[Lamellar macular holes-In the center of vitreomacular interface diseases : Pathophysiology, spontaneous courses and treatment concepts]. / Makulaschichtforamen ­ im Zentrum der vitreomakulären Grenzflächenerkrankungen : Pathophysiologie, Spontanverläufe und Therapiekonzepte.

BACKGROUND: A lamellar macular hole (LMH) is characterized by a distinct morphologic configuration and can be distinguished from related entities such as macular pseudohole (MPH) and epiretinal membrane with foveoschisis (ERM-FS) by clear morphologic features. PURPOSE: Based on current knowledge, the pathophysiologic function of LMH in the spectrum of vitreomacular interface diseases will be described and therapeutic concepts will be presented. METHODS: Current studies are supplemented by case reports to provide a schematic overview of the natural history and therapeutic concepts at the vitreomacular interface. RESULTS: The LMH is as a retrospective marker for pathologic posterior vitreous detachment in adult patients and may be interpreted as the pathophysiologic center of tractional maculopathies. Various vitreomacular pathologies can result in LMH: a detached vitreomacular traction, a spontaneously closed penetrating macular hole, or an epiretinal membrane with foveoschisis. Pathophysiologically, a degenerative, progressive loss of the architecture of the foveal muller cell cone may be the underlaying mechanism, resulting in the typical undermining of the hole edges and occasionally in a full thickness macular hole. The optimal timing and the appropriate surgical method are the focus of current clinical studies. CONCLUSION: The pathophysiology of LMH indicates a smooth transition of tractive maculopathies. These should be prospectively evaluated in order to develop evidence-based treatment strategies for LMH.

Glyphosate modifies the gene expression and migration of trophoblastic cells without altering the process of angiogenesis or the implantation of blastocysts in vitro.

Adverse pregnancy outcomes have been associated with the presence of glyphosate (G) in umbilical cord, serum, and urine samples from pregnant women. Our aim was to study the effect of G on blastocyst implantation using an in vitro mouse model, and the migration and acquisition of endothelial phenotype of the human trophoblastic HTR8/SVneo (H8) cells. In mouse blastocysts, no differences in attachment time and implantation outgrowth area were observed after G exposure. H8 cell migration was stimulated by 0.625 µM G without cytotoxicity. After 6 h, the mRNA expression of vascular endothelial growth factor (VEGF) and C-C motif chemokine ligand 2 (CCL2) was upregulated in H8 cells exposed to 1.25 µM G when compared vehicle-treated cells (p ≤ 0.05). No differences were observed in interleukin 11, VEGF receptor 1, and coagulation factor II thrombin receptor in H8 cells exposed to different concentrations of G for 6 h compared to the vehicle. Interestingly, exposure to G did not alter angiogenesis as measured by a tube formation assay. Taken all together, these results suggest that G exposure may contribute as a risk factor during pregnancy, due to its ability to alter trophoblast migration and gene expression.

Assessing pollution degree and human health risks from hazardous element distribution in soils near gold mines in a Colombian Andean region: Correlation with phytotoxicity biomarkers.

The assessment of human health risk due to the presence of hazardous elements in the environment is now necessary for environmental management and legislative initiatives. This study aims to determine the contamination by As, Cd, Pb, and Cr in soils near gold mines in three municipalities located in the Andean region of Colombia. One of the main objectives of the study is to explore possible correlations between the Lifetime Cancer Risk (LCR) and phytotoxicity biomarkers using a simple and rapid-response plant model, radish (Raphanus sativus L.). In the municipality of Yalí, Puerto Berrío, and Buriticá, the hazardous elements concentrations ranged from 8.1 to 35.5, 1.7 to 892, and 5.8 to 49.8 for As, 0.1 to 4.6, 0.1 to 65.2, and 0.5 to 18.2 for Cd, 18.5 to 201.3, 13.0 to 1908, and 189 to 2345 for Pb, and 5.4 to 118.4, 65.4 to 301, and 5.4 to 102.3 for Cr, respectively. The results showed that the biomarkers intracellular H2O2 concentration, antioxidant activity, and radicle elongation exhibited significant (P < 0.05) variations associated with the concentration of hazardous elements in the soils. Significant correlations (P < 0.05, r > 0.58) were found between the biomarkers and the LCR for Cd, Pb, and Cr, but not for As. The results using biomarkers reveal that soil pH and organic matter content are important variables that control the bioavailability of these elements in the soil. The use of indicators like LCR alone has limitations and should be accompanied by the use of biomarkers that allow for a better understanding of the biological system's response to exposure to potentially toxic elements. The results obtained show the urgent need to implement public policies to minimize exposure to hazardous substances in areas near gold mining projects.

