D1 D5 Research Articles

Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease

Understanding the intricate role of dopamine D1–D5 receptors is pivotal in addressing the challenges posed by the aging global population, as well as by social stress and advancing therapeutic interventions. Central to diverse brain functions such as movement, cognition, motivation, and reward, dopamine receptors are ubiquitously distributed across various brain nuclei. This comprehensive review explores the nuanced functions of each dopamine receptor, D1, D2, D3, D4, and D5, in distinct brain regions, elucidating the alterations witnessed in several neurological and psychiatric disorders. From the substantia nigra and ventral tegmental area, crucial for motor control and reward processing, to the limbic system influencing emotional responses, motivation, and cognitive functions, each brain nucleus reveals a specific involvement of dopamine receptors. In addition, genetic variations in dopamine receptors affect the risk of developing schizophrenia and parkinsonism. The review further investigates the physiological significance and pathogenic impacts of dopamine receptors in critical areas like the prefrontal cortex, hypothalamus, and striatum. By unraveling the complexities of dopamine receptor biology, especially those focused on different brain nuclei, this review provides a foundation for understanding their varied roles in health and disease, which is essential for the development of targeted therapeutic strategies aimed at mitigating the impact of aging and mental health on neurological well-being.

Ripening induced degradation of pectin and cellulose affects the medium-and short-wave infrared drying characteristics of mulberry

Mulberries were categorized into five stages of ripening (D1–D5, 0.905–1.055 g/cm3) based on their density, and their physicochemical properties, tissue structure, cell wall polysaccharide properties, and drying characteristics were investigated. As mulberry ripening progressed, the TSS and water-soluble pectin content rapidly increased, while the contents of TA, hardness, chelate-, sodium carbonate-soluble pectin, hemicellulose, and cellulose decreased gradually. Pectin nanostructure and monosaccharide composition indicated that both the main and side chains of pectin undergo depolymerization. Medium- and short-wave infrared drying time initially decreased and then increased during mulberry ripening, with D4 fruits exhibiting the shortest drying time. Compared with D4 fruits, the collapse of cell structure in D5 fruits prolongs their drying time. The results demonstrate that ripeness significantly affects mulberry drying characteristics, which is related to changes in cell structure and pectin properties. Utilizing mulberry density to determine ripeness and grading is an effective approach to achieving optimal drying.

Design of a D–Di–π–A Architecture with Different Auxiliary Donors for Dye‐Sensitized Solar Cells: Density Functional Theory/Time‐Dependent‐Density Functional Theory Study of the Effect of Secondary Donors

AbstractIn this work, five novel D–Di–π–A molecules based on ethoxy donor moiety are designed from the reference molecule R to optimize the photovoltaic performance of dye‐sensitized solar cell (DSSC) systems. The geometrical, electronic, optical, and photovoltaic characteristics of the D1–D5 compounds are analyzed. D1–D5 show band gaps (Egap) in the range of 2.13–2.25 eV with the maximum absorption wavelength (λabs) in 427–451 nm. Charge transport characteristics are examined by employing frontier molecular orbitals and density of states. The transition density matrix is employed to predict the characteristics of the electronic excitation mechanisms and the localization of the electronic holes betwixt the donor and acceptor moieties. The data obtained indicate that adding the various auxiliary donors to dye (R) facilitate its electron injection and improve the impact of intramolecular charge‐transfer (ICT), which lead to a red‐shifted absorption. The open‐circuit voltage (Voc) data obtained from theoretical computations vary from 1.26 to 1.30 eV, while the data for the light harvesting efficiency range from 0.97 to 1.00. Indeed, this study may help chemists to synthesize efficient dyes for DSSC.

