Individual Carriers Research Articles

1/f noise in semiconductors arising from the heterogeneous detrapping process of individual charge carriers

Abstract We propose a model of 1 / f noise in semiconductors based on the drift of individual charge carriers and their interaction with the trapping centers. We assume that the trapping centers are homogeneously distributed in the material. The trapping centers are assumed to be heterogeneous and have unique detrapping rates. We show that uniform detrapping rate distribution emerges as a natural consequence of the vacant trap depths following the Boltzmann distribution, and the detrapping process obeying Arrhenius law. When these laws apply, and if the trapping rate is low in comparison to the maximum detrapping rate, 1 / f noise in the form of Hooge’s relation is recovered. Hooge’s parameter, α H, is shown to be a ratio between the characteristic trapping rate and the maximum detrapping rate. The proposed model implies that 1 / f noise arises from the temporal charge carrier number fluctuations, not from the spatial mobility fluctuations.

Contribution of circulating Mfge8 to human T2DM and cardiovascular disease

MFGE8 is a major exosome (EV) protein known to mediate inflammation and atherosclerosis in type 2 diabetes mellitus (T2DM) in animal studies. The pathophysiological role of this protein in obesity, T2DM, and cardiovascular disease is less investigated in humans. Earlier we reported a rare Asian Indian population-specific missense variant (rs371227978; Arg148His) in the MFGE8 gene associated with increased circulating Mfge8 and T2DM. We have further investigated the role of Mfge8 with T2DM risk in additional Asian Indians (n = 4897) and Europeans and other multiethnic cohorts from UK Biobank (UKBB) (n = 455,808) and the US (n = 1150). We also evaluated the exposure of Mfge8-enriched human EVs in zebrafish (ZF) for their impact on cardiometabolic organ system.Most individual carriers of Arg148His variant not only had high circulating Mfge8 but also revealed a positive significant correlation with glucose (r = 0.42; p = 4.9 × 10−04), while the non-carriers showed a negative correlation of Mfge8 with glucose (r = −0.38; p = 0.001) in Asian Indians. The same variant was monomorphic in non-South Asian ethnicities. Even without the variant, serum Mfge8 correlated significantly with blood glucose in other non-South Asian ethnicities (r = 0.47; p = 2.2 × 10−13). Since Mfge8 is an EV marker, we tested the exposure of Mfge8-enriched human EVs to ZF larvae as an exploratory study. The ZF larvae showed rapid effects on insulin-sensitive organs, developing fatty liver disease, heart hypertrophy and exhibiting redundant growth with poor muscular architecture with and without the high-fat diet (HFD). In contrast, the control group fishes developed fatty liver disease and heart hypertrophy only after the HFD feeding. Backed with strong support from animal studies on the role of Mfge8 in obesity, insulin resistance, and atherosclerosis, the current research suggests that circulating Mfge8 may become a potential marker for predicting the risk of T2DM and cardiovascular disease in humans.

Cell migration dynamics explained by the coupling of mechanics with electrochemistry and pH regulation

Anisotropic environmental signals or polarized membrane ion/solute carriers can generate spatially varying intracellular gradients, leading to polarized cell dynamics. For example, the directional migration of neutrophils, galvanotaxis of glioblastoma, and water flux in kidney cells all result from the polarized distribution of membrane ion carriers and other intracellular components. The underlying physical mechanisms behind how polarized ion carriers interact with environmental signals are not well studied. Here, we use a physiology-relevant, physics-based mathematical model to reveal how ion carriers generate intracellular ion and voltage gradients. The model can discern the contribution of individual ion carriers to the intracellular pH gradient, electric potential, and water flux. We discover that an extracellular pH gradient leads to an intracellular pH gradient via chloride-bicarbonate exchangers, whereas an extracellular electric field leads to an intracellular electric potential gradient via passive potassium channels. In addition, mechanical-biochemical coupling can modulate actin distribution and flow, creating a biphasic dependence of cell speed on water flux. Moreover, we find that F-actin interaction with NHE alone can generate cell movement, even when other ion carriers are not polarized. Taken together, the model highlights the importance of cell ion dynamics in modulating cell migration and cytoskeletal dynamics. Published by the American Physical Society 2024

