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In this paper we investigate the asymptotic behaviour of the classical continuous and unbounded almost periodic function in the Lebesgue measure.Using diophantine approximations we show that this function can be estimated by functions of polynomial type and we give the best polynomial estimation.

Abstract Upon stimulation of membrane receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) is formed as second messenger within seconds and evokes Ca2+ signaling in many different cell types. Here, to directly stimulate NAADP signaling, MASTER-NAADP, a Membrane permeAble, STabilized, bio-rEversibly pRotected precursor of NAADP is synthesized and release of its active NAADP mimetic, benzoic acid C-nucleoside, 2’-phospho-3’F-adenosine-diphosphate, by esterase digestion is confirmed. In the presence of NAADP receptor HN1L/JPT2 (hematological and neurological expressed 1-like protein, HN1L, also known as Jupiter microtubule-associated homolog 2, JPT2), this active NAADP mimetic releases Ca2+ and increases the open probability of type 1 ryanodine receptor. When added to intact cells, MASTER-NAADP initially evokes single local Ca2+ signals of low amplitude. Subsequently, also global Ca2+ signaling is observed in T cells, natural killer cells, and Neuro2A cells. In contrast, control compound MASTER-NADP does not stimulate Ca2+ signaling. Likewise, in cells devoid of HN1L/JPT2, MASTER-NAADP does not affect Ca2+ signaling, confirming that the product released from MASTER-NAADP is a bona fide NAADP mimetic.

Fractures of the posterolateral part of the tibial plateau (PLTP) are rare and complex fractures among other orthopedic entities. This case report describes a 54-year-old male who suffered a twisting injury of the left knee in a scooter crash. As a result, impaction fracture and displacement of the posterolateral margin of the tibial plateau were diagnosed with concomitant avulsion of the intercondylar eminence of the tibia and medial tibial condyle cleft fracture. The treatment comprised reduction of the medial tibial condyle (MTC) cleft fracture with one cancellous screw, arthroscopic bone-suture of the intercondylar eminence, and reduction of compressed PLTP with fixation of the displaced fragment on a distal radius T-plate working as a “buttress” rather than firm stabilizer. The operative technique of PLTP impaction fracture reduction is described in an instructional manner.

The anteroinferior tibiofibular ligament (AITFL) is 1 of the 4 ligaments forming the distal tibiofibular syndesmosis. When damaged, it is crucial to assess and address the lesion properly because a neglected or underdiagnosed lesion may invoke ankle osteoarthritis with underlying tibiofibular joint instability. In this technical note, we present a fully arthroscopic stabilization of the AITFL without the need for soft-tissue grafting. Our technique aims to create horizontal suture fixation over the damaged AITFL that serves as a mechanically efficient stabilization for the anterior aspect of the distal tibiofibular syndesmosis.

Abstract Patients with breast tumours that metastasise to the brain have limited treatment options and a very poor prognosis. More effective therapeutic strategies are desperately needed for this patient population. Recent evidence demonstrates that brain metastases arising from breast tumours display altered energy production that results in enhanced autophagy. Preclinical studies have shown that genetically or pharmacologically disrupting the autophagy pathway significantly decreases the brain metastatic burden, resulting in improved animal survival and increased sensitivity to lapatinib. These findings pave the way for the development of novel strategies targeting autophagy for breast cancer patients with brain metastatic disease.