Effect of Stocking Density on Culture Efficiency and Physiological Indicators of Largemouth Bass (Micropterus salmoides) under Recirculating Water Conditions in Land-Based Round Ponds

To identify the optimal stocking rate of Micropterus salmoides culture in a land-based round pond recirculating aquaculture system, five stocking densities were tested, i.e., D1–D5 with 60, 70, 80, 90, and 100 fish/m2, respectively. The water temperature of the experimental pond was 20.0–26.5°C. The effects of stocking density on culture productivity and physiological indexes of M. salmoides (initial body weight 50.83 ± 7.28 g) were examined. The D1 and D5 treatments exhibited significantly improved growth performance. The population weight gain in the D5 treatment was the highest, which increased by 63.73%, 52.82%, 60.93%, and 45.08%, compared with groups D1–D4 ( P < 0.05 , each), and the feed conversion ratio was the lowest, which was decreased by 5.65%, 12.03%, 26.42%, and 21.48% compared with groups D1–D4. The levels of crude protein, essential amino acids, and total free amino acids in muscle tissue of group D3 were higher than those in the other groups. Stocking density did not differ significantly on muscle fatty acid composition P > 0.05 , each). The activities of serum AKP and LZM and liver SOD, AKP, and LZM in group D5 were significantly higher than those in the other groups. Thus, 100 fish/m2 was the optimal stocking density of M. salmoides at a size stage of 50.83∼130.13 g in the circulating water of land-based round ponds.

Multisensory Preclinical Training Strategy of Periodontal Scaling for Undergraduates

BackgroundInvisibility of subgingival scaling is the most important negative factor affecting the performance of periodontal treatment. A multisensory teaching strategy is used in the preclinical training of undergraduates in order to increase the haptic-auditory-visual feedback, aiming to overcome the invisibility and achieve minimal postoperative complications, improving patients’ treatment experience. MethodsOne hundred undergraduate dental students in grade 5 were divided into a multisensory teaching strategy group (MTS: n = 50) and a conventional training pattern group (CTP: n = 50). All participants attended a lecture on using an ultrasonic subgingival scaler (USS) and Gracey curettes (GRA), followed by a 3-week training programme. Students in the MTS group were trained in a haptic/auditory-visual feedback manner, whereas students in the CTP group were trained conventionally. After the training phase, paired students in the 2 different groups performed subgingival scaling in paired patients with equivalent teeth of periodontitis using USS and GRA. Objective and subjective postoperative evaluations were recorded. Probing depth (PD) and gingival index (GI) were evaluated before and 4 weeks after scaling by the same periodontal specialist. ResultsMTS significantly reduced treatment time and ameliorated postoperative complications (gingival injury, haemorrhage and root surface roughness; P < .05). Postoperative sensitivity was reduced in the MTS group from day 1 to day 7 (D1–D5: P < .001; D6: P = .002; D7: P = .003), whereas postoperative pain was reduced on day 1 (P = .006), compared with that in the CTP group. The PD reduction was not significant between the groups (MTS: 3.17 ± 0.95 mm vs CTP: 3.07 ± 0.97 mm, P > .05), whereas the GI change showed a significant difference between the groups (MTS: 1.71 ± 0.41 vs CTP: 1.67 ± 0.41, P < .05). ConclusionsMultisensory teaching strategies in the preclinical periodontal training of undergraduates can reduce postoperative complications (gingival injury, postoperative haemorrhage, and root surface roughness) and provide a better treatment experience (decreased treatment time and postoperative pain and sensitivity) for patients.

Epigenetics and field cancerization as the caveats of carcinogenesis and recurrence of gastrointestinal malignancies: a systematic review and meta-analysis protocol

Abstract Gastrointestinal malignancies constitute the most common neoplasms with increasing prevalence worldwide, which portend a dismal morbidity and higher mortality rate. Epigenetic phenotypes and field cancerization impute a cutting edge for precursor of several gastrointestinal malignancies; this genetic aberration has been implicated in tumorigenesis and recurrence of gastrointestinal malignancies. This systematic review aims at assessing the effect of epigenetics and field cancerization on carcinogenesis and recurrence of gastrointestinal malignancies. This systematic review and meta-analysis will administer the provisions of Preferred Reporting Items for Systematic Review and Meta-analysis 2020 guideline, and the review protocol has been registered at PROSPERO. The literature search will be executed through several electronic databases including EMBASE, PubMed, Scopus, Web of Science, Cochrane, Global Index Medicus, Semantic Scholar and Google Scholar. All original research articles reporting on the effect of epigenetic signatures, epigenetics and field cancerization on the carcinogenesis and recurrence of gastrointestinal cancers in adults will be included. Only articles with Newcastle–Ottawa Scale score above 4 and low risk of bias based on D1–D5 for randomized controlled trials will be included for a meta-analysis. There is no involvement of human subject participation in this review, thus giving no effect to ethical clearance approval. The evidence report of this review will be disseminated on scientific conferences and will be published to a reputable journal of gastroenterology oncology. This review has been registered at PROSPERO registry ID CRD 42023391339.

