting. Data were obtained from individuals aged 40 to 70 years old, without prior CVD, registered during the entire year in 2018 at one of the 51 general practices participating in the Julius General Practitioner's Network (JGPN). History of CVD was defined based on the International Classification of Primary Care (ICPC). Linear and Poisson regressions were used to investigate sex differences in risk factor assessment, risk factor levels, treatment, and meeting of treatment targets. We included 83,903 individuals (50% women). With the exception of glycated hemoglobin (HbA1c), all risk factors for CVD were more often measured in women than in men. Lipid measurements and body mass index values were higher in women, while blood pressure (BP) and HbA1c levels were higher in men, along with estimated glomerular filtration rate (eGFR) levels. Among individuals with elevated BP or cholesterol levels, no sex difference was observed in the prescription of antihypertensive medications (RR 1.00, 95% CI: 0.94-1.06) but women were less likely than men to receive lipid-lowering medications (RR 0.87, 95% CI: 0.79-0.95). Among treated individuals, women were more likely than men to meet adequate levels of blood pressure (RR 1.17, 95% CI: 1.09-1.25) and less likely to meet target levels of cholesterol (RR 0.90, 95% CI: 0.83-0.98). While women were more likely to have their CVD risk factors measured, they were less likely to be prescribed lipid-lowering medications and to meet target levels. When treated, men were less likely to achieve adequate blood pressure control.

Inhibition of the Progression of Chronic Kidney Disease With Hyperuricemia

The final product of the catabolism of purine compounds in humans is uric acid (UA), which is a weak organic acid, over 98% of which is ionized into monosodium urate. UA is excreted by the kidneys, approximately 80-99% is reabsorbed in the proximal tubules of the kidneys. About 20% of UA is excreted through the intestine, where it is destroyed by microflora to carbon dioxide and water. The reference value of UA in blood plasma is 6.5-7 mg/dl in men and 6–6.5 mg/dl in women. The content of UA in the range of 360-400 μmol/l or 6-6.8 mg / dl increases the risk of crystallization under physiological conditions, and regardless of gender. UA levels greater than 7.0 mg/dl are associated with an increased risk of developing gout or nephrolithiasis. Hyperuricemia may occur due to increased production and / or decreased renal excretion of UA. Hyperuricemia is high in the general population and is associated with the development and progression of chronic kidney disease (CKD). Currently, allopurinol and febuxostat are used to correct hyperuricemia. The use of allopurinol should begin with a low dose (50-100 mg/day) and gradually titrate until the target level of UA in the blood is reached or until it is reached to the maximum. If necessary, the dose of allopurinol is increased by 100 mg every 2–4 weeks until the target serum UA level is reached. According to EULAR's recommendations for the treatment of gout, if the target level of UA cannot be achieved with an adequate dose of allopurinol, it should be replaced with febuxostat or uricosuric or a combination of febucostat with uricosuric. Febuxostat is also indicated for allopurinol intolerance. Febuxostat in doses of 80 and 120 mg/day was more effective than allopurinol at a dose of 300 mg/day. With CKD with mild or moderate renal failure, as well as in the elderly, it is not necessary to adjust the dose of febuxostat. The likelihood of reaching the target level of UA in the blood with reduced kidney function is higher in febuxostat. If the patient does not have serious cardiovascular diseases, the patient can be transferred to febuxostat, starting with a dose of 40 mg/day, and gradually titrated, especially in the case of CKD.

The Development of a Wearable Biofeedback System to Elicit Temporal Gait Asymmetry using Rhythmic Auditory Stimulation and an Assessment of Immediate Effects.

