Obrienjochumsen8458

Histone Deacetylase 2 Suppresses Skeletal Muscle Wither up as well as Senescence by way of NF-κB Signaling Walkway inside Cigarette Smoke-Induced Rats along with Emphysema.

Inbuilt Lymphoid Tissue Initial and also Transcriptomic Modifications in Reaction to Human being Dengue An infection.

However, increased awareness of the implicit and explicit learning systems and their cognitive demands will allow clinicians to choose the most appropriate intervention for the target behavior.

Many intervention characteristics (e.g., instructions, elicitation techniques, feedback) can be manipulated to move an intervention along the implicit-explicit continuum. Given the bias for using explicit learning strategies that develops throughout childhood and into adulthood, clinicians should be aware that most interventions (even those that promote implicit learning) will engage the explicit learning system. However, increased awareness of the implicit and explicit learning systems and their cognitive demands will allow clinicians to choose the most appropriate intervention for the target behavior.

Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer.

In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 11 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided

≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2

0.2 to ≤ 4

> 4 ng/mL), and adverse event profile.

Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm ase with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.Building and changing a microbiome at will and maintaining it over hundreds of generations has so far proven challenging. Despite best efforts, complex microbiomes appear to be susceptible to large stochastic fluctuations. Current capabilities to assemble and control stable complex microbiomes are limited. Here, we propose a looped mass transfer design that stabilizes microbiomes over long periods of time. Five local microbiomes were continuously grown in parallel for over 114 generations and connected by a loop to a regional pool. Mass transfer rates were altered and microbiome dynamics were monitored using quantitative high-throughput flow cytometry and taxonomic sequencing of whole communities and sorted subcommunities. Increased mass transfer rates reduced local and temporal variation in microbiome assembly, did not affect functions, and overcame stochasticity, with all microbiomes exhibiting high constancy and increasing resistance. Mass transfer synchronized the structures of the five local microbiomes and nestedness of certain cell types was eminent. Mass transfer increased cell number and thus decreased net growth rates μ′. Subsets of cells that did not show net growth μ′SCx were rescued by the regional pool R and thus remained part of the microbiome. The loop in mass transfer ensured the survival of cells that would otherwise go extinct, even if they did not grow in all local microbiomes or grew more slowly than the actual dilution rate D would allow. The rescue effect, known from metacommunity theory, was the main stabilizing mechanism leading to synchrony and survival of subcommunities, despite differences in cell physiological properties, including growth rates.CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.Lysosomes are the digestive center of the cell and play important roles in human diseases, including cancer. Previous work has suggested that late endosomes, also known as multivesicular bodies (MVBs), and lysosomes are essential for canonical Wnt pathway signaling. Sequestration of Glycogen Synthase 3 (GSK3) and of β‐catenin destruction complex components in MVBs is required for sustained canonical Wnt signaling. Little is known about the role of lysosomes during early development. In the Xenopus egg, a Wnt-like cytoplasmic determinant signal initiates formation of the body axis following a cortical rotation triggered by sperm entry. Here we report that cathepsin D was activated in lysosomes specifically on the dorsal marginal zone of the embryo at the 64-cell stage, long before zygotic transcription starts. Expansion of the MVB compartment with low-dose hydroxychloroquine (HCQ) greatly potentiated the dorsalizing effects of the Wnt agonist lithium chloride (LiCl) in embryos, and this effect required macropinocytosis. Formation of the dorsal axis required lysosomes, as indicated by brief treatments with the vacuolar ATPase (V-ATPase) inhibitors Bafilomycin A1 or Concanamycin A at the 32-cell stage. Inhibiting the MVB-forming machinery with a dominant-negative point mutation in Vacuolar Protein Sorting 4 (Vps4-EQ) interfered with the endogenous dorsal axis. The Wnt-like activity of the dorsal cytoplasmic determinant Huluwa (Hwa), and that of microinjected xWnt8 messenger RNA, also required lysosome acidification and the MVB-forming machinery. We conclude that lysosome function is required for early dorsal axis development in Xenopus. The results highlight the intertwining between membrane trafficking, lysosomes, and vertebrate axis formation.Circadian pacemaker neurons in the Drosophila brain display daily rhythms in the levels of intracellular calcium. These calcium rhythms are driven by molecular clocks and are required for normal circadian behavior. To study their biological basis, we employed genetic manipulations in conjunction with improved methods of in vivo light-sheet microscopy to measure calcium dynamics in individual pacemaker neurons over complete 24-h durations at sampling frequencies as high as 5 Hz. This technological advance unexpectedly revealed cophasic daily rhythms in basal calcium levels and in high-frequency calcium fluctuations. Further, we found that the rhythms of basal calcium levels and of fast calcium fluctuations reflect the activities of two proteins that mediate distinct forms of calcium fluxes. link= selleck One is the inositol trisphosphate receptor (ITPR), a channel that mediates calcium fluxes from internal endoplasmic reticulum calcium stores, and the other is a T-type voltage-gated calcium channel, which mediates