Effects of Different Commercial Feeds on Growth Performance of Backcrossed Clarias gariepinus Hatchlings

Different commercial feeds were fed to the hatchlings from the backcross of albino hybrid and parental Clarias gariepinus to improve their growth rate and percentage survival. The fish were fed with D1 Aqualis, D2 vital, D3 Skretting, D4 Coppens, and D5 Prime feeds. The results revealed an increase in weight and length gain of the hatchlings. However, the fish fed with Skrettings and Coppens gave the best growth rate. The weight gain was highest in Skretting D3 (18.500±0.042a), followed by Coppens D4 (18.18±0.52), then the Vital feed (17.767±0.07), Aqualis (17.466±0.13) and Prime had the least (17.200±0.20). In the length gain, Skretting and Vital had the same results (4.734±0.10), followed by Coppens (4.633±0.12), Prime (4.567±0.06) and the least was Aqualis (4.100±0.15). Prime had the highest percentage of survival 86%, this was followed by Coppens at 80%, Vital at 73.33%, Skretting at 66.67% and the least Aqualis at 53.33%. The Coppens had the best feed conversion ratio (0.007), while the rest of the treatments had 0.001. The research showed that both skretting and Coppens gave the best results. However, when considering the cost of the feeds skretting should be used since it is cheaper.

Physicochemical properties and phytochemical components of white mulberry (Morus alba L.) fruits with different density at harvest

Reducing waste and controlling fruit quality is a challenge for retailers and processors. The fresh fruit and processing industries are seeking a reliable method to comprehend fruit characteristics to meet consumer demands for high-quality fruit. The harvested white mulberry was divided into five density stages (D1–D5, 0.960–1.060 g/cm3) using a densimetric flotation method, and the effects of fruit density on its physicochemical properties, phenolics content, volatile compounds, and cellular structure were investigated. Low-density fruits (D1, D2) contain less glucose, fructose, and more citric acid, hexanal and methyl acetate. The highest contents of chlorogenic acid, caffeic acid, and syringic acid were found in fruits at the D3 stage, with 64.6 mg/100 g DW, 15.8 mg/100 g DW and 14.1 mg/100 g DW, respectively. They may better eliminate free radicals and promote the health of the body. Moreover, rapid loss of fruit firmness, damage to cell structure, and a decrease in phenolics content after the fruit density exceeded 1.020 g/cm3 (D4, D5) indicate that the fruit is overripe, unsuitable for further storage and should be processed immediately. The presented data demonstrate the effect of fruit density on white mulberry quality and will serve as a valuable resource for retailers and processors.

Retrospective analysis algorithm for identifying and localizing residual reserves of the developed multilayer oil field

Long-term phased development of a multi-layer field, including tens and hundreds of oil-bearing horizons and local deposits, combined with their vertical and horizontal separation, creates conditions for the formation of residual oil reserves. For the purpose of identifying and spatial localization of residual reserves, an algorithm for retrospective analysis was developed and applied on the example of the Upper and Lower Devonian terrigenous deposits of the Romashkinskoe oil field, which have been developed since 1952. The long history of geological study and development of oil-bearing formations of the Pashiysky D1 (layers g and e), Mullinsky D2, Ardatovsky D3, Vorobyevsky D4 and Biysky D5 horizons is analyzed according to the data of 2605 wells. It is proposed to single out 6 categories of formations and the reserves contained in them. Previously undeveloped formations composed of conditioned reservoirs are classified as category 1. Formations composed of more clayey and less permeable reservoirs are awarded with category 2. Category 3 includes previously developed formations, but left before reaching the limit of water cut, and category 4 – currently being developed intervals. The least promising are those that are stopped after reaching the maximum water cut (category 5), as well as wedged out, replaced by non-reservoirs or considered water-bearing (category 6) formations. Categories were mapped to identify, visualize and describe the main patterns in the distribution of residual reserves, which are established both in single wells and in bypassed oil that include a group of wells. The algorithm was tested on the corporate information base of historical data on geological exploration, research and development of the Abdrakhmanovskaya area of ​​the Romashkinskoe oil field. Examples of experimental workover operations to include the identified residual reserves in the development are given.