Temporal gait asymmetry (TGA) is commonly observed in individuals facing mobility challenges. Rhythmic auditory stimulation (RAS) can improve temporal gait parameters by promoting synchronization with external cues. While biofeedback for gait training, providing real-time feedback based on specific gait parameters measured, has been proven to successfully elicit changes in gait patterns, RAS-based biofeedback as a treatment for TGA has not been explored. In this study, a wearable RAS-based biofeedback gait training system was developed to measure temporal gait symmetry in real time and deliver RAS accordingly. Three different RAS-based biofeedback strategies were compared: open- and closed-loop RAS at constant and variable target levels. The main objective was to assess the ability of the system to induce TGA with able-bodied (AB) participants and evaluate and compare each strategy. With all three strategies, temporal symmetry was significantly altered compared to the baseline, with the closed-loop strategy yielding the most significant changes when comparing at different target levels. Speed and cadence remained largely unchanged during RAS-based biofeedback gait training. Setting the metronome to a target beyond the intended target may potentially bring the individual closer to their symmetry target. These findings hold promise for developing personalized and effective gait training interventions to address TGA in patient populations with mobility limitations using RAS.

Genipin inhibits proliferation of gastric cancer cells by inducing ferroptosis: an integrated study of network pharmacology and bioinformatics study.

Ferroptosis has been demonstrated to suppress cancer development and is targeted for cancer therapy. Genipin, an iridoid constituent in Gardeniae Fructus, has been reported to exert anti-cancer abilities. However, whether genipin could induce ferroptosis remains unclear. The purpose of this study is to explore the anti-gastric cancer (GC) effects of genipin by inducing ferroptosis and to identify the potential targets. CCK-8 and colony formation assays were performed to evaluate the anti-GC effects of genipin. Flowcytometry and western blot were used to indicate ferroptosis-inducing ability of genipin. The potential targets of genipin were analyzed by network pharmacology, screened using UALCAN and KM-plotter database and evaluated by molecular docking. The results showed that genipin inhibited cell viability and proliferation of GC cells. Genipin treatment decreased levels of GPX4 and SLC7A11, induced accumulation of lipid peroxidation intracellularly and led to ferroptosis in GC cells. Network pharmacology analysis identified that lipid- and ROS-related pathways involved in ferroptosis ranked high among genipin-GC common targets. Data from UALCAN and KM-plotter database demonstrated that expression levels of ferroptosis-related targets, including AURKA, BCAT2, DHODH, and GPI, increased in GC tissues and the higher levels of the above four targets were related to tumor stage, tumor grade, and poor prognosis. Among these four targets, AURKA, BCAT2, and DHODH were confirmed by molecular docking with binding energies less than -5. Taken together, our study demonstrates that genipin could exert anti-GC ability by inducing ferroptosis and provides evidence for the potential application of genipin in GC treatment.

Role of UPF1-LIN28A interaction during early differentiation of pluripotent stem cells

UPF1 and LIN28A are RNA-binding proteins involved in post-transcriptional regulation and stem cell differentiation. Most studies on UPF1 and LIN28A have focused on the molecular mechanisms of differentiated cells and stem cell differentiation, respectively. We reveal that LIN28A directly interacts with UPF1 before UPF1-UPF2 complexing, thereby reducing UPF1 phosphorylation and inhibiting nonsense-mediated mRNA decay (NMD). We identify the interacting domains of UPF1 and LIN28A; moreover, we develop a peptide that impairs UPF1-LIN28A interaction and augments NMD efficiency. Transcriptome analysis of human pluripotent stem cells (hPSCs) confirms that the levels of NMD targets are significantly regulated by both UPF1 and LIN28A. Inhibiting the UPF1-LIN28A interaction using a CPP-conjugated peptide promotes spontaneous differentiation by repressing the pluripotency of hPSCs during proliferation. Furthermore, the UPF1-LIN28A interaction specifically regulates transcripts involved in ectodermal differentiation. Our study reveals that transcriptome regulation via the UPF1-LIN28A interaction in hPSCs determines cell fate.