Engineering and management approach in the sphere of transport and logistics

The article is devoted to the analysis (consideration) of peculiarities of management in the sphere of transport at the present stage of social and technological development. The role of transport and infrastructure projects as a key element of the country’s economic development is described. Being linked into a single comprehensive plan, infrastructure solutions become the basis for the development of a country or territory. It was concluded that with the current form of organisation of transport activities, a two-circuit management system is believed to be optimal, when the role of the state is reduced to planning of long cycles and to the role of economic administrator. The private sector, individual carriers, small companies regulate the quality of service by individualising the supply. One of the most important points of contact between these systems is the sphere of education. The authors describe the concept of engineering and management approach to education. This approach will make it possible to systematically train specialists with both technological and managerial competencies which will become an impetus for the development of economic sectors and strengthening the technological sovereignty of the state. The purpose of the article is to determine the patterns of functioning of the transport and logistics sphere in the framework of supply-side economics, and to consider the engineering and management approach to the training of specialists (for the industry).

The Impact of Grain‐Size Distributions of Iron‐Oxides on Paleomagnetic Measurements

AbstractMagnetic signals in igneous rocks arise from assemblages of iron‐oxide bearing minerals that differ in for example, size, shape, and chemistry. Paleomagnetic measurements on bulk samples measure millions of such grains simultaneously, producing a statistical ensemble of the magnetic moments of the individual grains. Scanning magnetometry techniques such as the Quantum Diamond Microscope (QDM) measure magnetic signals on micrometer scales, allowing the identification of magnetic moments of individual grains in a sample using for example, Micromagnetic Tomography (MMT). Here we produce a grain‐size distribution of iron‐oxides in a typical Hawaiian basalt from the superparamagnetic threshold (∼40 nm) to grains with a diameter of 10 µm. This grain‐size distribution is obtained by combining FIB‐SEM and MicroCT data from sister specimens, and normalizing them to the mineral surface area of non‐magnetic minerals. Then we use this grain‐size distribution to determine the contributions of individual magnetic carriers to bulk magnetic measurements and surface magnetometry. We found that measurements on bulk samples are sensitive to relatively small grain sizes in the realm of single domain or vortex states (<200 nm), while signals in surface magnetometry arise mainly from larger grains with diameters >1 µm. This implies that bulk measurements cannot be compared straightforwardly to signals from surface magnetometry from the same sample. Moreover, our observations explain why MMT results are insensitive to the presence of many small grains in a sample that intuitively should hamper their outcome.

Uptake rate of carrier screening among consanguineous couples.

To quantify the uptake rates of Carrier Screening (CS) in consanguineous couples and compare this rate to that of non-consanguineous couples. We performed a matched case control study of 82 consanguineous couples seen at Rutgers-Robert Wood Johnson Medical school who were offered carrier screening between January 1, 2012 and October 10, 2022. We then matched each consanguineous female patient to a non-consanguineous female control patient who was also offered CS at the time of their genetic counseling appointment. A 2×2 contingency table analysis was used to compare rates of acceptance and declination between the consanguineous and non-consanguineous groups. The overall acceptance rate among consanguineous couples was 82.9%, whereas the overall acceptance rate among non-consanguineous couples was 56.1%. After statistical analysis, consanguineous couples were significantly more likely to accept CS as compared to non-consanguineous couples (OR=3.801, 95% CI; p<0.0001). We also report the carrier couple rates and individual carrier statistics between these two groups. This study supports the idea that consanguineous couples are more likely to pursue CS and have a higher carrier couple yield.

Effects of diets supplemented with bioactive peptides on nutrient digestibility, immune cell responsiveness, and fecal characteristics, microbiota, and metabolites of adult cats.