PB1849: TRIAL IN PROGRESS: PHASE IB/II STUDY OF SIREMADLIN IN COMBINATION WITH VENETOCLAX + AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY

Background: Treatment options for patients with AML who are not candidates for intensive chemotherapy (IC) are limited. The addition of venetoclax to hypomethylating agents demonstrated improved remission rates and survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive (DiNardo CD, N Engl J Med, 2020). Murine double minute-2 (MDM2) is a key negative regulator of tumor protein 53 (p53). Inhibition of the p53-MDM2 interaction results in up-regulation of the tumor-suppressive effect of p53. Siremadlin is a selective inhibitor of the p53-MDM2 interaction. Siremadlin + venetoclax has shown durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Findings from a first-in-human Phase I study with siremadlin demonstrated a tolerable safety profile and preliminary antitumor activity in patients with AML (Stein EM, Clin Cancer Res, 2021; NCT02143635). Preliminary results from the ongoing Phase Ib study exploring siremadlin in combination with venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352). Aims: Here we describe the study design of a Phase Ib/II study to assess the safety and efficacy of the novel combination of siremadlin + venetoclax + azacitidine in patients with AML who are unfit for IC (NCT05155709). Methods: The study will enroll approximately 55 adult patients with AML who are unfit for IC due to older age (≥75 y) or presence of comorbidities (cardiac or pulmonary, Eastern Cooperative Oncology Group performance status of 2 or 3). Patients with prior myelodysplastic syndrome, myelofibrosis, essential thrombocythemia, polycythemia, or therapy-related AML may also be eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated in 2 arms: patients with prior suboptimal response (no complete remission [CR], CR with partial/incomplete hematologic recovery [CRh/CRi], or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax + azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk clinical features that confer a low likelihood of response to venetoclax + hypomethylating agents (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2). The study will consist of a safety run-in (Part 1) and expansion phase (Part 2; Figure). The safety run-in will evaluate safety across 2 siremadlin dose levels (20 or 30 mg) from Day (D)1 to D5 in each 28-d treatment cycle in combination with venetoclax and azacitidine. In Arm 1, pts will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment. In Arm 2, venetoclax will be ramped up over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m2) will be administered from D1–D7 or from D1–D5, and D8 and D9). Upon confirmation of the recommended dose for expansion (RDE, determined for each arm separately), enrollment for the expansion phase (Part 2) will open; patients will be treated with siremadlin at the RDE in combination with venetoclax + azacitidine. The primary endpoints are incidence of dose-limiting toxicities (Arm 1 and Arm 2 separately) and CR rate (Arm 1 only). Secondary endpoints include safety and tolerability; CR rate (Arm 2 only); CR/CRh and CR/CRi rates; duration of CR, CRi, and CRh; overall survival; early mortality; MRD; and pharmacokinetics. Results: None, trial in progress. Image:Summary/Conclusion: None, trial in progress.

Hbox {AdS}_3 holography for non-BPS geometries

By using the approach introduced in Ganchev et al. (Q-Balls Meet Fuzzballs: Non-BPS Microstate Geometries. arXiv:2107.09677 [hep-th]) we construct non-BPS solutions of 6D (1, 0) supergravity coupled to two tensor multiplets as a perturbation of hbox {AdS}_3times S^3. These solutions are both regular and asymptotically hbox {AdS}_3times S^3, so according to the standard holographic framework they must have a dual CFT interpretation as non-supersymmetric heavy operators of the D1–D5 CFT. We provide quantitative evidence that such heavy CFT operators are bound states of a large number of light BPS operators that are mutually non-BPS.

Three-dimensional Quantification of Enamel Preservation in Tooth Preparation for Porcelain Laminate Veneers: A Fully Digital Workflow In Vitro Study.