Combined use of neuroprotective agents: A new treatment strategy for patients with glaucoma

Keywords: Glaucoma, Coenzyme Q10, Citicoline, Neuroprotection, Retinal ganglion cells.Glaucoma is a leading cause of irreversible blindness worldwide. Although the multifactorial genesis, by now, the main treatable risk factor is the elevated intraocular pressure. Nevertheless, some patients, whose intraocular pressure is considered at the target level, still experience a progression of the disease. New evidence strongly suggesting brain involvement in all aspects of the disease led to a growing interest in the pharmacological research of new neuroprotective agents with an intraocular pressure independent activity.Citicoline and coenzyme Q10 are among the most studied and used molecules in clinical practice for some forms of neurodegeneration. In particular, the neuromodulatory and neuroprotective properties of citicoline were extensively investigated either in vivo or in vitro studies. Among the activities of citicoline it has been proposed the capacity to increase neuronal viability as well as the vasomodulatory effect that results in an increased blood flow. Similarly, the neuroprotective effects of coenzyme Q10 has been proposed in experimental models of ocular neurodegeneration.The greater efficacy of the fixed combination over the single components could depend on the fact that each molecule exerts, at least in part, its activity on mitochondria. Coenzyme Q10 acts as an electron carrier from mitochondrial complexes I and II to III, while citicoline maintains proper levels of cardiolipin and sphingomyelin in the cellular and axon membranes. Thus, increasing the energetic rate of cells.Citicoline and coenzyme Q10 are reported to counteract excitotoxicity by respectively decreasing nitrosative stress and extracellular signal‐regulated kinases 1/2, and preventing the upregulation of NR1 and NR2A subunit receptors. In addition, coenzyme Q10 significantly prevents apoptosis by acting on Bax and pBad proteins expression and preserves mitochondrial DNA content and mitochondrial oxidative phosphorylation system in experimental models.Citicoline and coenzyme Q10 are also important in preventing retinal ganglion cells death possibly by acting on Bcl family regulation increasing retinal expression of Bcl‐2, and by significantly inducing Bcl‐xL protein expression, respectively.Citicoline and coenzyme Q10 also show an anti‐inflammatory effect; the first acting on inhibition of phospholipase A2 and downregulating synaptophysin, and the latter by downregulating tumour necrosis factor α and protein 1α, as well as acting on macrophage induced inflammation.Data on literature indicates that the combined use of molecules may be also beneficial for the metabolism of the molecules themselves. In fact, coenzyme Q10 increases the choline oxidase activity in ubiquinone‐depleted mitochondria, thus underling the importance of the presence of good plasmatic choline and coenzyme Q10 levels for energetic production.Overall, evidence seems to suggest the usefulness of coenzyme Q10 and citicoline, eventually combined, in the prevention of glaucomatous neurodegeneration.

Lipid Management in Kidney Transplant Recipients Per KDIGO and American Heart Association Guidelines: A Single-Center Experience.

The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommends statin treatment for all adult kidney transplant recipients (KTRs), except those aged <30 years of age and without prior cardiovascular risk factors (CVRF), but does not specify on-treatment low-density lipoprotein cholesterol (LDL) target levels. The 2018 American Heart Association (AHA) guidelines addressed the management of hyperlipidemia in the general population based on an individualized approach of the CVRF with a specific on-treatment LDL target. To analyze dyslipidemia management according to the recommendations of the KDIGO and AHA guidelines. This retrospective study included all KTRs who underwent transplantation between January 2017 and May 2020 at King Abdulaziz Medical Center, Riyadh, Saudi Arabia. The rate of statins prescription in general, rate of statins prescription among KTRs per their CVRF, and rate of achieving the proposed LDL goals, as defined by the AHA, were analyzed. A total of 287 KTRs were included. Of the 214 (74.6%) patients aged ≥30 years, 80% received a statin. Statins were prescribed in 93% and 96% of KTRs with diabetes or coronary artery disease, respectively. In patients aged ≥30 years, LDL targets, per AHA guidelines, were achieved in 62% with a target of 2.6 mmol/l, and in 19% with a target of 1.8 mmol/l. Statin therapy resulted in non-significant changes in the mean LDL values from baseline to 12 months after transplantation (P = 0.607), even when only patients prescribed statin after transplantation were included (P = 0.34). By applying the KDIGO guidelines, a high rate of statin prescriptions was achieved among KTRs with multiple CVRF and KTRs in general. However, a significant proportion of these KTRs did not achieve the LDL targets proposed by the AHA guidelines, suggesting that higher-intensity statins would be required to achieve these targets.