Carbapenem-resistant Acinetobacter baumannii complex in the United States-An epidemiological and molecular description of isolates collected through the Emerging Infections Program, 2019.

BACKGROUND: Understanding the epidemiology of carbapenem-resistant A. baumannii complex (CRAB) and the patients impacted is an important step toward informing better infection prevention and control practices and improving public health response. METHODS: Active, population-based surveillance was conducted for CRAB in 9 U.S. sites from January 1 to December 31, 2019. Medical records were reviewed, isolates were collected and characterized including antimicrobial susceptibility testing and whole genome sequencing. RESULTS: Among 136 incident cases in 2019, 66 isolates were collected and characterized; 56.5% were from cases who were male, 54.5% were from persons of Black or African American race with non-Hispanic ethnicity, and the median age was 63.5 years. Most isolates, 77.2%, were isolated from urine, and 50.0% were collected in the outpatient setting; 72.7% of isolates harbored an acquired carbapenemase gene (aCP), predominantly blaOXA-23 or blaOXA-24/40; however, an isolate with blaNDM was identified. The antimicrobial agent with the most in vitro activity was cefiderocol (96.9% of isolates were susceptible). CONCLUSIONS: Our surveillance found that CRAB isolates in the U.S. commonly harbor an aCP, have an antimicrobial susceptibility profile that is defined as difficult-to-treat resistance, and epidemiologically are similar regardless of the presence of an aCP.

Combining anaerobic digestion slurry and different biochars to develop a biochar-based slow-release NPK fertilizer.

In this research, we developed a biochar-based fertilizer using biogas slurry and biochar derived from lignocellulosic agro-residues. Biogas slurry was obtained through the anaerobic digestion of the organic fraction of municipal solid waste (fresh vegetable biomass and/or prepared food), while biochars were derived from residues from quinoa, maize, rice, and sugarcane. The biochar-based fertilizers were prepared using an impregnation process, where the biogas slurry was mixed with each of the raw biochars. Subsequently, we characterized the N, P and K concentrations of the obtained biochar-based fertilizers. Additionally, we analyzed their surface properties using SEM/EDS and FTIR and conducted a slow-release test on these biochar-based fertilizers to assess their capability to gradually release nutrients. Lastly, a bioassay using cucumber plants was conducted to determine the N, P, and K bioavailability. Our findings revealed a significant correlation (r > 0.67) between the atomic O/C ratio, H/C ratio, cation exchange capacity, surface area, and the base cations concentration with N, P, and/or K adsorption on biochar. These properties, in turn, were linked to the capability of the biochar-based fertilizer to release nutrients in a controlled manner. The biochar-based fertilizer derived from corn residues showed <15 % release of N, P and K at 24 h. Utilization of these biochar-based fertilizers had a positive impact on the mineral nutrition of cucumber plants, resulting in an average increase of 61 % in N, 32 % in P, and 19 % in K concentrations. Our results underscore the potential of biochar-based fertilizers in controlled nutrient release and enhanced plant nutrition. Integration of biochar and biogas slurry offers a promising and sustainable approach for NPK recovery and fertilizer production in agriculture. This study presents an innovative and sustainable approach combining the use of biochar for NPK recovery from biogas slurry and its use as a biochar-based fertilizer in agriculture.