extracellular calcium influx. These results suggest that Drosophila molecular clocks regulate ITPR and T-type channels to generate two distinct but coupled rhythms in basal calcium and in fast calcium fluctuations. We propose that both internal and external calcium fluxes are essential for circadian pacemaker neurons to provide rhythmic outputs and thereby, regulate the activities of downstream brain centers.The diversity of human faces and the contexts in which they appear gives rise to an expansive stimulus space over which people infer psychological traits (e.g., trustworthiness or alertness) and other attributes (e.g., age or adiposity). Machine learning methods, in particular deep neural networks, provide expressive feature representations of face stimuli, but the correspondence between these representations and various human attribute inferences is difficult to determine because the former are high-dimensional vectors produced via black-box optimization algorithms. Here we combine deep generative image models with over 1 million judgments to model inferences of more than 30 attributes over a comprehensive latent face space. The predictive accuracy of our model approaches human interrater reliability, which simulations suggest would not have been possible with fewer faces, fewer judgments, or lower-dimensional feature representations. Our model can be used to predict and manipulate inferences with respect to arbitrary face photographs or to generate synthetic photorealistic face stimuli that evoke impressions tuned along the modeled attributes.The common handsaw can be converted into a bowed musical instrument capable of producing exquisitely sustained notes when its blade is appropriately bent. Acoustic modes localized at an inflection point are known to underlie the saw’s sonorous quality, yet the origin of localization has remained mysterious. selleck Here we uncover a topological basis for the existence of localized modes that relies on and is protected by spatial curvature. By combining experimental demonstrations, theory, and computation, we show how spatial variations in blade curvature control the localization of these trapped states, allowing the saw to function as a geometrically tunable high-quality oscillator. Our work establishes an unexpected connection between the dynamics of thin shells and topological insulators and offers a robust principle to design high-quality resonators across scales, from macroscopic instruments to nanoscale devices, simply through geometry.In the Nandi society in Kenya, custom establishes that a woman’s “house property” can only be transmitted to male heirs. As not every woman gives birth to a male heir, the Nandi solution to sustain the family lineage is for the heirless woman to become the “female husband” to a younger woman by undergoing an “inversion” ceremony to “change” into a man. This biological female, now socially a man, becomes a “husband” and a “father” to the younger woman’s children, whose sons become the heirs of her property. Using this unique separation of biological sex and social roles holding constant the same society, I conduct competitiveness experiments. Similar to Western cultures, I find that Nandi men choose to compete at roughly twice the rate as Nandi women. Importantly, however, female husbands compete at the same rate as males, and thus around twice as often as females. These findings are robust to controlling for several risk aversion, selection, and behavioral factors. The results provide support for the argument that social norms, family roles, and endogenous preference formation are crucially linked to differences in competitiveness between men and women.Nonenzymatic template-directed RNA copying using chemically activated nucleotides is thought to have played a key role in the emergence of genetic information on the early Earth. A longstanding question concerns the number and nature of different environments that might have been necessary to enable all of the steps from nucleotide synthesis to RNA copying. Here we explore three sequential steps from this overall pathway nucleotide activation, synthesis of imidazolium-bridged dinucleotides, and template-directed RNA copying. We find that all three steps can take place in one reaction mixture undergoing multiple freeze-thaw cycles. Recent experiments have demonstrated a potentially prebiotic methyl isocyanide-based nucleotide activation chemistry. However, the original version of this approach is incompatible with nonenzymatic RNA copying because the high required concentration of the imidazole activating group prevents the accumulation of the essential imidazolium-bridged dinucleotide. Here we report that ice eutectic phase conditions facilitate not only the methyl isocyanide-based activation of ribonucleotide 5′-monophosphates with stoichiometric 2-aminoimidazole, but also the subsequent conversion of these activated mononucleotides into imidazolium-bridged dinucleotides. Furthermore, this one-pot approach is compatible with template-directed RNA copying in the same reaction mixture. Our results suggest that the simple and common environmental fluctuation of freeze-thaw cycles could have played an important role in prebiotic nucleotide activation and nonenzymatic RNA copying.Objectives. To assess linkages of patient data from a health care system in the southeastern United States to microdata from the American Community Survey (ACS) with the goal of better understanding health disparities and social determinants of health in the population. Methods. Once a data use agreement was in place, a stratified random sample of approximately 200 000 was drawn of patients aged 25 to 74 years with at least 2 visits between January 1, 2016, and December 31, 2019. Information from the sampled electronic health records (EHRs) was transferred securely to the Census Bureau, put through the Census Person Identification Validation System to assign Protected Identification Keys (PIKs) as unique identifiers wherever possible. EHRs with PIKs assigned were then linked to 2001-2017 ACS records with a PIK. Results. PIKs were assigned to 94% of the sampled patients. Of patients with PIKs, 15.5% matched to persons sampled in the ACS. Conclusions. Linking data from EHRs to ACS records is feasible and, with adjustments for differential coverage, will advance understanding of social determinants and enhance the ability of integrated delivery systems to reflect and affect the health of the populations served. (Am J Public Health. 