Bioactive peptides (BP) are recognized for their ability to function as antioxidants and maintain lipid stability. They may have positive health effects, including antihypertensive, anti-inflammatory, antimicrobial, osteoprotective, gut health, and immunomodulatory properties, but are poorly tested in cats. Our primary objective was to determine the apparent total tract digestibility (ATTD) of BP-containing kibble diets and assess how the fecal characteristics, metabolites, and microbiota were affected in adult cats. Our secondary objective was to test whether BP could impact blood oxidative stress markers and cytokine concentrations following transport stress. Twelve adult cats (4.83±0.37 yr; 4.76±0.14kg) were used in a replicated 4×4 Latin square design to test four extruded kibble diets: Control (no BP), Chicken (4% chicken BP), Marine1 (2% marine BP), and Marine2 (4% marine BP). Each experimental period lasted 28 d, with a 20-d adaptation phase, 5 d for fecal collection, 2 d for blood collection, and 1 d for transport stress testing (driven in vehicle in individual carriers for 45min). Salivary cortisol and blood oxidative stress markers and cytokines were measured after transport. Fecal microbiota data were evaluated using 16S rRNA gene amplicon sequencing and QIIME2. All other data were analyzed using the Mixed Models procedure of SAS, with P<0.05 being considered significant and P<0.10 considered trends. No differences were observed in animal health outcomes, with all cats remaining healthy and serum metabolites remaining within reference ranges. Cats fed the Marine2 diet had higher (P<0.05) ATTD of dry matter (84.5% vs. 80.9%) and organic matter (88.3% vs. 85.8%) than those fed the control diet. The ATTD of protein and energy tended to be higher (P<0.10) for cats fed the Marine2 diet. Fecal characteristics, metabolites, and bacterial alpha and beta diversity measures were not affected by treatment. However, the relative abundances of six bacterial genera were different (P<0.05) and two bacterial genera tended to be different (P<0.10) across treatments. Treatment did not alter salivary cortisol, blood oxidative stress markers, or blood cytokines after transport stress. Our data suggest that BP inclusion may increase nutrient digestibility and modify fecal microbiota and immune measures. More testing is required, however, to determine whether BP may provide additional benefits to cats.

Evaluating reliability in airport baggage handling: a time-based assessment of the individual carrier system

Evaluating reliability in airport baggage handling: a time-based assessment of the individual carrier system

Triple click chemistry for crosslinking, stiffening, and annealing of gelatin-based microgels.

Microgels are spherical hydrogels with physicochemical properties ideal for many biomedical applications. For example, microgels can be used as individual carriers for suspension cell culture or jammed/annealed into granular hydrogels with micron-scale pores highly permissive to molecular transport and cell proliferation/migration. Conventionally, laborious optimization processes are often needed to create microgels with different moduli, sizes, and compositions. This work presents a new microgel and granular hydrogel preparation workflow using gelatin-norbornene-carbohydrazide (GelNB-CH). As a gelatin-derived macromer, GelNB-CH presents cell adhesive and degradable motifs while being amenable to three orthogonal click chemistries, namely the thiol-norbornene photo-click reaction, hydrazone bonding, and the inverse electron demand Diels-Alder (iEDDA) click reaction. The thiol-norbornene photo-click reaction (with thiol-bearing crosslinkers) and hydrazone bonding (with aldehyde-bearing crosslinkers) were used to crosslink the microgels and to realize on-demand microgel stiffening, respectively. The tetrazine-norbornene iEDDA click reaction (with tetrazine-bearing crosslinkers) was used to anneal microgels into granular hydrogels. In addition to materials development, we demonstrated the value of the triple-click chemistry granular hydrogels via culturing human mesenchymal stem cells and pancreatic cancer cells.

Application of chiral recyclable catalysts in asymmetric catalysis.

Chiral drugs hold a significant position within the contemporary pharmaceutical market, and the chiral catalysts play a crucial role in their synthesis. However, current chiral catalysts encounter challenges pertaining to their separation from products and the recycling process. The utilization of chiral recyclable catalysts not only reduces production costs but also aligns with the growing emphasis on environmentally-friendly chiral synthetic chemistry. These recyclable catalysts exhibit diverse carriers and distinct characteristics. Chemists employ the distinctive attributes of individual carriers to render them recyclable, thereby yielding time and cost savings. This review examines the asymmetric recyclable catalytic reactions reported between January 2017 and October 2023, categorizing them based on carrier solubility, and elucidates the loading techniques, catalytic impacts, recovery approaches, and recycling processes associated with these carriers.

DON encapsulated carbon dot-vesicle conjugate in therapeutic intervention of lung adenocarcinoma by dual targeting of CD44 and SLC1A5.