Polyelectrolytes continue to find wide interest and application in science and engineering, including areas such as water purification, drug delivery, and multilayer thin films. We have been interested in the dynamics of small molecules in a variety of polyelectrolyte (PE) environments; in this paper, we report simulations and analysis of the small dye molecule rhodamine B (RB) in several very simple polyelectrolyte solutions. Translational diffusion of the RB zwitterion has been measured in fully atomistic, 2 μs long molecular dynamics simulations in four different polyelectrolyte solutions. Two solutions contain the common polyanion sodium poly(styrene sulfonate) (PSS), one with a 30-mer chain and the other with 10 trimers. The other two solutions contain the common polycation poly(allyldimethylammonium) chloride (PDDA), one with two 15-mers and the other with 10 trimers. RB diffusion was also simulated in several polymer-free solutions to verify its known experimental value for the translational diffusion coefficient, DRB, of 4.7 × 10-6 cm2/s at 300 K. RB diffusion was slowed in all four simulated PE solutions, but to varying degrees. DRB values of 3.07 × 10-6 and 3.22 × 10-6 cm2/s were found in PSS 30-mer and PSS trimer solutions, respectively, whereas PDDA 15-mer and trimer solutions yielded values of 2.19 × 10-6 and 3.34 × 10-6 cm2/s. Significant associations between RB and the PEs were analyzed and interpreted via a two-state diffusion model (bound and free diffusion) that describes the data well. Crowder size effects and anomalous diffusion were also analyzed. Finally, RB translation along the polyelectrolytes during association was characterized.

ObjectiveThe mitochondrial fission protein Drp1 was proposed to promote NAFLD, as inhibition of hepatocyte Drp1 early in life prevents liver steatosis induced by high-fat diet in mice. However, whether Drp1-knockdown in older mice can reverse established NASH is unknown.MethodsN-acetylgalactosamine-siRNA conjugates, an FDA approved method to deliver siRNA selectively to hepatocytes, were used to knockdown hepatocyte-Drp1 in mice (NAG-Drp1si). NASH was induced in C57BL/6NTac mice by Gubra-Amylin-NASH diet (D09100310, 40% fat, 22% fructose and 2% cholesterol) and treatment with NAG-Drp1si was started at week 24 of diet. Circulating transaminases, liver histology, gene expression of fibrosis and inflammation markers, and hydroxyproline synthesis determined NASH severity. Liver NEFA and triglycerides were quantified by GC/MS. Mitochondrial function was determined by respirometry. Western blots of Oma1, Opa1, p-eIf2α, as well as transcriptional analyses of Atf4-regulated genes determined ISR engagement.ResultsNAG-Drp1si treatment decreased body weight and induced liver inflammation in adult healthy mice. Increased hepatic Gdf15 production was the major contributor to body-weight loss caused by NAG-Drp1si treatment, as Gdf15 receptor deletion (Gfral KO) prevented the decrease in food intake and mitigated weight loss. NAG-Drp1si activated the Atf4-controlled integrated stress response (ISR) to increase hepatic Gdf15 expression. NAG-Drp1si in healthy mice caused ER stress and activated the mitochondrial protease Oma1, which are the ER and mitochondrial triggers that activate the Atf4-controlled ISR. Remarkably, induction of NASH was not sufficient to activate Oma1 in liver. However, NAG-Drp1si treatment was sufficient to activate Oma1 in adult mice with NASH, as well as exacerbating NASH-induced ER stress. Consequently, NAG-Drp1si treatment in mice with NASH led to higher ISR activation, exacerbated inflammation, fibrosis and necrosis.ConclusionDrp1 mitigates NASH by decreasing ER stress, preventing Oma1 activation and ISR exacerbation. The elevation in Gdf15 actions induced by NAG-Drp1si might represent an adaptive response decreasing the nutrient load to liver when mitochondria are misfunctional. Our study argues against blocking Drp1 in hepatocytes to combat NASH.