Using Spatial Modeling to Evaluate LED Light Intensity and Uniformity in Commercial Broiler Houses during Brooding and Tunnel Conditions

Highlights During brooding, more than 97% of the floor area of new broiler houses was above target light intensity, however, in aged houses less than 0.2% of the floor area was above the target. During tunnel conditions, less than 6% of the floor area met the target light intensity range (0.18–0.22 lx) for both aged and new houses. All floor areas in the fan section exceeded the target light intensity in both aged and new houses in all the farms due to light intrusion from the tunnel fans. Bulbs need to be periodically replaced to meet minimum target levels during brooding and light dimmer adjustments need to be made to meet light intensity targets during tunnel ventilation. Abstract. Commercial broiler companies set specific light intensities and photoperiods during different stages of live production to manage bird behavior and growth and to support health and welfare. However, it is currently unknown how much of the floor area in commercial houses is within the target levels set by companies. Therefore, a field survey of twenty 18.3 × 152.4 m broiler houses on five farms was performed to evaluate in-situ light intensity and uniformity in two house sections during brooding [evaporative pad section (pad) and the middle of the house section (mid)] and three sections during tunnel ventilation [pad, mid, and tunnel exhaust fan section (fan)]. Houses ranged in age from new (never used) to aged (5–8 years old). Light intensity measurements were recorded at 70 locations in each of the house sections (140 per house during brooding; 210 per house during tunnel). For tunnel mode, target light intensity values were categorized into above target (&amp;gt;0.22), within target (0.18–0.22 lx), and below target (&amp;lt;0.18 lx). For brooding mode, target light intensity values were below target (&amp;lt;43 lx) and within target (=43 lx). Geostatistics was used to map and calculate the percentage of floor area above, below, or within target thresholds. During brooding and tunnel conditions, the percent of floor area below target (&amp;lt;43 lx and &amp;lt;0.18 lx, respectively) was higher for aged houses than for new houses in the pad and midsections. All the floor area in the fan section was above target due to light intrusion from operating fans. During tunnel ventilation in the new houses, 4.5%, 6.0%, and 0.0% of the floor area at the pad, center, and fan sections, respectively, were within the 0.18 to 0.22 lx target threshold. However, in the aged houses, only 0.6%, 0.7%, and 0.0% of the floor area at the pad, center, and fan sections, respectively, were within the target range. This research illustrates that the newer houses did a better job at meeting or exceeding target light intensities and that very little of the floor area in new and aged houses during tunnel ventilation was within a 10% threshold of target intensities. Lack of light dimmer adjustment to account for lumen depreciation and accumulation of dust on the bulbs in the aged house most likely led to the lower overall light intensities. Because brood bulbs have a 100% lumen capacity and are not dimmed, a deep cleaning of the bulbs and periodic replacement are recommended if they are not reaching lighting targets. Periodic checking of light intensity is recommended, especially in older houses. Keywords: Broilers, House age, Light intensity, Spatial variation, Target.

Network pharmacology and experimental verification: Unraveling Zhiwei Fuwei Pills's role and mechanism in angiogenesis of precancerous lesions of gastric cancer.