2022;112(6)923-930. https//doi.org/10.2105/AJPH.2022.306783).In May 2020, Baltimore City, Maryland, implemented the Lord Baltimore Triage, Respite, and Isolation Center (LBTC), a multiagency COVID-19 isolation and quarantine site tailored for people experiencing homelessness. In the first year, 2020 individuals were served, 78% completed isolation at LBTC, and 6% were transferred to a hospital. Successful isolation can mitigate outbreaks in shelters and residential recovery programs, and planning for sustainable isolation services integrated within these settings is critical as the COVID-19 pandemic continues. (Am J Public Health. link2 2022;112(6)876-880. https//doi.org/10.2105/AJPH.2022.306778).Between 2015 and 2018, we provided training for 1806 municipal police officers in Tijuana, Mexico, in an effort to improve their knowledge and behaviors related to HIV and injection drug use. Correct knowledge of syringe possession laws improved from 56% before training to 94% after training and was sustained at 24 months (75%). Knowledge improvement was associated with decreases in arrests for syringe possession over time (adjusted odds ratio [AOR] = 0.87; 95% confidence interval [CI] = 0.85, 0.90). Officers with correct knowledge had significantly lower odds of reporting arrests (AOR = 0.63; 95% CI = 0.44, 0.89). Training was associated with sustained improvements in knowledge and practices that advance public health. (Am J Public Health. 2022;112(6)860-864. https//doi.org/10.2105/AJPH.2021.306702).There is a positive association between cardiorespiratory fitness and cognitive health, but the interaction between cardiorespiratory fitness and aging on cerebral hemodynamics is unclear. These potential interactions are further influenced by sex differences. The purpose of this study was to determine the sex-specific relationships between cardiorespiratory fitness, age, and cerebral hemodynamics in humans. Measurements of unilateral middle cerebral artery blood velocity (MCAv) and cerebral pulsatility index obtained using transcranial Doppler ultrasound and cardiorespiratory fitness [maximal oxygen consumption (V̇o2max)] obtained from maximal incremental exercise tests were retrieved from study records at three institutions. A total of 153 healthy participants were included in the analysis (age = 42 ± 20 yr, range = 18-83 yr). There was no association between V̇o2max and MCAv in all participants (P = 0.20). The association between V̇o2max and MCAv was positive in women, but no longer significant after age awomen, but not in men. Furthermore, cardiorespiratory fitness was inversely associated with cerebral pulsatility index in both men and women, which remained significant in women when adjusting for age. These data suggest a sex-specific impact of cardiorespiratory fitness on resting cerebral hemodynamics.Aerobic exercise is an increasing trend worldwide. However, people are increasingly exercising outdoors, alongside roadways where heavy vehicles release diesel exhaust. We analyzed respiratory effects caused by inhaled diesel particulate emitted by vehicles adhering to Brazilian legislation, PROCONVE Phase P7 (equivalent to EURO 5), as well the effects of exposure during moderate-intensity aerobic exercise. Male C57BL/6 mice were divided into four groups for a 4-wk treadmill protocol CE (n = 8) received intranasal sterile physiological saline and then performed moderate-intensity exercise (control), CS (n = 10) received saline and then remained stationary on the treadmill (control), DS (n = 9) received intranasal diesel exhaust particles and then remained stationary, and DE (n = 10) was exposed to diesel exhaust and then exercised at moderate intensity. Mice were subsequently connected to a mechanical ventilator (SCIREQ flexiVent, Canada) to analyze the following respiratory mechanics parameters tissue resistwe show this effect using mice exposed to controlled diesel particle inhalation and moderate aerobic exercise. Diesel particle inhalation, without or with exercise, worsened both respiratory mechanical properties associated with changes in lung tissue mechanics and morphometry.Multiple breath washout (MBW) testing is increasingly used as a physiological measurement in the clinic, due in part to the availability of commercial equipment and reference values for MBW indices. Commercial N2 washout devices are usually based on indirect measurement of N2 concentration (CN2), by directly measuring either molar mass and O2 and CO2, or molar mass and CO2. We aim to elucidate the role of two potential pitfalls associated with N2-MBW testing that could override its physiological content indirect N2 measurement and blood-solubility of N2. We performed MBW in 12 healthy adult subjects using a commercial device (MBWindirect) with simultaneous direct gas concentration measurements by mass spectrometry (MBWdirect) and compared CN2 between MBWdirect and MBWindirect. We also measured argon concentration during the same washouts to verify the maximal effect gas solubility can have on N2-based functional residual capacity (FRC) and lung clearance index (LCI). Continuous N2 concentration traces were very similar for MBWindirect and MBWdirect, resulting in comparable breath-by-breath washout plots of expired concentration and in no significant differences in FRCN2, LCIN2, Scond, and Sacin between the two methods. Argon washouts were slightly slower than N2 washouts, as expected for a less diffusive and more soluble gas. Finally, comparison between LCIN2 and LCIAr indicates that the maximum impact from blood-tissue represents less