Femtosecond Dynamics of the Excited Primary Electron Donor in Reaction Centers of the Purple Bacterium Rhodobacter sphaeroides.

Femtosecond transient absorption spectroscopy was used to study the dynamics of the excited primary electron donor in the reaction centers of the purple bacterium Rhodobacter sphaeroides. Using global analysis and the interval method, we found a correlation between the vibrational coherence damping of the excited primary electron donor and the lifetime of the charge-separated state P+BA-, indicating the reversibility of electron transfer to the primary electron acceptor, the BA molecule. In the reaction centers, the signs of superposition of two electronic states of P were found for a delay time of less than 200 fs. It is suggested that the admixture value of the charge transfer state PA+PB- with the excited primary electron donor P* is about 24%. The results obtained are discussed in terms of the two-step electron transfer mechanism.

Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase.

Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (MKPs) directly dephosphorylate and inactivate the MAPKs. Although the catalytic mechanism of dephosphorylation of the MAPKs by the MKPs is established, a complete molecular picture of the regulatory interplay between the MAPKs and MKPs still remains to be fully explored. Here, we sought to define the molecular mechanism of MKP5 regulation through an allosteric site within its catalytic domain. We demonstrate using crystallographic and NMR spectroscopy approaches that residue Y435 is required to maintain the structural integrity of the allosteric pocket. Along with molecular dynamics simulations, these data provide insight into how changes in the allosteric pocket propagate conformational flexibility in the surrounding loops to reorganize catalytically crucial residues in the active site. Furthermore, Y435 contributes to the interaction with p38 MAPK and JNK, thereby promoting dephosphorylation. Collectively, these results highlight the role of Y435 in the allosteric site as a novel mode of MKP5 regulation by p38 MAPK and JNK.

Fluocinolone acetonide 0.18-mg implant for treatment of recurrent inflammation due to non-infectious uveitis: a case series of 15 patients.

INTRODUCTION: Uncontrolled non-infectious uveitis affecting the posterior segment (NIU-PS) can lead to vision loss due to repeated bouts of inflammation and consequent tissue damage. Patients with chronic NIU-PS who experience recurrent uveitis after being treated with systemic and short-acting local corticosteroids may benefit from the sustained-release 0.18-mg fluocinolone acetonide implant (FAi). METHODS: In this case series, 18 eyes with chronic, recurrent NIU-PS and cystoid macular edema (CME) treated with the 0.18-mg FAi were analyzed retrospectively. Data on patient demographics, clinical history, previous and concomitant treatments for uveitis recurrence, time to and number of uveitis recurrences, intraocular pressure (IOP), central subfield thickness (CST), and visual acuity (VA) were collected and summarized. RESULTS: A majority of patients (14/15 [93%]) had a history of ocular surgery, largely cataract extraction, and all developed chronic and recurrent NIU-PS and CME. At baseline, patients had a mean age of 72 years (range: 46 to 93), were 53% male, and had a mean duration of NIU-PS of 3 years (range: 1 to 19). Patients were followed for an average of 16.5 months (range: 2 to 42.5 months) post FAi. Eleven of the 18 eyes (61%) had ≥ 5 recurrences of uveitis since diagnosis, with an average time to recurrence of approximately 12 weeks (range: 1 to 27). All eyes treated with the 0.18-mg FAi showed reduced NIU-PS recurrence and visual and anatomical improvement, as measured by VA and CST, respectively. Two eyes had an IOP elevation that was managed with topical therapy, and one eye was treated with topical prednisolone for additional inflammation management. Two eyes required adjunct therapy with short-acting intravitreal corticosteroids at 7 and 16 weeks for NIU-PS recurrence after 0.18-mg FAi insertion. CONCLUSION: After receiving the 0.18-mg FAi, eyes with uncontrolled NIU-PS had sustained resolution of CME and inflammation with limited need for supplementary steroid drops or injections and minimal steroid class-specific adverse effects; none required incisional IOP-lowering surgery.

Exploring h-BN as a hydrogen conductor and depository.

The use of hexagonal boron nitride (h-BN) as a material for hydrogen storage is attributed to its ability to accommodate atomic and molecular hydrogen. However, the low diffusion barrier of molecular hydrogen within the h-BN structure does not fully explain the long-term stability of hydrogen bubbles observed in experimental work [L. He, H. Wang, L. Chen, X. Wang, H. Xie, C. Jiang, C. Li, K. Elibol, J. Meyer, K. Watanabe, T. Taniguchi, Z. Wu, W. Wang, Z. Ni, X. Miao, C. Zhang, D. Zhang, H. Wang and X. Xie, Nat. Commun., 2019, 10, 2815, https://doi.org/10.1038/s41467-019-10660-9]. Another unresolved inquiry is the method by which hydrogen infiltrates the h-BN layer in a perpendicular direction. In this study, we conducted a comprehensive examination of several aspects that can impact the permeation of hydrogen in the h-BN structure. We employed DFT within the rPBE (DFT-D3(0)) functional to suggest a process for the penetration of atomic hydrogen through the h-BN sheet along the normal direction by sequential hydrogen passivation.