Precancerous lesions of gastric cancer (PLGC) are key pathological stages in the transformation of gastric "inflammation-cancer", and timely and effective intervention at this stage is of great importance in the prevention and treatment of gastric cancer. Zhiwei Fuwei Pills (ZWFW), as a traditional Chinese medicine formulation, has been proven to have good clinical efficacy in the treatment of PLGC, but its specific mechanism of action has not been fully explained. Thus, this study validated the efficacy and explored the potential mechanisms of ZWFW in treating PLGC by integrating network pharmacology analyses and experimental verification. The TCMSP database was used to obtain the active ingredients of ZWFW and their corresponding targets, and the GeneCards database was used to retrieve PLGC-related targets. The intersecting targets between ZWFW and PLGC were obtained through mapping, and protein-protein interaction (PPI) networks and "drug-active ingredient-target" networks were constructed by using Cytoscape software. The DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. AutoDockTools software was used for molecular docking of key active ingredients and key targets. In order to verify the analysis results of network pharmacology, TEM and H&E were used to observe the effects of different dosage groups of ZWFW on gastric mucosal microvasculature in PLGC rats. Subsequently, the ELISA, IF, IHC, RT-PCR and western blot were used to detected the expression levels of relevant targets in the tissues, so as to verify the potential mechanism of ZWFW in intervening PLGC. After the screening, 258 effective active ingredients and 325 targets were obtained, and 1294 disease-related targets were determined, resulting in 139 intersection targets through mapping. The KEGG enrichment results showed that PI3K/Akt and HIF-1 signaling pathway might play important roles in the treatment mechanism of PLGC. The molecular docking results showed that active ingredients of ZWFW all had a strong affinity and stable structure with key targets, including AKT1 and VEGF. In vivo experiments confirmed that ZWFW could improve gastric mucosal microvascular abnormalities in PLGC, effectively intervene in gastric mucosal pathological grading. Meanwhile, compared with the model group, this formulation could reduce the expression levels of PI3K, Akt, mTOR, HIF-1α, and VEGF in gastric mucosa, showing a dose-effect relationship. ZWFW can intervene in the neovascularization and pathological evolution of PLGC, and this mechanism of action may be achieved by inhibiting abnormal activation of the PI3K/Akt/mTOR/HIF-1α/VEGF signaling pathway.

Comparative Transcriptomics Data Profiling Reveals E2F Targets as an Important Biological Pathway Overexpressed in Intellectual Disability Disorder.

Intellectual disability (ID) is an early childhood neurodevelopmental disorder that is characterized by impaired intellectual functioning and adaptive behavior. It is one of the major concerns in the field of neurodevelopmental disorders across the globe. Diversified approaches have been put forward to overcome this problem. Among all these approaches, high throughput transcriptomic analysis has taken an important dimension. The identification of genes causing ID rapidly increased over the past 3 to 5 years owing to the use of sophisticated high throughput sequencing platforms. Early monitoring and preventions are much important for such disorder as their progression occurs during fetal development. This study is an attempt to identify differentially expressed genes (DEGs) and upregulated biological processes involved in development of ID patients through comparative analysis of available transcriptomics data. A total of 7 transcriptomic studies were retrieved from National Center for Biotechnology Information (NCBI) and were subjected to quality check and trimming prior to alignment. The normalization and differential expression analysis were carried out using DESeq2 and EdgeR packages of Rstudio to identify DEGs in ID. In progression of the study, functional enrichment analysis of the results obtained from both DESeq2 and EdgeR was done using gene set enrichment analysis (GSEA) tool to identify major upregulated biological processes involved in ID. Our findings concluded that monitoring the level of E2F targets, estrogen, and genes related to oxidative phosphorylation, DNA repair, and glycolysis during the developmental stage of an individual can help in the early detection of ID disorder.

How does political ambition affect carbon emission intensity in China?

We try to expand the political promotion tournaments in Chinese local governments from raising GDP to the level of increasing fiscal revenues. From the vantage point of officials' performance appraisal, we investigate the impact of local government officials' political ambitions, represented by the ex-ante commitment level of fiscal revenue targets, on carbon emission intensity (CEI). Utilizing a sample of 209 prefecture-level cities in China spanning 2006 to 2019, this paper empirically scrutinizes the influence of local government political ambition on CEI. The findings reveal that the greater the political ambition of local government officials, the more pronounced the reduction in CEI. Furthermore, our study demonstrates that political ambition contributes to the decline of CEI by elevating the levels of environmental attention and green innovation. This research not only aids in comprehending the rationale and necessity of the political promotion tournaments implemented by the Chinese central government but also offers valuable insights for other developing countries seeking to mitigate CEI.