than half a LCI unit in normal subjects. In conclusion, we have demonstrated by direct measurement of N2 and twice as soluble argon, that indirect N2 measurement can be safely used as a meaningful physiological measurement.NEW & NOTEWORTHY The physiological content of N2 multibreath washout testing has been questioned due to N2 indirect measurement accuracy and N2 blood solubility. With direct measurement of N2 and twice as soluble argon, we show that these effects are largely outweighed by ease of use.We examined the effects of carbohydrate (CHO) delivery form on exogenous CHO oxidation, gastrointestinal discomfort, and exercise capacity. In a randomized repeated-measures design [after 24 h of high CHO intake (8 g·kg-1) and preexercise meal (2 g·kg-1)], nine trained males ingested 120 g CHO·h-1 from fluid (DRINK), semisolid gel (GEL), solid jelly chew (CHEW), or a coingestion approach (MIX). Participants cycled for 180 min at 95% lactate threshold, followed by an exercise capacity test (150% lactate threshold). Peak rates of exogenous CHO oxidation (DRINK 1.56 ± 0.16, GEL 1.58 ± 0.13, CHEW 1.59 ± 0.08, MIX 1.66 ± 0.02 g·min-1) and oxidation efficiency (DRINK 72 ± 8%, GEL 72 ± 5%, CHEW 75 ± 5%, MIX, 75 ± 6%) were not different between trials (all P > 0.05). Despite ingesting 120 g·h-1, participants reported minimal symptoms of gastrointestinal distress across all trials. Exercise capacity was also not significantly different (all P > 0.05) between conditions (DRINK 446 ± 350, GEL 529 ± 396, CHEW 596 ± 416, e CHO forms) typically reported by endurance athletes.Flipped teaching (FT) is a student-centered instructional method that shifts lectures out of the classroom and uses a variety of activities to apply content during class time. FT has gained attention among educators as a student-centered instructional method. However, many faculty still lack the skills, knowledge, confidence, and expertise to implement FT in their classrooms. Therefore, course-specific training and focused mentorship are critical in successfully implementing FT. Four faculty members, from an adjunct professor to a full professor, from four diverse institutions around the country, were recruited and funded through the American Physiological Society's Teaching Career Enhancement Award to receive training in the implementation of FT in their courses. This study aimed to provide specific tools and strategies to engage students in deeper learning through activities in the participants' courses. selleck A course was built using the Blackboard Learning Management System for the participants to receive relevant readings to be completed prior to the FT workshop. Upon completing this training, the participants examined the design and execution of FT in their classrooms and, subsequently, reflected on and refined their future course offerings. The facilitator mentored the participants throughout the process, including an on-site observation of a live FT session. Both qualitative and quantitative data were collected before and after their FT experiences. Based on the survey results, this study helped improve the FT knowledge and self-efficacy of all participants. In conclusion, the faculty utilized the training and mentoring to implement FT in their classrooms successfully and disseminate their experiences and findings.Anecdotal data suggest great variation in breadth and depth of skeletal muscle coverage between undergraduate human anatomy (HA) and anatomy and physiology (A&P) courses. This manuscript is the second in a series (Reynolds A, Goodwin M, O'Loughlin VD. Adv Physiol Educ 46 309-318, 2022. doihttps//doi.org/10.1152/advan.00084.2021) that methodically assesses skeletal muscle content coverage across undergraduate HA and A&P courses. The authors developed an online skeletal muscle coverage survey and collected 342 responses worldwide, 156 from instructors of HA courses and 186 from A&P course instructors. Demographic results showed that HA courses are primarily taught at 4-year baccalaureate institutions, have relatively larger class sizes, and are more likely to use human (vs. animal) prosections or dissections. In contrast, A&P courses are primarily taught at community colleges, have relatively smaller class sizes, and are more likely to use animal (vs. human) dissections. HA courses tend to require their students to learn all skeletal muscle aspects (i.e., identification, action, attachments, innervation), whereas A&P courses tend to focus on muscle identification or action only. The proportions of courses that require identification of large, superficial skeletal muscles are similar between the two course types. However, HA courses are more likely to require their students to identify deeper and smaller muscles, including more distal appendicular muscles and pelvic muscles. These differences likely are due, in part, to the more anatomical focus of HA courses and the slightly different student populations between these courses. These findings provide much-needed information about muscular system coverage between HA and A&P courses and may guide instructor discussions about curricula.Substitution reactions of acyclic β-alkoxy acetals proceeded with generally high diastereoselectivities (>9010) to form the anti product. Mechanistic experiments supplemented with computational studies suggest that, upon activation of the acetal, the resulting oxocarbenium ion is electrostatically stabilized by the β-alkoxy group. This stabilization defines the conformation of the reactive intermediate, which can be attacked preferentially from the more exposed face, leading to the observed products.Minisci-type reaction is one of the important means to construct C(sp3)-H functionalization of heteroarenes. According to traditional methods, stoichiometric amounts of precious transition metal catalysts and chemical oxidants were required at high temperatures. Here, a green and gentle novel Minisci-type method was developed via visible-light-induced cross-dehydrogenative coupling of heteroarenes with aliphatic C(sp3)-H