Correction: Inferring school district learning modalities during the COVID-19 pandemic with a hidden Markov model.

[This corrects the article DOI: 10.1371/journal.pone.0292354.].

Bringing into focus the central domains C3-C6 of myosin binding protein C.

Myosin binding protein C (MyBPC) is a multi-domain protein with each region having a distinct functional role in muscle contraction. The central domains of MyBPC have often been overlooked due to their unclear roles. However, recent research shows promise in understanding their potential structural and regulatory functions. Understanding the central region of MyBPC is important because it may have specialized function that can be used as drug targets or for disease-specific therapies. In this review, we provide a brief overview of the evolution of our understanding of the central domains of MyBPC in regard to its domain structures, arrangement and dynamics, interaction partners, hypothesized functions, disease-causing mutations, and post-translational modifications. We highlight key research studies that have helped advance our understanding of the central region. Lastly, we discuss gaps in our current understanding and potential avenues to further research and discovery.

Mutagenesis techniques for evolutionary engineering of microbes - exploiting CRISPR-Cas, oligonucleotides, recombinases, and polymerases.

The natural process of evolutionary adaptation is often exploited as a powerful tool to obtain microbes with desirable traits. For industrial microbes, evolutionary engineering is often used to generate variants that show increased yields or resistance to stressful industrial environments, thus obtaining superior microbial cell factories. However, even in large populations, the natural supply of beneficial mutations is typically low, which implies that obtaining improved microbes is often time-consuming and inefficient. To overcome this limitation, different techniques have been developed that boost mutation rates. While some of these methods simply increase the overall mutation rate across a genome, others use recent developments in DNA synthesis, synthetic biology, and CRISPR-Cas techniques to control the type and location of mutations. This review summarizes the most important recent developments and methods in the field of evolutionary engineering in model microorganisms. It discusses how both in vitro and in vivo approaches can increase the genetic diversity of the host, with a special emphasis on in vivo techniques for the optimization of metabolic pathways for precision fermentation.

Ligandability assessment of the C-terminal Rel-homology domain of NFAT1.

Transcription factors are generally considered challenging, if not "undruggable", targets but they promise new therapeutic options due to their fundamental involvement in many diseases. In this study, we aim to assess the ligandability of the C-terminal Rel-homology domain of nuclear factor of activated T cells 1 (NFAT1), a TF implicated in T-cell regulation. Using a combination of experimental and computational approaches, we demonstrate that small molecule fragments can indeed bind to this protein domain. The newly identified binder is the first small molecule binder to NFAT1 validated with biophysical methods and an elucidated binding mode by X-ray crystallography. The reported eutomer/distomer pair provides a strong basis for potential exploration of higher potency binders on the path toward degrader or glue modalities.

Hypertrophic cardiomyopathy in MYBPC3 carriers in aging.

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3, underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.

Cold adaptation does not handicap warm tolerance in the most abundant Arctic seabird.

Arctic birds and mammals are physiologically adapted to survive in cold environments but live in the fastest warming region on the planet. They should therefore be most threatened by climate change. We fitted a phylogenetic model of upper critical temperature (TUC) in 255 bird species and determined that TUC for dovekies (Alle alle; 22.4°C)-the most abundant seabird in the Arctic-is 8.8°C lower than predicted for a bird of its body mass (150 g) and habitat latitude. We combined our comparative analysis with in situ physiological measurements on 36 dovekies from East Greenland and forward-projections of dovekie energy and water expenditure under different climate scenarios. Based on our analyses, we demonstrate that cold adaptation in this small Arctic seabird does not handicap acute tolerance to air temperatures up to at least 15°C above their current maximum. We predict that climate warming will reduce the energetic costs of thermoregulation for dovekies, but their capacity to cope with rising temperatures will be constrained by water intake and salt balance. Dovekies evolved 15 million years ago, and their thermoregulatory physiology might also reflect adaptation to a wide range of palaeoclimates, both substantially warmer and colder than the present day.