Viral peptide conjugates for metal-warhead delivery to chromatin.

The presence of heavy metal groups can endow compounds with unique structural and chemical attributes beneficial for developing highly potent therapeutic agents and effective molecular labels. However, metallocompound binding site specificity is a major challenge that dictates the level of off-site targeting, which is a limiting factor in finding safer and more effective metal-based drugs. Here we designed and tested a family of metallopeptide conjugates based on two different chromatin-tethering viral proteins and a drug being repurposed for cancer, the Au(i) anti-arthritic auranofin. The viral peptides associate with the acidic patch of the nucleosome while the gold moiety can bind allosterically to the H3 H113 imidazole. To achieve synthesis of the conjugates, we also engineered a sulfur-free, nucleosome-binding Kaposi's sarcoma herpesvirus LANA peptide with a methionine-to-ornithine substitution and coupled the peptide to the metal group in a final step using click chemistry. The four conjugates tested are all selectively cytotoxic towards tumor cell lines, but the choice of viral peptide and mode of linkage to the Au(i) group influences metal binding site preference. Our findings suggest that viral peptide-metalloconjugates have potential for use in chromatin delivery of therapeutic warheads and as nucleosome-specific tags.

Динамика промышленного производства регионов: оценка резилиентности реакции на внешние ограничения

The Russian economy is at the centre of destabilising events. The article assesses the resilience of responses of industrial production to external constraints. Long – and short-term regional responses were examined using the methods of estimation of trend and cyclical components of production volume changes, construction of phase dynamics models (sectoral and cross-sectoral tracers) of relevant and prospective specialisation areas, assessment of the resilience of industrial regions based on the indicators of long-term, short-term and prospective dynamics. Analysis of particular resilience indicators demonstrated regional differences in production indices before and after destabilising events, duration of the recovery period, degree of reaching the pre-shock level, presence or absence of stabilising industries, etc. Three levels of production resilience were distinguished: elastic response characterises regions that managed to reach the pre-shock level; super-elastic response indicates compensatory recovery and positive post-shock growth; plastic response means negative consequences after the normalisation of events. The paper analysed export-oriented single-industry metallurgical regions using official statistics on industrial production indices for 2006–2021. As a result, their resilience profiles were differentiated: the research noted a negative impact and slowdown in economic growth in Chelyabinsk and Sverdlovsk oblasts, as well as a positive reaction in Vologda and Lipetsk oblasts. Additionally, it was revealed that stabilising industries with counter-phase dynamics are present in Vologda and Lipetsk oblasts and absent in Sverdlovsk and Chelyabinsk oblasts. According on the identified levels of production resilience, targets and tools of regional industrial policy were determined. Regions with plastic responses to external constraints require support for prospective specialisations. In regions with elastic and super-elastic responses, it is necessary to implement strategies and policy measures for the stabilisation of development through economic diversification.

Immediate cross-language transfer of novel articulatory plans in bilingual speech.

Current models of second language (L2) acquisition focus on interactions with a first language (L1) at the level of speech sound targets. In multilinguals, the degree of interaction between the articulatory plans that guide speech in each language remains unclear. Here, we directly address this question in bilingual speakers. We use a sensorimotor adaptation paradigm to drive the acquisition of novel articulatory plans for speech in one language and then measure the extent to which these new motor plans influence articulatory plans in the speaker's other language. Twenty L1-French, L2-English bilinguals adapted their speech production to a real-time alteration of vowel sounds. In one session, the adaptation was acquired during French sentence production; in a second session, the adaptation was acquired during English sentence production. In each session, cross-language transfer of these novel articulatory plans for speech was assessed using a transfer task that involved the production of French and English words with heavily noise-masked auditory feedback. Sensorimotor adaptation that countered the vowel sound alteration was observed in both French and English. Regardless of the linguistic context in which the adaptation was acquired, the adaptation transferred to the production of words in both languages. The amount of transfer did not depend on whether the adaptation was acquired in the participant's L1 or L2. In a second experiment, the result was replicated with 20 L1-English, L2-French speakers. The experiments support the idea that, in bilinguals, the interaction between L1 and L2 articulatory motor plans is rapid and bidirectional. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Ресурсно-прогностическая детерминация личностно-профессионального развития педагога: научное обоснование и технологические решения