bonds under oxidant-free and transition-metal-catalyst-free conditions. Only the catalytic equivalent of CF3SO2Na and room temperature were required to maintain an efficient reaction.Photocages can provide spatial and temporal control to accurately release the various chemicals and bioactive groups when excited by light. Although the absorption spectra of most photocages are in the ultraviolet absorption region, only a few absorb in the visible or near-infrared region. Blebbistatin (Bleb) would release a hydroxyl radical under blue one-photon or two-photon near-infrared light (800 nm) irradiation. In this work, typical chlorine and bromine as leaving groups substituted hydroxyl compounds (Bleb-Cl, Bleb-Br) are synthesized to evaluate the photocage's capability of Bleb's platform. Driven by the excited-state charge transfer, Bleb-Cl and Bleb-Br show good photolysis quantum yield to uncage the halogen anion and the uncaging process would be accelerated in water solution. The photochemical reaction, final product's analysis, and femtosecond transient absorption studies on Bleb-Cl/Bleb-Br demonstrate that Bleb can act as a photocage platform to release the halogen ion via heterolytic reaction when irradiated by blue or near-infrared light. Therefore, Bleb can be a new generation of visible or near-infrared light-triggered photocage.The uptake of molecules on nanometer-size clusters of polyaromatic hydrocarbons (PAHs) is important for the condensation of water on PAH aerosols in the atmosphere and for ice mantle growth on nanoparticles in the interstellar medium. We generate benzene clusters BzN of mean size N̅ ≈ 300 (radius R̅ ≈ 2.2 Å) as a model system for the PAH nanoparticles. link2 Using molecular beams and mass spectrometry detection, we investigate the uptake of water, methanol, and ethanol by these clusters. All picked up molecules are highly mobile on BzN and generate clusters within less then 3 ms. The relative uptakes for the different investigated molecules can be directly compared and quantified. Water molecules exhibit the lowest relative pickup probability that is ∼30% lower than those for methanol and ethanol, which are approximately the same.Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFRT790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively, which is 10-20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance in NSCLC patients.Non-platinum-metal complexes show great potential as anticancer agents. Herein, a series of dithiocarbazate non-Pt-metal complexes, including [FeIII(L)2]·Cl·2H2O 1, [CoIII(L)2]·NO3·2.5H2O 2, [NiII(L)2] 3, and [ZnII(L)2] 4, have been designed and evaluated for their efficacy as antineoplastic agents. Among them, complex 2 exhibited higher anticancer efficacy than complexes 1, 3, 4, and cisplatin against several cancer cell lines. Hemolysis assays revealed that complex 2 showed comparable hemolysis with cisplatin. In vivo anticancer evaluations showed that complex 2 could retard tumor xenograft growth effectively with low systemic toxicity. Further studies revealed that complex 2 suppressed cancer cells by triggering multiple mechanisms involving the simultaneous inhibition of mitochondria and glycolytic bioenergetics. Overall, our study provides new insights into the anticancer mechanism of Co complexes, which can be used as a good strategy to overcome the flexibility of cancer cells to chemotherapy adaptation.The first total syntheses of two 4,10-dihydroxy-8,12-guaianolides that were reported to be natural products were achieved. Toward the syntheses of a collection of related guaianolides, the typical 5,7-fused system of 8,12-guaianolides was constructed by a ring expansion reaction of a hydroxylated coronafacic acid analogue that can be practically synthesized and optically resolved. The total syntheses of these compounds revealed that the previously reported structures of both natural products were incorrect.Frost is common when a solid surface is subjected to a humid and cold environment. It can cause various inconveniences, complications, or fatal accidents. Water-repellent surfaces have demonstrated an antifreezing capability by enabling the water droplets to roll or bounce off before they freeze. However, these surfaces are often limited by their inability to shed the small water condensates, which can eventually grow and freeze. Recently, surfaces that can rapidly absorb and hydrogen bond with these water condensates have demonstrated significant delay in frost formation and growth. This is attributed to a lower freezing temperature of the absorbed water which makes it stay in a nonfreezing state. Herein, we report a surface with preferential wettability of water over oil (i.e., superhydrophilic and oleophobic wettability) that can significantly delay frost formation. The surface is fabricated by copolymerizing poly(ethylene glycol) diacrylate (PEGDA) and perfluorinated acrylate (1H,1H,2H,2H-heptadecafluorodecyl acrylate, HDF-acrylate) applied to a silane-grafted glass substrate (HDF-PEGDA). An HDF-PEGDA surface can quickly absorb condensed water which enables it to delay frost formation and growth for up to 20 min at a surface temperature of -35 °C. Also, the surface demonstrates that its frost-resistant capability remains almost unaffected even after being submerged in an oil bath due to its in-air oil repellency. Differential scanning calorimetry (DSC) measurements reveal that the significant quantity of absorbed water in an HDF-PEGDA surface remains in a nonfreezing state with a Tm value as low as -33 °C. A mathematical model that can predict the time at which the surface begins to be covered with frost is developed. Finally, an HDF-PEGDA is layered with a PEGDA copolymerized with sodium acrylate (Na-acrylate) that enables the continuous release of the absorbed water by posing forward osmotic pressure and regeneration of an HDF-PEGDA surface.Carcinogenic N-nitrosamines were recently found in the sartan family of drugs and caused many drug recalls. link3 Both of their detection and quantification are