Lung adenocarcinoma, recognized as one of the most formidable malignancies with a dismal prognosis and low survival rates, poses a significant challenge in its treatment. This article delineates the design and development of a carbon dot-vesicle conjugate (HACD-TMAV) for efficient cytotoxicity towards lung cancer cells by target selective delivery of the glutamine inhibitor 6-diazo-5-oxo-L-norleucine (DON) within CD44-enriched A549 cancer cells. HACD-TMAV is composed of hyaluronic acid-based carbon dots (HACDs) and trimesic acid-based vesicles (TMAV), which are bound via electrostatic interactions. TMAVs are formed by positively charged trimesic acid-based amphiphiles through H-type aggregation in water. HACDs were synthesized through a one-step hydrothermal route. The blue-emitting HACD-TMAV conjugate demonstrated selective bioimaging in CD44-overexpressed A549 lung cancer cells due to specific ligand-receptor interactions between HA and CD44. HACD-TMAV exhibited notably improved DON loading efficiency compared to individual nano-vehicles. HACD-TMAV-DON exhibited remarkable (∼6.0-fold higher) cytotoxicity against CD44-overexpressing A549 cells compared to CD44- HepG2 cells and HEK 293 normal cells. Also, DON-loaded HACD-TMAV showed ∼2.0-fold higher cytotoxicity against A549 cells compared to individual carriers and ∼4.5-fold higher cytotoxicity than by DON. Furthermore, HACD-TMAV-DON induced a ∼3.5-fold reduction in the size of 3D tumor spheroids of A549 cells. The enhanced anticancer effectiveness was attributed to starvation of the A549 cells of glutamine by dual targeting of glutamine metabolism and solute linked carrier family 1 member A5 (SLC1A5) through HA-linked CD44-mediated targeted delivery of DON. This led to over-production of reactive oxygen species (ROS) that induced apoptosis of cancer cells through downregulation of the PI3K/AKT/mTOR signaling cascade.

PSIX-2 Effects of Diets Supplemented with Bioactive Peptides on Nutrient Digestibility, Immune Cell Responsiveness, and Fecal Characteristics, Microbiota, and Metabolites of Adult Cats

Abstract Bioactive peptides (BP) are recognized for their ability to function as antioxidants and maintain lipid stability. They may have positive health effects, including antihypertensive, anti-inflammatory, antimicrobial, osteoprotective, gut health and immunomodulatory properties. Our objective was to determine the apparent total tract digestibility (ATTD) of bioactive peptide-containing kibble diets and assess how the fecal characteristics, metabolites, and microbiota were affected in adult cats. All procedures were approved by the University of Illinois IACUC. Twelve adult cats (4-5 yr; 4.84 kg avg. BW) were used in a replicated 4x4 Latin square design (n = 12/group) and fed to maintain BW. In each experimental period, cats were allotted to one of four extruded kibble experimental diets: control (4% dried chicken), chicken (4% chicken BP), marine1 (2% marine BP), and marine2 (4% marine BP). Health was confirmed by baseline serum chemistry and complete blood count analysis. Each experimental period lasted 28 days, with a 20-day adaptation phase, 5-day fecal collection [for nutrient digestibility, microbiota, metabolites, IgA, calprotectin, lactoferrin, pH, and dry matter (DM) analysis], 2-day blood collection (for serum chemistry, complete blood count, and immune cell functionality analysis), and 1 day for transport stress testing. For transport stress, cats were transported in a vehicle in individual carriers for 45 minutes. Upon return, their behavior was evaluated using the cat stress score (CSS). Saliva samples were collected within 15 minutes to measure cortisol concentrations and blood samples were collected after 3 hours to measure concentrations of oxidative stress markers [superoxide dismutase (SOD) and malondialdehyde (MDA)] and inflammatory cytokines. Fecal microbiota data were evaluated using QIIME2. All other data were analyzed using the Mixed Models procedure of SAS, with P &amp;lt; 0.05 being considered significant. No significant differences were observed in animal health outcomes, with all cats remaining healthy within reference ranges. There were no differences in fecal characteristics, metabolites, and microbiota diversity. Cats fed the marine2 diet had a 3.61% greater (P &amp;lt; 0.05) ATTD of DM and a 2.5% greater organic matter digestibility than those fed the control diet. The relative abundance of fecal Blautia was greater (P &amp;lt; 0.05) in cats fed the control diet than those fed the chicken diet, while relative abundance of fecal Slackia was greater (P &amp;lt; 0.05) in cats fed the control diet than those fed the chicken or marine1 diets. In comparison with cats fed the marine1 diet, the relative abundances of fecal Sellimonas and Bifidobacterium were less (P &amp;lt; 0.05) in cats fed the control diet. Neither transport stress nor diet impacted the oxidative stress markers, cytokines, cortisol, or CSS. Furthermore, the diet did not affect immune cell functionality. In conclusion, including BP, in particular marine2 at 4% inclusion to feline diets may increase nutrient digestibility and modify fecal microbiota.