Background. The current situation of society development is characterized by the emergence of new external stimuli as the challenges generating contradictions and barriers in the education system on the one hand, and on the other hand-expanding horizons, prospects, resources and meta-resources for the development of personality of subjects of education and especially the teachers as the future of children and youth largely depends on them. Objectives. Theoretical substantiation, empirical verification and technological actualization of psychological resources for determining the personal and professional development of a teacher. Study Participants. University students (n = 663), university professors (n = 100), high school students (n = 118), school teachers (n = 34). Methods. The study consisted of four stages. A special methodological program has been developed for each stage. Results. The study revealed the specifics of the content structure of psychological resources relevant for the personal and professional development of teachers: reflexive projecting, constructive coping, emotional and value engagement. It is demonstrated that the complex of interrelated and interdependent resource-prognostic constructs — meta-resources acts as the main factor (predictor) determining the high level of personal and professional development of a teacher. The data analysis allowed to create a structural model of resource determination of personal and professional development of the subjects of education at the target, content (personal, interpersonal), technological, organizational, and strategic levels of psychological training for teachers. Conclusions. The concept of resource-prognostic determination of the teachers’ development, based on the idea of the maximum possible reliance on self-development and self-organization, assumes the most effective implementation of the totality of a teacher’s resources (meta-resources) in an individually unique situation. The technology of actualization of psychological resources for determining the personal and professional development of teachers (future teachers) has proven its effectiveness in experiments, which allows to recommend this technology for implementation in the educational process of schools, colleges, universities.

Enhancing ASPP2 promotes acute liver injury via an inflammatory immunoregulatory mechanism.

Acute liver injury (ALI), which is a type of inflammation-mediated hepatocellular injury, is a clinical syndrome that results from hepatocellular apoptosis and hemorrhagic necrosis. Apoptosis stimulating protein of p53-2 (ASPP2) is a proapoptotic member of the p53 binding protein family. However, the role of ASPP2 in the pathogenesis of ALI and its regulatory mechanisms remain unclear. The expression of ASPP2 were compared between liver biopsies derived from patients with CHB, patients with ALI, and normal controls. Acute liver injury was modelled in mice by administration of D-GalN/LPS. Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. ASPP2-knockdown mice (ASPP2+/-) were used to determine its role in acute liver injury. Mouse bone marrow macrophages (BMMs) were isolated from wildtype and ASPP2+/- mice and stimulated with LPS, and the supernatant was collected to incubate with the primary hepatocytes. Quantitative real-time PCR and western blot were used to analyze the expression level of target. The expression of ASPP2 was significantly upregulated in the liver tissue of ALI patients and acute liver injury mice. ASPP2+/- mice significantly relieved liver injury through reducing liver inflammation and decreasing hepatocyte apoptosis. Moreover, the conditioned medium (CM) of ASPP2+/- bone marrow-derived macrophages (BMMs) protected hepatocytes against apoptosis. Mechanistically, we revealed that ASPP2 deficiency in BMMs specifically upregulated IL-6 through autophagy activation, which decreased the level of TNF-α to reduce hepatocytes apoptosis. Furthermore, up-regulation of ASPP2 sensitizes hepatocytes to TNF-α-induced apoptosis. Our novel findings show the critical role of ASPP2 in inflammatory immunoregulatory mechanism of ALI and provide a rationale to target ASPP2 as a refined therapeutic strategy to ameliorate acute liver injury.