therefore important. Methods reported for N-nitrosamine quantitation rely on the use of standards and are just applicable to simple N-nitrosamines. There is an urgent need to quantify N-nitrosamines derived from drugs with a complicated structure that lack standards. To tackle the issue, this study describes a novel absolute quantitation strategy for N-nitrosamines using coulometric mass spectrometry (CMS) without standards. In our approach, N-nitrosamine is first converted into electrochemically active hydrazine via zinc reduction under acidic condition and the resulting hydrazine can then be easily quantified using CMS. To validate our method, six simple N-nitrosamines, N-nitrosodiethylamine (NDEA), N-nitroso-4-phenylpiperidine (NPhPIP), N-nitrosodiphenylamine (NDPhA), N-nitrosodibutylamine (NDBA), N-nitrosodipropylamine (NDPA), and N-nitrosopiperidine (NPIP), were chosen as test samples, and they all were quantified with excellent measurement accuracy (quantitation error ≤1.1%). Taking this one step further, as a demonstration of the method utility, a drug-like N-nitrosamine, (R)-N-(2-(6-chloro-5-methyl-1'-nitroso-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)propan-2-yl)acetamide (VII), was also synthesized and successfully quantified using our method at 15 ppb level in a complex formulation matrix, following solvent extraction, N-nitrosamine isolation, and reductive conversion. Because of the feature of requiring no standards, CMS provides a simple and powerful approach for N-nitrosamine absolute quantitation and has great potential for analysis of other drug impurities or metabolites.In orthopedics, developing functionalized biomaterials to enhance osteogenesis and bacterial resistance is crucial. Although poly(ether ether ketone) (PEEK) is regarded as an important engineering plastic for biomedical material with excellent mechanical properties and biocompatibility, its biological inertness has greatly compromised its application in biomedical engineering. Inspired by the catecholamine chemistry of mussels, we propose a universal and versatile approach for enhancing the osteogenesis and antibacterial performances of PEEK based on surface functionalization of polydopamine-modified nanohydroxyapatite and lysozyme simultaneously. The characterizations of surface morphology and elemental composition revealed that the composite coating was successfully added to the PEEK surface. Additionally, the in vitro cell experiment and biomineralization assay indicated that the composite coating-modified PEEK was biocompatible with significantly improved bioactivity to promote osteogenesis and biomineralization compared with the untreated PEEK. Furthermore, the antibacterial test demonstrated that the composite coating had a strongly destructive effect on two bacteria (Staphylococcus aureus and Escherichia coli) with antibacterial ratios of 98.7% and 96.1%, respectively. In summary, the bioinspired method for surface functionalization can enhance the osteogenesis and bacterial resistance of biomedical materials, which may represent a potential approach for designing functionalized implants in orthopedics.All contemporary oxygenic phototrophs─from primitive cyanobacteria to complex multicellular plants─split water using a single invariant cluster comprising Mn4CaO5 (the water oxidation catalyst) as the catalyst within photosystem II, the universal oxygenic reaction center of natural photosynthesis. This cluster is unstable outside of PSII and can be reconstituted, both in vivo and in vitro, using elemental aqueous ions and light, via photoassembly. Here, we demonstrate the first functional substitution of manganese in any oxygenic reaction center by in vitro photoassembly. Following complete removal of inorganic cofactors from cyanobacterial photosystem II microcrystal (PSIIX), photoassembly with free cobalt (Co2+), calcium (Ca2+), and water (OH-) restores O2 evolution activity. Photoassembly occurs at least threefold faster using Co2+ versus Mn2+ due to a higher quantum yield for PSIIX-mediated charge separation (P*) Co2+ → P* → Co3+QA-. However, this kinetic preference for Co2+ over native Mn2+ during photoae needed for further interpretation.The increasing world population, impact of food production on climate change, and ongoing issues with diet-related diseases (e.g., malnutrition and obesity) are global major challenges. Recent advances in how food structure impacts the extent and kinetics of uptake of nutrients and its consequent effects on the physiological outcomes are beginning to shift our understanding of nutrition. This understanding is important to designing future foods that provide optimum nutrient bioavailability and deliver healthy outcomes. We discuss perspectives and scientific challenges in understanding the complex relationship between food structure/matrix modification during the digestion process and the absorption of nutrients as well as designing food structures with more sustainable materials.With extremely high extinction coefficients and other unique optical properties, gold nanoparticles (AuNPs) have received growing interest in developing biosensors. DNA hairpin structures are very popular probes for the detection of not only complementary DNA or RNA but also aptamer targets. This work aims to understand the effect of the structure and sequence of hairpin DNA for the stabilization of AuNPs and its implications in AuNP-based label-free colorimetric biosensors. A series of hairpin DNA with various loop sizes from 4 to 26 bases and sequences (random sequences, poly-A and poly-T) were tested, but they showed similar abilities to protect AuNPs from aggregation. Using hairpin DNA with a tail under the same conditions, optimal protection was achieved with a six-base or longer tail. DNA hairpins are likely adsorbed via their tail regions or with their terminal bases if no tail is present. Molecular dynamics simulations showed that the rigidity of the hairpin loop region disfavored its adsorption to AuNPs, while the flexible tail region is