The horizontal-to-vertical (H/V) method is a fundamental fast tool to estimate local site effect parameters by using the registered signals of the translational motion. The spectral ratio is mostly calculated using the Fourier Spectrum Analysis (FSA), which may lead to problems with accurate resonant frequency determination due to evident multi-amplification peaks occurrence on the spectrum. Alternatively the H/V ratio may be estimated by use Response Spectrum Analysis (RSA), where only a general amplification peak is expected. However, the fundamental limitations of the RSA assumption are related to the real impact of the events’ scenario dependence (i.e., magnitude, distance, focal mechanism, etc.). The limitations and advantages of the RSA and FSA are commonly known in the case of the analysis performed for the translational signals. Therefore, the critical question is: should the RSA and FSA methods be used to estimate the H/V ratio of the recorded rotational signals of the events? The article presents horizontal-to-vertical (H/V) spectral ratios calculated for rotational and translational signals registered as an effect of mining-induced seismicity by four independent seismic stations located in Poland's Upper Silesian Coal basin. The spectral ratios of the signals were estimated using the RSA and the FSA method. The studies show that in the case of translational motion, the H/V estimations using the RSA derived clear information of the resonant frequency peak, confirming the method’s usefulness in the case of multi-amplification peaks. The opposite situation was noticed in the case of the rotational motion. The derived H/V spectrum, using the RSA, produced single amplification peaks for the seismic stations, where the sensors were mounted on a small floor at a significant distance from the walls. In cases where the sensors were deployed on the building floor, a decrease in the reliability of the RSA and the FSA method was noticed. The results of the studies suggested that the possibility of the estimations of the H/V spectrum using the RSA and FSA algorithm is strongly limited for rotational motions due to the size of the floor and distance to the building walls where the sensors were mounted. The explanation of that fact is related to the effects of kinematic soil-structure interaction, which may significantly affect rotational measurements due to the tendency to obtain higher frequency content than in the case of the translations. Consequently, the values of the Z- component of the rotational motion may be lovered than in the free-field measurements, decreasing the reliability of the H/V estimations for rotational motion.

BackgroundPrimary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC.MethodsMdr2-deficient mice or DDC-fed mice were used as experimental models for sclerosing cholangitis. Additionally, colitis was induced in mice with experimental sclerosing cholangitis, either through infection with Citrobacter rodentium or by feeding with DSS. Lastly, fibrosis levels were determined through FibroScan analysis in people with PSC and PSC-IBD.ResultsUsing two distinct experimental models of colitis and two models of sclerosing cholangitis, we found that colitis does not aggravate liver pathology, but rather reduces liver inflammation and liver fibrosis. Likewise, people with PSC-IBD have decreased liver fibrosis compared to those with PSC alone.ConclusionsWe found evidence that intestinal inflammation attenuates liver pathology. This study serves as a basis for further research on the pathogenesis of PSC and PSC-IBD, as well as the molecular mechanism responsible for the protective effect of IBD on PSC development. This study could lead to the discovery of novel therapeutic targets for PSC.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for eliciting Coronavirus disease 2019 (COVID-19) still challenges healthcare services worldwide. While many patients only suffer from mild symptoms, patients with some pre-existing medical conditions are at a higher risk for a detrimental course of disease. However, the underlying mechanisms determining disease course are only partially understood. One key factor influencing disease severity is described to be immune-mediated. In this report, we describe a post-mortem analysis of 45 individuals who died from SARS-CoV-2 infection. We could show that although sociodemographic factors and premedical conditions such as obesity and diabetes mellitus reduced survival time in our cohort, they were not associated with changes in the expression of immune-related signature genes at the RNA level in the blood, the gut, or the liver between these different groups. Our data indicate that obesity and diabetes mellitus influence SARS-CoV-2-related mortality, without influencing the extrapulmonary gene expression of immunity-related signature genes at the RNA level.

Antimicrobial resistance (AMR) trends in 114 generic Escherichia coli isolated from channel catfish and related fish species were investigated in this study. Of these, 45 isolates were from commercial-sized channel catfish harvested from fishponds in Alabama, while 69 isolates were from Siluriformes products, accessed from the U.S. Department of Agriculture Food Safety and Inspection Service’ (FSIS) National Antimicrobial Resistance Monitoring System (NARMS) program. Antibiotic susceptibility testing and whole genome sequencing were performed using the GenomeTrakr protocol. Upon analysis, the fishpond isolates showed resistance to ampicillin (44%), meropenem (7%) and azithromycin (4%). The FSIS NARMS isolates showed resistance to tetracycline (31.9%), chloramphenicol (20.3%), sulfisoxazole (17.4%), ampicillin (5.8%) and trimethoprim-sulfamethoxazole, nalidixic acid, amoxicillin-clavulanic acid, azithromycin and cefoxitin below 5% each. There was no correlation between genotypic and phenotypic resistance in the fishpond isolates, however, there was in NARMS isolates for folate pathway antagonists: Sulfisoxazole vs. sul1 and sul2 (p = 0.0042 and p < 0.0001, respectively) and trimethoprim-sulfamethoxazole vs. dfrA16 and sul1 (p = 0.0290 and p = 0.013, respectively). Furthermore, correlations were found for tetracyclines: Tetracycline vs. tet(A) and tet(B) (p < 0.0001 each), macrolides: Azithromycin vs. mph(E) and msr(E) (p = 0.0145 each), phenicols: Chloramphenicol vs. mdtM (p < 0.0001), quinolones: Nalidixic acid vs. gyrA_S83L=POINT (p = 0.0004), and β-lactams: Ampicillin vs. blaTEM-1 (p < 0.0001). Overall, we recorded differences in antimicrobial susceptibility testing profiles, phenotypic-genotypic concordance, and resistance to critically important antimicrobials, which may be a public health concern.