This in vitro study aimed to evaluate the preservation of enamel after tooth preparation for porcelain laminate veneers (PLVs) at different preparation depths based on a fully digital workflow. Sixty extracted human maxillary anterior teeth, including 20 maxillary central incisors (MCIs), 20 maxillary lateral incisors (MLIs), and 20 maxillary canines (MCs) underwent microcomputed tomography (CT) scanning, and were reconstructed as three-dimensional (3D) enamel and dentin models. Subsequently, the three-dimensional (3D) enamel models were imported into Materialise, where each enamel model underwent seven types of virtual preparation for PLVs at preparation depths at 0.1-mm increments from 0.1-0.3-0.5 mm (D1) to 0.7-0.9-1.1 mm (D7). The enamel surface was depicted by merging the virtual preparation and, respective, dentin models. The enamel area and prepared surface were measured to calculate the percentage of enamel (R%). The data were statistically analyzed using one-way analysis of variance (ANOVA) (α=0.05). The group-wise mean (standard deviation) R values for the MCIs were as follows: D1-D3: 100.00 (0) each, and D4-D7: 74.70 (2.45), 51.40 (5.12), 24.40 (3.06), and 0.00 (0), respectively. The group-wise mean R values for the MLIs were 100.00 (0), 73.70 (3.40), 53.50 (3.44), 25.20 (3.79), and 0.90 (0.99) for the D1-D5 groups, respectively; and 0.00 (0) each for the D6-D7 groups. The group-wise mean (standard deviations) R values for the MCs were as follows: D1-D3: 100.00 (0) each, and D4-D7: 99.00 (1.34), 77.10 (3.28), 74.20 (3.61), and 52.20 (4.09), respectively. The one-way ANOVA revealed significant differences between the seven groups in the MCIs, MLIs, and MCs (p<0.05). Our results recommended preparation depths of up to 0.3-0.5-0.7 mm (MCIs), 0.1-0.3-0.5 mm (MLIs), and 0.4-0.6-0.8 mm (MCs) to facilitate complete intraenamel preparation. Moreover, 50% enamel was preserved at preparation depths of 0.5-0.7-0.9 mm (MCIs), 0.3-0.5-0.7 mm (MLIs), and 0.7-0.9-1.1 mm (MCs).

The effect of omega-3 as diet-enhanced immunity on sepsis outcome in critically ill patients

BackgroundNutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of proinflammatory and anti-inflammatory mediators in sepsis and acute lung injury.ObjectivesTo evaluate the effect of omega-3 fatty acids as diet-enhanced immunity on sepsis outcome in critically ill patients.Patients and methodsSixty patients with early sepsis were divided equally into two groups: group A who received high-dose omega-3 fatty acids for consecutive 7 days besides conventional sepsis treatment, group B: control group who received only conventional sepsis treatment. Both groups were followed up by inflammatory markers, sequential organ failure assessment score monitoring, need for organ-supportive measures, length of ICU stay, mortality rate, final outcome, and complications.ResultsCompared with the control group, the high-dose omega-3 fatty acids exhibited lower levels of white blood cells, C-reactive protein, and procalcitonin at day 5 (P = 0.001, 0.012, and 0.001, respectively) and at day 7 (P = 0.014, 0.008, and 0.29, respectively). As regards serum lactate, there was an insignificant difference between D1–D5 and D1–D7 (P = 0.087 at day 5 and P = 0.80 at day 7). Group A showed a significant decrease in the length of ICU stay (P = 0.035), with the insignificant difference in sequential organ failure assessment score, the need for vasopressor, days free from mechanical ventilation, and mortality rate (P = 0.293, 0.796, 0.201, and 0.781, respectively).ConclusionThe use of omega-3 therapy is safe and associated with promising effects on inflammatory cascade and may play a role in these patients.