favored. Finally, a DNA sensing assay was conducted using different structured DNA, where hairpin DNA with a tail doubled the sensitivity compared to the tail-free hairpin.Maintaining high sensitivity while limiting false positives is a key challenge in peptide identification from mass spectrometry data. link3 Here, we investigate the effects of integrating the machine learning-based postprocessor Percolator into our spectral library searching tool COSS (CompOmics Spectral library Searching tool). To evaluate the effects of this postprocessing, we have used 40 data sets from 2 different projects and have searched these against the NIST and MassIVE spectral libraries. The searching is carried out using 2 spectral library search tools, COSS and MSPepSearch with and without Percolator postprocessing, and using sequence database search engine MS-GF+ as a baseline comparator. The addition of the Percolator rescoring step to COSS is effective and results in a substantial improvement in sensitivity and specificity of the identifications. COSS is freely available as open source under the permissive Apache2 license, and binaries and source code are found at https//github.com/compomics/COSS.Only a few dozens of the several thousand existing per- and polyfluoroalkyl substances (PFAS) are monitored using conventional target analysis. This study employed suspect screening to examine patterns of emerging and novel PFAS in German and Chinese river water affected by industrial point sources. In total, 86 PFAS were (tentatively) identified and grouped into 18 structure categories. Homologue patterns revealed distinct differences between fluoropolymer production sites of the two countries. In the Chinese Xiaoqing River Basin, the C8 homologue was the most prevalent compound of the emerging series of chlorinated perfluoroalkyl carboxylic acids (Cl-PFCAs) and perfluoroalkylether carboxylic acids (PFECAs). In contrast, C6 and shorter homologues were dominant in the German Alz River. This indicates that the phaseout of long-chain compounds in Europe and their ongoing production in Asian countries also apply to unregulated emerging PFAS classes. Additional characteristics to differentiate the point sources were the peak area ratio of perfluorobutane sulfonic acid (PFBS) versus the emerging compound hydro-substituted PFBS (H-PFBS) as well as the occurrence of byproducts of the sulfonated tetrafluoroethylene-based polymer Nafion. The large number of identified unregulated PFAS underlines the importance of a grouping approach on a regulatory level, whereas the revealed contamination patterns can be used to estimate, prioritize, and minimize contributions of specific sources.Tryptophan synthase (TRPS) is a bifunctional enzyme consisting of α and β-subunits and catalyzes the last two steps of l-tryptophan (L-Trp) biosynthesis, namely, cleavage of 3-indole-d-glycerol-3'-phosphate (IGP) into indole and glyceraldehyde-3-phosphate (G3P) in the α-subunit, and a pyridoxal phosphate (PLP)-dependent reaction of indole and l-serine (L-Ser) to produce L-Trp in the β-subunit. Importantly, the IGP binding at the α-subunit affects the β-subunit conformation and its ligand-binding affinity, which, in turn, enhances the enzymatic reaction at the α-subunit. The intersubunit communications in TRPS have been investigated extensively for decades because of the fundamental and pharmaceutical importance, while it is still difficult to answer how TRPS allostery is regulated at the atomic detail. Here, we investigate the allosteric regulation of TRPS by all-atom classical molecular dynamics (MD) simulations and analyze the potential of mean-force (PMF) along conformational changes of the α- and β-subunits. The present simulation has revealed a widely opened conformation of the β-subunit, which provides a pathway for L-Ser to enter into the β-active site. The IGP binding closes the α-subunit and induces a wide opening of the β-subunit, thereby enhancing the binding affinity of L-Ser to the β-subunit. Structural analyses have identified critical hydrogen bonds (HBs) at the interface of the two subunits (αG181-βS178, αP57-βR175, etc.) and HBs between the β-subunit (βT110 - βH115) and a complex of PLP and L-Ser (an α-aminoacrylate intermediate). The former HBs regulate the allosteric, β-subunit opening, whereas the latter HBs are essential for closing the β-subunit in a later step. The proposed mechanism for how the interdomain communication in TRPS is realized with ligand bindings is consistent with the previous experimental data, giving a general idea to interpret the allosteric regulations in multidomain proteins.Covalent organic frameworks (COFs) are promising hosts in heterogeneous catalysis. Herein, we report a dual metalation strategy in a single two-dimensional-COF TpBpy for performing a variety of C-N cross-coupling reactions. [Ir(ppy)2(CH3CN)2]PF6 [ppy = 2-phenylpyridine], containing two labile CH3CN groups, and NiCl2 are used as iridium and nickel-metal precursors, respectively, for postsynthetic decoration of the TpBpy COF. Moving from the traditional approach, we focus on the COF-backbone host for visible-light-mediated nickel-catalyzed C-N coupling reactions. The controlled metalation and recyclability without deactivation of both catalytic centers are unique with respect to previously reported coupling strategies. We performed various photoluminescence, electrochemical, kinetic, and Hammett correlation studies to understand the salient features of the catalyst and reaction mechanism. Furthermore, theoretical calculations delineated the feasibility of electron transfer from the Ir center to the Ni center inside the confined pore of the TpBpy COF. The dual metal anchoring within the COF backbone prevented nickel-black formation. The developed protocol enables selective and reproducible coupling of a diverse range of amines (aryl, heteroaryl, and alkyl), carbamides, and sulfonamides with electron-rich, neutral, and poor (hetero) aryl iodides up to 94% isolated yield. The reaction can also be performed on a gram