Investment preference for either technical or operational energy efficiency measures to achieve sustainable maritime shipping

AbstractThe reduction in energy consumption in shipping is a crucial issue to achieve a more sustainable sector. Nevertheless, investments in energy efficiency are inhibited by barriers. Consequently, under a Principal-Agent approach, this study aims to analyze the factors affecting the investment preference for either technical or operational measures. To date, the research problem has barely been addressed from a similar approach. This work further integrates agency theory with the identification of barriers and drivers, as well as the cost–benefit ratio from both an environmental and a financial perspective. This makes it possible to consider shipping management from a more comprehensive perspective. The study sample is current and representative (658 individual bulk carriers). The research was carried out utilizing two binominal logistic models that provide similar results when testing the proposed hypotheses. The outcomes show that regulatory factors, such as the distance of a vessel’s technical emissions from EEDI requirements (standardized coefficients: −2.8352 and −2.5069), and Principal-Agent problems, such as split incentives (standardized coefficients: −1.0059 and −0.9828), have the greatest influence on investment preferences. As a consequence of Principal-Agent problems, vessels operating under Time Charter contracts are less likely to invest in technical measures than in operational ones. Verified information and activity promote technical measures. Maritime regulation promotes technical measures in younger vessels, especially those meeting only the minimum requirements. Better knowledge can help achieve a more environmentally responsible shipping sector. The role of shipowners and charterers should be highlighted, and transparency should be promoted to enable well-informed decisions to be made.

Rs1800890 Polymorphism of IL-10 and Susceptibility to Idiopathic Thrombocytopenic Purpura.

Immune thrombocytopenic purpura (ITP) is an immune bleeding disorder that is reported in approximately 2 out of every 100,000 adults with a mean age of 50 years. Several factors such as various genetic backgrounds are associated with the pathogenesis of ITP. Interleukin (IL)-10 is a complicated cytokine that has a role in tumor progression, antitumor immunity, and immune system regulation. rs1800890 is an IL-10 single nucleotide polymorphism linked to lower levels of IL-10. A total of 67 patients with ITP and 70 healthy individuals (controls) were considered in this study. The IL-10 polymorphism was detected by the amplification refractory mutation system-polymerase chain reaction technique. According to our analysis, individual carriers of the AA genotype were less likely to develop ITP. The AT genotype was more common in patients with ITP in comparison to the control group. However, there was no significant association between rs1800890 genotypes ( p = 0.775, odds ratio =1.517, 95%) in the acute and chronic groups. We observed that women had a higher mean frequency of this polymorphism ( p = 0.0012). The rs1800890 AA genotype was associated with the highest platelet counts. However, the mean platelet volume and platelet distribution width values among alleles of the polymorphisms did not vary significantly. The IL-10 rs1800890 polymorphism may have a role in idiopathic thrombocytopenic purpura etiology. As a result, more research with a larger number of sample sizes is suggested.

Encapsulation of phenolic-rich lemon-scented tea tree extract in lemon pomace powder

The Australian native plant, lemon-scented tea tree (LSTT) is rich in polyphenols with strong antioxidant activities. Encapsulation enhances the potential applications of plant extracts and additionally protects them from degradation. The encapsulating agent is one of the key elements in the encapsulation process. In this study, lemon pomace powder (LPP) was investigated as a new carrier agent for LSTT leaf phenolic extract, and its performance was compared with the commonly used polysaccharide (i.e., maltodextrin (MD)) and protein-based (i.e., soy protein isolate (SPI)) coating materials. The encapsulation efficiency, colour, polyphenol and antioxidant property retention, particle morphology, crystallinity, flow properties, and release behaviour in food simulants and gastrointestinal fluid were studied to compare the performance of the carrier agents individually and in combinations. The encapsulation efficiency of lemon pomace powder (LPP) was above 95 % and the order for the retention of polyphenol and antioxidant capacities were MD>LPP>SPI. LPP offers better flow properties and unique particle morphology, which was also amorphous in nature with some degree of crystallinity. The release profile in the food simulants showed a controlled and sustained release rate over the tested period, which was comparable with MD and SPI. In gastrointestinal fluids, the percent release followed the order of SPI>LPP>MD for the carrier agents. The incorporation of LPP with MD and SPI can improve several properties of the individual carrier agents. Thus, LPP can be used as a potential carrier agent for polyphenols in functional food formulation either on its own or in combination with other coating materials.

Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

Allogeneic HSCT for Symptomatic Female X-linked Chronic Granulomatous Disease Carriers

X-linked chronic granulomatous disease (XL-CGD) is an inherited disorder of superoxide production, causing failure to generate the oxidative burst in phagocytes. It is characterized by invasive bacterial and fungal infections, inflammation, and chronic autoimmune disease. While XL-CGD carriers were previously assumed to be healthy, a range of clinical manifestations with significant morbidity have recently been described in a subgroup of carriers with impaired neutrophil oxidative burst due to skewed lyonization. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment for CGD but has rarely been reported in individual symptomatic carriers to date. We undertook a retrospective international survey of outcome of HSCT for symptomatic XL-CGD carriers. Seven symptomatic female XL-CGD carriers aged 1–56 years underwent HSCT in four centers, indicated for severe and recurrent infection, colitis, and autoimmunity. Two patients died from transplant-related complications, following donor engraftment and restoration of oxidative burst. All surviving patients demonstrated resolution of their neutrophil oxidative burst defect with concordant reduction in infection and inflammatory symptoms and freedom from further immunosuppressive therapy. In conclusion, allogeneic HSCT may cure the phagocyte defect in symptomatic XL-CGD carriers and improve their recurrent and disabling infective and inflammatory symptoms but risks transplant-related complications.

Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation

Mutations in CD46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs. healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs. diseased individuals carrying a rare, heterozygous CD46 mutation identified within a large single family. Five out of six studied individuals carried a CD46 gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4+ T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs. healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted CD46 variant as intracellularly—but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-CD46 immune-gene variants may contribute to clinically manifest CD46 haploinsufficiency-associated immune-dysregulation.

Calculation of Reinforced Concrete Rod Structures of Bearing Frame Systems of Multi-storey Buildings

In the context of limited land resources and their ever-increasing cost, cities cannot expand immensely in breadth, they increase, and will grow upwards due to the growth in the number of storeys of residential, civil and public buildings. With an increase in the number of storeys, buildings become complex and responsible engineering structures. Thousands of people are simultaneously in a residential and administrative high-rise building, the life and well-being of one or the other openly depend on the knowledge and skills of designers and builders. In this regard, cutting a multi-storey frame frame into prefabricated elements has a significant impact on the technical and economic performance of the building. The mass, geometric dimensions, configuration of prefabricated elements, the manufacturability of their manufacture and installation, as well as the number of assembly units and their connections, the composition of the latter but their functional purpose depend on it. In calculations, the most important phase is the construction of calculation models for individual elements and carrier systems as a whole, at the same time, the calculation model must be elementary and freely implementable using computer technology. At the present stage, calculation methods that take into account cracking and nonlinear compliance of joints to the operation of frames are not sufficiently developed, and the effect of the effect of unloading the middle zone of sections on the feature of the stress-strain state of sections has not been determined even for the stage of work before cracking, due to the unsolved problem of opening the internal static indefinability. The relevance of this article is the formation of a discrete calculation model in the form of the method of concentrated deformations and analytical, using it to calculate reinforced concrete bar structures of the load-bearing systems of multi-storey buildings.

Versatile delivery platform for nucleic acids, negatively charged protein drugs, and genome-editing ribonucleoproteins using a multi-step transformable polyrotaxane

Various biopharmaceuticals, such as nucleic acids, proteins, and genome-editing molecules, have been developed. Generally, carriers are prepared for each biopharmaceutical to deliver it intracellularly; thus, the applications of individual carriers are limited. Moreover, the development of carriers is laborious and expensive. Therefore, in the present study, versatile and universal delivery carriers were developed for various biopharmaceuticals using aminated polyrotaxane libraries. Step-by-step and logical screening revealed that aminated polyrotaxane, including the carbamate bond between the axile molecule and endcap, is suitable as a backbone polymer. Movable and flexible properties of the amino groups modified on polyrotaxane facilitated efficient complexation with various biopharmaceuticals, such as small interfering RNA, antisense oligonucleotides, messenger RNA, β-galactosidase, and genome-editing ribonucleoproteins. Diethylenetriamine and cystamine modifications of polyrotaxane provided endosomal-escape abilities and drug-release properties in the cytosol, allowing higher delivery efficacies than commercially available high-standard carriers without cytotoxicity. Thus, the resulting polyrotaxane might serve as a versatile and universal delivery platform for various biopharmaceuticals.