Abstract Growth Differentiation Factor‐15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half‐life is ~3 h and activates the glial cell line‐derived neurotrophic factor family receptor alpha‐like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half‐life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long‐acting GLP‐1 analog dulaglutide. Mechanism‐based longitudinal exposure‐response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure‐dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose‐proportional pharmacokinetics (terminal half‐life ~8 days) and treatment caused exposure‐dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9–12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure‐dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long‐acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.

Abstract Lightweight, flexible, and conformal bioelectronics are essential for wearable technologies. This paper introduces 270 nm thin organic electronics amplifying circuits that are self-adhesive, skin conformal, and long-term air-stable. This report studies the effect of total device thickness, namely 3 μm and 270 nm devices, on the characterization of organic devices before and after buckling, the longevity of organic field-effect transistors (OFETs) over 5 years, and the lamination of OFETs on the human skin. A single-stage organic complementary inverter and a pseudo-complementary amplifier are fabricated to compare their electrical characteristics, with amplification gains of 10 and 64, respectively. Finally, the study demonstrates a five-stage organic complementary inverter can successfully amplify artificial electromyogram and electrocardiogram signals with gains of 1000 and 1088, respectively.

Abstract While photosynthesis transforms sunlight energy into sugar, aerobic and anaerobic respiration (fermentation) catabolizes sugars to fuel cellular activities. These processes take place within one cell across several compartments, however it remains largely unexplored how they interact with one another. Here we report that the weak acids produced during fermentation down-regulate both photosynthesis and aerobic respiration. This effect is mechanistically explained with an “ion trapping” model, in which the lipid bilayer selectively traps protons that effectively acidify subcellular compartments with smaller buffer capacities – such as the thylakoid lumen. Physiologically, we propose that under certain conditions, e.g., dim light at dawn, tuning down the photosynthetic light reaction could mitigate the pressure on its electron transport chains, while suppression of respiration could accelerate the net oxygen evolution, thus speeding up the recovery from hypoxia. Since we show that this effect is conserved across photosynthetic phyla, these results indicate that fermentation metabolites exert widespread feedback control over photosynthesis and aerobic respiration. This likely allows algae to better cope with changing environmental conditions.

The swift integration of ‘Gummetal’ into the orthodontic armamentarium can be attributed to its distinct advantages as an entirely new Ti-Nb-based beta titanium alloy. Developed by Toyota Central R&D Labs and publicly revealed in April 2003, this innovative material is rapidly reshaping orthodontic practices. Its sui generis properties allow its use as a potential substitute for the Multi-Loop Edgewise Archwire (MEAW) method. Three-dimensional orthodontic movement using this new alloy could eliminate the disadvantages of the MEAW method, such as its technical complexity and patient discomfort. In our comprehensive review of the current literature, we examined relevant publications sourced from the PUBMED database and explored one seminal work on Gummetal from the journal literature. Characteristic properties of Gummetal, such as its exceptional flexibility, superelasticity, and malleability (approximately 10 times greater than conventional metals), enable seamless formation of bends without posing challenges, thereby allowing precise control over orthodontic force application. Also worthy of mention are Gummetal’s biocompatibility and non-toxic properties, along with its low coefficient of friction. The wire seems to be a relatively easy way to achieve good occlusion. Its usage does not require extensive experience in terms of manual skill, and it is not time consuming. Diligent usage of any prescribed plastics by the patient is crucial to prevent complications and ensure successful orthodontic outcomes.