Does warming erode network stability and ecosystem multifunctionality?

Environmental warming is thought to alter food web stability and functioning, but whether warming reduces food web resistance and resilience to further climatic events remains surprisingly unexplored. Warming experiments that superimpose acute disturbances are urgently needed to understand how extreme events further threaten the stability and multifunctionality of ecological networks.

miR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression.

The complexity of the mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of MASLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 was elevated in the livers of humans and mice with MASLD and that its deletion in hepatocytes (miR-33 HKO) improved multiple aspects of the disease, including steatosis and inflammation, limiting the progression to metabolic dysfunction-associated steatotic hepatitis (MASH), fibrosis, and HCC. Mechanistically, hepatic miR-33 deletion reduced lipid synthesis and promoted mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 altered the expression of several known miR-33 target genes involved in metabolism and resulted in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of MASLD, MASH, and HCC in obesity.

Biological Effects of CYP11A1-Derived Vitamin D and Lumisterol Metabolites in the Skin.

Novel pathways of vitamin D3, lumisterol 3 (L3), and tachysterol 3 (T3) activation have been discovered, initiated by CYP11A1 and/or CYP27A1 in the case of L3 and T3. The resulting hydroxymetabolites enhance protection of skin against DNA damage and oxidative stress; stimulate keratinocyte differentiation; exert anti-inflammatory, antifibrogenic, and anticancer activities; and inhibit cell proliferation in a structure-dependent manner. They act on nuclear receptors, including vitamin D receptor, aryl hydrocarbon receptor, LXRα/ß, RAR-related orphan receptor α/γ, and peroxisome proliferator-activated receptor-γ, with selectivity defined by their core structure and distribution of hydroxyl groups. They can activate NRF2 and p53 and inhibit NF-κB, IL-17, Shh, and Wnt/ß-catenin signaling. Thus, they protect skin integrity and physiology.

MAPK Phosphatase-5 is required for TGF-ß signaling through a JNK-dependent pathway.

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-ß (TGF-ß) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-ß are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-ß signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-ß signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-ß signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-ß signaling and provides insight into the role of MKP-5 in fibrosis.

Rise and Fall of Anderson Localization by Lattice Vibrations: A Time-Dependent Machine Learning Approach.

The intricate relationship between electrons and the crystal lattice is a linchpin in condensed matter, traditionally described by the Fröhlich model encompassing the lowest-order lattice-electron coupling. Recently developed quantum acoustics, emphasizing the wave nature of lattice vibrations, has enabled the exploration of previously uncharted territories of electron-lattice interaction not accessible with conventional tools such as perturbation theory. In this context, our agenda here is two-fold. First, we showcase the application of machine learning methods to categorize various interaction regimes within the subtle interplay of electrons and the dynamical lattice landscape. Second, we shed light on a nebulous region of electron dynamics identified by the machine learning approach and then attribute it to transient localization, where strong lattice vibrations result in a momentary Anderson prison for electronic wavepackets, which are later released by the evolution of the lattice. Overall, our research illuminates the spectrum of dynamics within the Fröhlich model, such as transient localization, which has been suggested as a pivotal factor contributing to the mysteries surrounding strange metals. Furthermore, this paves the way for utilizing time-dependent perspectives in machine learning techniques for designing materials with tailored electron-lattice properties.

A nonparametric measure of contrast in x-ray images.

Objective.We propose a nonparametric figure of merit, the contrast equivalent distance CED, to measure contrast directly from clinical images.Approach.A relative brightness distanceδis calculated by making use of the order statistic of the pixel values. By multiplyingδwith the grey value rangeR, the mean brightness distance MBD is obtained. From the MBD, the CED and the distance-to-noise ratio DNR can be derived. The latter is the ratio of the MBD and a previously suggested nonparametric measureτfor the noise. Since the order statistic is independent of the spatial arrangement of the pixel values, the measures can be obtained directly from clinical images. We apply the new measures to mammography images of an anthropomorphic phantom and of a phantom with a step wedge as well as to CT images of a head phantom.Main results.For low-noise images of a step wedge, the MBD is equivalent to the conventional grey value distance. While this measure permits the evaluation of clinical images, it is sensitive to noise. Therefore, noise has to be quantified at the same time. When the ratioσ/τof the noise standard deviationσtoτis available, validity limits for the CED as a measure of contrast can be established. The new figures of merit can be calculated for entire images as well as on regions of interest (ROI) with an edge length not smaller than 32 px.Significance.The new figures of merit are suited to quantify the quality of clinical images without relying on the assumption of a linear, shift-invariant system. They can be used for any kind of greyscale image, provided the ratioσ/τcan be estimated. This will hopefully help to achieve the optimisation of image quality vs dose required by radioprotection laws.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling.

Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.

Studying the small extracellular vesicle capture efficiency of magnetic beads coated with tannic acid.

The isolation of small extracellular vesicles (sEVs), including those secreted by pathological cells, with high efficiency and purity is highly demanded for research studies and practical applications. Conventional sEV isolation methods suffer from low yield, presence of contaminants, long-term operation and high costs. Bead-assisted platforms are considered to be effective for trapping sEVs with high recovery yield and sufficient purity for further molecular profiling. In this study, magnetically responsive beads made of calcium carbonate (CaCO3) particles impregnated with iron oxide (Fe3O4) nanoparticles are fabricated using a freezing-induced loading (FIL) method. The developed magnetic beads demonstrate sufficient magnetization and can be collected by a permanent magnet, ensuring their rapid and gentle capture from an aqueous solution. The tannic acid on the surface of magnetic beads is formed by a layer-by-layer (LbL) method and is used to induce coupling of sEVs with the surface of magnetic beads. These tannic acid coated magnetic beads (TAMB) were applied to capture sEVs derived from MCF7 and HCT116 cell lines. Quantitative data derived from nanoparticle tracking analysis (NTA) and BCA methods revealed the capture efficiency and recovery yield of about 60%. High-resolution transmission electron microscopy (HRTEM) imaging of sEVs on the surface of TAMBs indicated their structural integrity. Compared with the size exclusion chromatography (SEC) method, the proposed approach demonstrated comparable efficiency in terms of recovery yield and purity, while offering a relatively short operation time. These results highlight the high potential of the TAMB approach for the enrichment of sEVs from biological fluids, such as cell culture media.

Chaos-Assisted Dynamical Tunneling in Flat Band Superwires.

Recent theoretical investigations have revealed unconventional transport mechanisms within high Brillouin zones of two-dimensional superlattices. Electrons can navigate along channels we call superwires, gently guided without brute force confinement. Such dynamical confinement is caused by weak superlattice deflections, markedly different from the static or energetic confinement observed in traditional wave guides or one-dimensional electron wires. The quantum properties of superwires give rise to elastic dynamical tunneling, linking disjoint regions of the corresponding classical phase space, and enabling the emergence of several parallel channels. This paper provides the underlying theory and mechanisms that facilitate dynamical tunneling assisted by chaos in periodic lattices. Moreover, we show that the mechanism of dynamical tunneling can be effectively conceptualized through the lens of a paraxial approximation. Our results further reveal that superwires predominantly exist within flat bands, emerging from eigenstates that represent linear combinations of conventional degenerate Bloch states. Finally, we quantify tunneling rates across various lattice configurations and demonstrate that tunneling can be suppressed in a controlled fashion, illustrating potential implications in future nanodevices.

Titanium mesh for guided bone regeneration: a systematic review.

This systematic review aimed to evaluate results reported in the literature regarding the success rate of the titanium mesh technique for the placement of dental implants. The topic focused on titanium mesh used as a physical barrier for ridge reconstruction in cases of partial or total edentulism. The authors conducted an electronic search of four databases up to October 2023. Six articles fulfilled the inclusion criteria and were analysed. A total of 100 titanium meshes with a minimum of 4.6 months follow up after surgery were studied, and 241 implants were placed. The review shows that the use of titanium mesh is a predictable method for the rehabilitation of complex atrophic sites. Further investigation generating long-term data is needed to confirm these findings.

Quantum-Acoustical Drude Peak Shift.

Quantum acoustics-a recently developed framework parallel to quantum optics-establishes a nonperturbative and coherent treatment of the electron-phonon interaction in real space. The quantum-acoustical representation reveals a displaced Drude peak hiding in plain sight within the venerable Fröhlich model: the optical conductivity exhibits a finite frequency maximum in the far-infrared range and the dc conductivity is suppressed. Our results elucidate the origin of the high-temperature absorption peaks in strange or bad metals, revealing that dynamical lattice disorder steers the system towards a non-Drude behavior.

Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease.

Mouse models of autosomal dominant polycystic kidney disease (ADPKD) show that intact primary cilia are required for cyst growth following the inactivation of polycystin-1. The signaling pathways underlying this process, termed cilia-dependent cyst activation (CDCA), remain unknown. Using translating ribosome affinity purification RNASeq on mouse kidneys with polycystin-1 and cilia inactivation before cyst formation, we identify the differential 'CDCA pattern' translatome specifically dysregulated in kidney tubule cells destined to form cysts. From this, Glis2 emerges as a candidate functional effector of polycystin signaling and CDCA. In vitro changes in Glis2 expression mirror the polycystin- and cilia-dependent changes observed in kidney tissue, validating Glis2 as a cell culture-based indicator of polycystin function related to cyst formation. Inactivation of Glis2 suppresses polycystic kidney disease in mouse models of ADPKD, and pharmacological targeting of Glis2 with antisense oligonucleotides slows disease progression. Glis2 transcript and protein is a functional target of CDCA and a potential therapeutic target for treating ADPKD.