Effects of dietary vitamin E on growth performance, antioxidant capacity and lipid metabolism of juvenile golden pompano Trachinotus ovatus

In order to investigate the dietary requirement of Trachinotus ovatus for vitamin E (VE) and its effects on tissue polyunsaturated fatty acids (PUFA) reservation, a 56-day feeding trial was performed with five diets (D1–D5) supplemented with different levels of VE at 34.56, 47.35, 61.16, 91.06 and 144.88 mg VE/kg diet. A total of 375 fish (initial weight 13.40 ± 0.08 g) were randomly distributed equally into 15 sea cages and each diet in triplicate cages. After 8 weeks of feeding, fish fed diet D3 exhibited significantly higher weight gain (WG), serum superoxide dismutase and glutathione peroxidase activities and also had higher docosahexaenoic acid (DHA) and n-3 PUFA contents in the raw muscle than those of fish fed diets D1 and D5 (p < .05). Moreover, n-6 PUFA and n-3 PUFA contents in cooked muscle of D3 and D4 groups were significantly higher than those of other groups (p < .05). Besides, the contents of hepatic arachidonic acids, eicosapentaenoic acid, DHA, n-6 PUFA and n-3 PUFA in fish of D3 and D4 groups were also significantly higher than those of D1 group (p < .05). Correspondingly, the transcript levels of genes related to PUFA β-oxidation (cpt1 and pparα) and synthesis (fas and elovl5) were lower in D3 and D4 groups. Based on regression analysis for WG, the optimum dietary VE level was 90.75 mg/kg, which was consistent with the above results that fish fed diets D3 and D4 displayed better growth performance, antioxidant capacity and muscle PUFA stability, where the last suggesting an effect of dietary VE against PUFA β-oxidation.

Isolation of a novel variant of secretory component with low affinity to dimeric immunoglobulin a by immobilised metal ion affinity chromatography

By applying immobilised metal affinity chromatography to a free secretory component (FSC) preparation from bovine milk, we identified a novel FSC variant with lower affinity to dimeric immunoglobulin A. Using cDNA analysis, we found a novel His to Arg mutation at the 81st residue where the amino acid is well conserved among species. The IgA-binding portion of polymeric immunoglobulin receptor (pIgR) consists of five Ig-like domains (D1–D5); the first complementarity-determining region (CDR1) of D1 is especially critical to the noncovalent binding of pIgR to IgA. The mutation at position 81 occurred within D1, but at the beginning of the E/F loop on the opposite side of CDRl; this region is located at the interface with D2. Given that residues in D2 may form hydrogen bonds with D1, the mutation to Arg may have caused a positive charge that disturbed hydrogen bonding, altered domain relative orientation, and thereby lowered affinity.

Two key switches in regional stress field during multi-stage deformation in the Carboniferous–Triassic southernmost Altaids (Beishan, NW China): Response to orocline-related roll-back processes

AbstractThe orogenic architecture of the Altaids of Central Asia was created by multiple large-scale slab roll-back and oroclinal bending. However, no regional structural deformation related to roll-back processes has been described. In this paper, we report a structural study of the Beishan orogenic collage in the southernmost Altaids, which is located in the southern wing of the Tuva-Mongol Orocline. Our new field mapping and structural analysis integrated with an electron backscatter diffraction study, paleontology, U-Pb dating, 39Ar-40Ar dating, together with published isotopic ages enables us to construct a detailed deformation-time sequence: During D1 times many thrusts were propagated northwards. In D2 there was ductile sinistral shearing at 336–326 Ma. In D3 times there was top-to-W/WNW ductile thrusting at 303–289 Ma. Two phases of folding were defined as D4 and D5. Three stages of extensional events (E1–E3) separately occurred during D1–D5. Two switches of the regional stress field were identified in the Carboniferous to Early Permian (D1-E1-D2-D3-E2) and Late Permian to Early Triassic (D4-E3-D5). These two switches in the stress field were associated with formation of bimodal volcanic rocks, and an extensional interarc basin with deposition of Permian-Triassic sediments, which can be related to two stages of roll-back of the subduction zone on the Paleo-Asian oceanic margin. We demonstrate for the first time that two key stress field switches were responses to the formation of the Tuva-Mongol Orocline.

Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications.

The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1–D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.