Luminescent lanthanides possess ideal properties for biological imaging, including long luminescent lifetimes and emission within the optical window. Here, we report a novel approach to responsive luminescent Tb(iii) probes that involves direct modulation of the antenna excited triplet state energy. If the triplet energy lies too close to the 5D4 Tb(iii) excited state (20 500 cm-1), energy transfer to 5D4 competes with back energy transfer processes and limits lanthanide-based emission. To validate this approach, a series of pyridyl-functionalized, macrocyclic lanthanide complexes were designed, and the corresponding lowest energy triplet states were calculated using density functional theory (DFT). Subsequently, three novel constructs L3 (nitro-pyridyl), L4 (amino-pyridyl) and L5 (fluoro-pyridyl) were synthesized. Photophysical characterization of the corresponding Gd(iii) complexes revealed antenna triplet energies between 25 800 and 30 400 cm-1 and a 500-fold increase in quantum yield upon conversion of Tb(L3) to Tb(L4) using the biologically relevant analyte H2S. The corresponding turn-on reaction can be monitored using conventional, small-animal optical imaging equipment in presence of a Cherenkov radiation emitting isotope as an in situ excitation source, demonstrating that antenna triplet state energy modulation represents a viable approach to biocompatible, Tb-based optical turn-on probes.

Abstract Arginyl-tRNA-protein transferase 1 (ATE1) is a master regulator of protein homeostasis, stress response, cytoskeleton maintenance, and cell migration. The diverse functions of ATE1 arise from its unique enzymatic activity to covalently attach an arginine onto its protein substrates in a tRNA-dependent manner. However, how ATE1 (and other aminoacyl-tRNA transferases) hijacks tRNA from the highly efficient ribosomal protein synthesis pathways and catalyzes the arginylation reaction remains a mystery. Here, we describe the three-dimensional structures of Saccharomyces cerevisiae ATE1 with and without its tRNA cofactor. Importantly, the putative substrate binding domain of ATE1 adopts a previously uncharacterized fold that contains an atypical zinc-binding site critical for ATE1 stability and function. The unique recognition of tRNAArg by ATE1 is coordinated through interactions with the major groove of the acceptor arm of tRNA. Binding of tRNA induces conformational changes in ATE1 that helps explain the mechanism of substrate arginylation.

Abstract Since the 1970s, waterfowl hunting participation has declined in the United States, which has resulted in socioeconomic consequences for waterfowl conservation and management. Attempts to increase the waterfowl hunter population have been difficult, partly due to social factors (e.g., constraints, motivations, demographics) influencing who participates, frequency of participation, and diversity of desired outcomes from hunting experiences. We examined the preferences of 10 potential management options by hunters and anglers from several states in the central U.S. during 2018. Respondents were grouped into the following activity groups based on responses to survey questions: frequent waterfowl hunters, sporadic waterfowl hunters, previous waterfowl hunters, hunters (never hunted waterfowl), and nonhunters (anglers who have never hunted). All ordinal models indicated that the ability of the scenario to increase participation significantly (P 0.35 for all activity groups) and Special areas for new waterfowl hunters, had the greatest indication (probability > 0.40) of increased waterfowl hunting participation across activity groups. Frequent and sporadic waterfowl hunters ranked Special areas to allow for a quality hunt highest, while hunters and non‐hunters ranked Someone to take me hunting as the most preferred scenario. Information for what new/inexperienced hunters need, Classes or materials to teach waterfowl ID, and Ability to rent equipment were scenarios consistently ranked as the lowest for all activity groups. Our research underscores that only some of the scenarios had the same appeal to all activity groups, which implies a need for a greater diversity of experiences in the landscape of public waterfowl hunting access. Also, continued promotion of current waterfowl hunters taking new or inexperienced individuals may increase waterfowl hunting participation.