Valorization of steelmaking slag and coal fly ash as amendments in combination with Betula pubescens for the remediation of a highly As- and Hg-polluted mining soil.

Soil pollution by As and Hg is a pressing environmental issue given their persistence. The intricate removal processes and subsequent accumulation of these elements in soil adversely impact plant growth and pose risks to other organisms in the food chain and to underground aquifers. Here we assessed the effectiveness of non-toxic industrial byproducts, namely coal fly ash and steelmaking slag, as soil amendments, both independently and in conjunction with an organic fertilizer. This approach was coupled with a phytoremediation technique involving Betula pubescens to tackle soil highly contaminated. Greenhouse experiments were conducted to evaluate amendments' impact on the growth, physiology, and biochemistry of the plant. Additionally, a permeable barrier made of byproducts was placed beneath the soil to treat leachates. The application of the byproducts reduced pollutant availability, the production of contaminated leachates, and pollutant accumulation in plants, thereby promoting plant development and survival. Conversely, the addition of the fertilizer alone led to an increase in As accumulation in plants and induced the production of antioxidant compounds such as carotenoids and free proline. Notably, all amendments led to increased thiolic compound production without affecting chlorophyll synthesis. While fertilizer application significantly decreased parameters associated with oxidative stress, such as hydrogen peroxide and malondialdehyde, no substantial reduction was observed after byproduct application. Thermal desorption analysis of the byproducts revealed Hg immobilization mechanisms, thereby indicating retention of this metalloid in the form of Hg chloride. In summary, the revalorization of industrial byproducts in the context of the circular economy holds promise for effectively immobilizing metal(loid)s in heavily polluted soils. Additionally, this approach can be enhanced through synergies with phytoremediation.

Seasonal fluctuations of litter and soil Collembola and their drivers in rainforest and plantation systems.

Rainforest conversion and expansion of plantations in tropical regions change local microclimate and are associated with biodiversity decline. Tropical soils are a hotspot of animal biodiversity and may sensitively respond to microclimate changes, but these responses remain unexplored. To address this knowledge gap, here we investigated seasonal fluctuations in density and community composition of Collembola, a dominant group of soil invertebrates, in rainforest, and in rubber and oil palm plantations in Jambi province (Sumatra, Indonesia). Across land-use systems, the density of Collembola in the litter was at a maximum at the beginning of the wet season, whereas in soil it generally varied little. The community composition of Collembola changed with season and the differences between land-use systems were most pronounced at the beginning of the dry season. Water content, pH, fungal and bacterial biomarkers, C/N ratio and root biomass were identified as factors related to seasonal variations in species composition of Collembola across different land-use systems. We conclude that (1) conversion of rainforest into plantation systems aggravates detrimental effects of low moisture during the dry season on soil invertebrate communities; (2) Collembola communities are driven by common environmental factors across land-use systems, with water content, pH and food availability being most important; (3) Collembola in litter are more sensitive to climatic variations than those in soil. Overall, the results document the sensitivity of tropical soil invertebrate communities to seasonal climatic variations, which intensifies the effects of the conversion of rainforest into plantation systems on soil biodiversity.

MAPK phosphatase 1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution.

Fibrosis following tissue injury is distinguished from normal repair by the accumulation of pathogenic and apoptosis-resistant myofibroblasts (MFs), which arise primarily by differentiation from resident fibroblasts. Endogenous molecular brakes that promote MF dedifferentiation and clearance during spontaneous resolution of experimental lung fibrosis may provide insights that could inform and improve the treatment of progressive pulmonary fibrosis in patients. MAPK phosphatase 1 (MKP1) influences the cellular phenotype and fate through precise and timely regulation of MAPK activity within various cell types and tissues, yet its role in lung fibroblasts and pulmonary fibrosis has not been explored. Using gain- and loss-of-function studies, we found that MKP1 promoted lung MF dedifferentiation and restored the sensitivity of these cells to apoptosis - effects determined to be mainly dependent on MKP1's dephosphorylation of p38α MAPK (p38α). Fibroblast-specific deletion of MKP1 following peak bleomycin-induced lung fibrosis largely abrogated its subsequent spontaneous resolution. Such resolution was restored by treating these transgenic mice with the p38α inhibitor VX-702. We conclude that MKP1 is a critical antifibrotic brake whose inhibition of pathogenic p38α in lung fibroblasts is necessary for fibrosis resolution following lung injury.