Crystal structure of bacterial cytotoxic necrotizing factor CNFY reveals molecular building blocks for intoxication

Cytotoxic necrotizing factors (CNFs) are bacterial single‐chain exotoxins that modulate cytokinetic/oncogenic and inflammatory processes through activation of host cell Rho GTPases. To achieve this, they are secreted, bind surface receptors to induce endocytosis and translocate a catalytic unit into the cytosol to intoxicate host cells. A three‐dimensional structure that provides insight into the underlying mechanisms is still lacking. Here, we determined the crystal structure of full‐length Yersinia pseudotuberculosis CNFY. CNFY consists of five domains (D1–D5), and by integrating structural and functional data, we demonstrate that D1–3 act as export and translocation module for the catalytic unit (D4–5) and for a fused β‐lactamase reporter protein. We further found that D4, which possesses structural similarity to ADP‐ribosyl transferases, but had no equivalent catalytic activity, changed its position to interact extensively with D5 in the crystal structure of the free D4–5 fragment. This liberates D5 from a semi‐blocked conformation in full‐length CNFY, leading to higher deamidation activity. Finally, we identify CNF translocation modules in several uncharacterized fusion proteins, which suggests their usability as a broad‐specificity protein delivery tool.

AML-187: The STIMULUS Clinical Trial Program: Evaluating Combination Therapy with MBG453 in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) or Acute Myeloid Leukemia

Context TIM-3, an inhibitory receptor with a key role in regulating adaptive and innate immunity, is expressed on multiple immune cell types as well as leukemic stem cells and blasts, but not normal hematopoietic stem cells, making it a promising target in MDS and AML. In a phase 1b study ( NCT03066648 ), the anti–TIM-3 monoclonal antibody, MBG453, plus decitabine showed promising preliminary efficacy with a good safety profile in patients with higher-risk MDS or AML (Borate et al, ASH 2019). Objective The STIMULUS clinical trial program is evaluating the efficacy and safety of MBG453 combination therapy in patients with HR-MDS or AML. Design Two study designs from the STIMULUS clinical trial program are described. STIMULUS-MDS1 (N≈120; NCT03946670 ) is a double-blind study evaluating whether MBG453 plus hypomethylating agents (HMA) improves complete remission (CR) rate and progression-free survival (PFS) vs HMA alone in HR-MDS. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival (LFS), transfusion independence, safety, pharmacokinetics, and immunogenicity. Eligible patients are treatment-naive, aged ≥18 years, with HR-MDS (IPSS-R high-/very high-risk MDS, or intermediate-risk MDS with ≥5% bone marrow blasts). Patients are randomized 1:1 to receive MBG453 400 mg or placebo IV D8, D22, plus decitabine 20 mg/m2 IV D1–D5; or azacitidine (AZA) 75 mg/m2 IV/SC D1–D7, or D1–D5, D8-D9 of each 28-day cycle. This study is currently recruiting patients worldwide. STIMULUS-AML1 (N≈86; NCT04150029 ) is an open-label study evaluating the safety (incidence of dose-limiting toxicities) and efficacy (CR rate) of MBG453+AZA+venetoclax. Secondary endpoints include safety and tolerability, CR/CRi rate, MRD-negative rate, CR durability, relapse-free survival, EFS, OS, pharmacokinetics, transfusion independence, and immunogenicity. Eligible patients are adults with newly diagnosed untreated AML who are not suitable for IC or HSCT based on age (≥75 years old) or comorbidities (including renal impairment, cardiac and pulmonary comorbidities). Part 1 is a safety run-in (n≈18) across 2 MBG453 dose levels (400/800 mg IV D8 of each 28-day cycle) plus AZA (75 mg/m2 IV/SC D1–D7, or D1–D5, D8-D9) and venetoclax 400 mg PO QD. If the triplet is assessed to be safe, Part 2 (expansion; n≈68) will investigate MBG453 at 800 mg Q4W in combination with AZA+venetoclax.

Superstrata

We give a survey of the present status of the microstate geometries called superstrata. Superstrata are smooth, horizonless solutions of six-dimensional supergravity that represent some of the microstates of the D1–D5–P black hole in string theory. They are the most general microstate geometries of that sort whose CFT dual states are identified. After reviewing relevant features of the dual CFT, we discuss the construction of superstratum solutions in supergravity, based on the linear structure of the BPS equations. We also review some of recent work on generalizations of superstrata and physical properties of superstrata. Although the number of superstrata constructed so far is not enough to account for the black-hole entropy, they give us valuable insights into the microscopic physics of black holes.