scale. Furthermore, to establish the practical implementation of this approach, we have applied the synthetic strategy for the late-stage diversification of the derivatives of ibuprofen, naproxen, gemfibrozil, helional, and amino acids. The methodology could also be applied to synthesize pharmacophore N,5-diphenyloxazol-2-amine and Food and Drug Administration-approved drugs, including flufenamic acid, flibanserin, and tripelennamine.The isomerization of hydrogen cyanide to hydrogen isocyanide on icy grain surfaces is investigated by an accurate composite method (jun-Cheap) rooted in the coupled cluster ansatz and by density functional approaches. After benchmarking density functional predictions of both geometries and reaction energies against jun-Cheap results for the relatively small model system HCN···(H2O)2, the best performing DFT methods are selected. A large cluster containing 20 water molecules is then employed within a QM/QM' approach to include a realistic environment mimicking the surface of icy grains. Our results indicate that four water molecules are directly involved in a proton relay mechanism, which strongly reduces the activation energy with respect to the direct hydrogen transfer occurring in the isolated molecule. Further extension of the size of the cluster up to 192 water molecules in the framework of a three-layer QM/QM'/MM model has a negligible effect on the energy barrier ruling the isomerization. Computation of reaction rates by the transition state theory indicates that on icy surfaces, the isomerization of HNC to HCN could occur quite easily even at low temperatures thanks to the reduced activation energy that can be effectively overcome by tunneling.Previously, we performed nontargeted proteome analysis using dried blood spots (DBSs) that are widely used in newborn screening for the clinical diagnosis of congenital genetic diseases and immunodeficiency. We have developed an efficient and simple pretreatment method for DBSs that can detect more than 1000 proteins. To complement proteins that are difficult to detect via DBS analysis with less invasive alternative body fluids, we conducted this study to investigate the proteins detected from dried saliva spots (DSSs) using single-shot LC-MS/MS, which is practical in clinical settings. We also clarified whether DSSs have the same advantages as DBSs, and we investigated the influence of saliva collection conditions and the storage environment on their protein profile. As a result, we detected approximately 5000 proteins in DSSs and whole saliva, and we concluded that they were sufficient to complement the proteins lacking in the blood analysis. DSSs could be used as an alternative tool to DBSs for detecting the presence of causative proteins.Hybrid lead halides are a diverse family of compounds, of interest for their optoelectronic properties, that vary in the dimensionality and connectivity of their inorganic substructures. The great majority of these compounds are based on lead-centered octahedra, with few examples featuring inorganic architectures containing higher coordination numbers. Here, we report the synthesis and characterization of a pyridinium lead bromide phase that is based on seven-coordinate Pb(II) centers. Through edge- and face-sharing, the polyhedra form a corrugated, two-dimensional inorganic substructure. Electronic structure calculations were used to examine the band structure and the role of the stereoactive lone pair in the inherently asymmetric, seven-coordinate Pb(II) geometry. For reference, we have visualized the role of the lone pair in the binary halide PbBr2, which also has a seven-coordinate inner ligand sphere. A comparison of the new structure with the limited number of existing hybrid lead halides with similar inorganic architectures highlights the templating role of the organic cation for these compounds. We also contribute characterization and discussion of isomorphic pyridinium lead chloride, which had been deposited in the Cambridge Structural Database but never, to our knowledge, addressed in the literature. The compounds were synthesized using solution conditions and structures determined with single-crystal X-ray diffraction. The materials were also characterized via powder X-ray diffraction, combustion elemental analysis, and diffuse reflectance UV-vis spectroscopy. While the structures reported here are centrosymmetric, the seven-coordinate, capped trigonal prismatic geometry that we have identified is a source of local asymmetry that could be used as a component in designing globally noncentrosymmetric structures.Metal-organic cages are a class of supramolecular structures that often require the careful selection of organic linkers and metal nodes. Of this class, few examples of metal-organic cages exist where the nodes are composed of main group metals. Herein, we have prepared an aluminum-based metal-organic cage, H8[Al8(pdc)8(OAc)8O4] (Al-pdc-AA), using inexpensive and commercially available materials. The cage formation was achieved via solvothermal self-assembly of solvated aluminum and pyridine-dicarboxylic linkers in the presence of a capping agent, acetic acid. The obtained supramolecular structure was characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis, and NMR spectroscopy. Based on crystal structure and computational analyses, the cage has a 3.7 Å diameter electron-rich cavity suitable for the binding of cations such as cesium (ionic radius of 1.69 Å). The host-guest interactions were probed with 1H and 133Cs NMR spectroscopy in DMSO, where at low concentrations, Cs+ binds to Al-pdc-AA in a 11 ratio. The binding site was identified from the crystal structure of CsH7[Al8(pdc)8(OAc)8O4] (Cs+⊂Al-pdc-AA), and a binding affinity of ∼106-107 M-1 was determined from NMR titration experiments. The Al-pdc-AA showed improved selectivity for cesium binding over alkali metal cations (Cs+ > Rb+ > K+ ≫ Na+ ∼ Li+). Collectively, the study reports a novel aluminum cage that can serve as a promising host for efficient and selective cesium removal.