Temperature and nutrition do not interact to shape the evolution of metabolic rate.

Metabolic cold adaptation, or Krogh's rule, is the controversial hypothesis that predicts a monotonically negative relationship between metabolic rate and environmental temperature for ectotherms living along thermal clines measured at a common temperature. Macrophysiological patterns consistent with Krogh's rule are not always evident in nature, and experimentally evolved responses to temperature have failed to replicate such patterns. Hence, temperature may not be the sole driver of observed variation in metabolic rate. We tested the hypothesis that temperature, as a driver of energy demand, interacts with nutrition, a driver of energy supply, to shape the evolution of metabolic rate to produce a pattern resembling Krogh's rule. To do this, we evolved replicate lines of Drosophila melanogaster at 18, 25 or 28°C on control, low-calorie or low-protein diets. Contrary to our prediction, we observed no effect of nutrition, alone or interacting with temperature, on adult female and male metabolic rates. Moreover, support for Krogh's rule was only in females at lower temperatures. We, therefore, hypothesize that observed variation in metabolic rate along environmental clines arises from the metabolic consequences of environment-specific life-history optimization, rather than because of the direct effect of temperature on metabolic rate. This article is part of the theme issue 'The evolutionary significance of variation in metabolic rates'.

Phosphorus-Loaded Biochar-Assisted Phytoremediation to Immobilize Cadmium, Chromium, and Lead in Soils.

Soil contamination with heavy metals (HM) poses significant challenges to food security and public health, requiring the exploration of effective remediation strategies. This study aims to evaluate the remediation process of soils contaminated with Cd, Cr, and Pb using Lolium perenne assisted by four types of biochar: (i) activated coffee husk biochar (BAC), (ii) nonactivated biochar coffee husk (BSAC), (iii) activated sugar cane leaf biochar (BAA), and (iv) nonactivated biochar sugar cane leaf (BSAA). Biochar, loaded with phosphorus (P), was applied to soils contaminated with Cd, Cr, and Pb. L. perenne seedlings, averaging 2 cm in height, were planted. The bioavailability of P and heavy metals (HM) was monitored every 15 days until day 45, when the seedlings reached an average height of 25 cm. At day 45, plant harvesting was conducted and stems and roots were separated to determine metal concentrations in both plant parts and the soil. The study shows that the combined application of biochar and L. perenne positively influences the physicochemical properties of the soil, resulting in an elevation of pH and electrical conductivity (EC). The utilization of biochar contributes to an 11.6% enhancement in the retention of HM in plant organs. The achieved bioavailability of heavy metals in the soil was maintained at levels of less than 1 mg/kg. Notably, Pb exhibited a higher metal retention in plants, whereas Cd concentrations were comparatively lower. These findings indicate an increase in metal immobilization efficiencies when phytoremediation is assisted with P-loaded biochar. This comprehensive assessment highlights the potential of biochar-assisted phytoremediation as a promising approach for mitigating heavy metal contamination in soils.

High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia.

Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adapter protein complex 4 (AP-4) deficiency, a rare but prototypical form of childhood-onset hereditary spastic paraplegia characterized by mislocalization of the autophagy protein ATG9A. Using high-content microscopy and an automated image analysis pipeline, we screened a diversity library of 28,864 small molecules and identified a lead compound, BCH-HSP-C01, that restored ATG9A pathology in multiple disease models, including patient-derived fibroblasts and induced pluripotent stem cell-derived neurons. We used multiparametric orthogonal strategies and integrated transcriptomic and proteomic approaches to delineate potential mechanisms of action of BCH-HSP-C01. Our results define molecular regulators of intracellular ATG9A trafficking and characterize a lead compound for the treatment of AP-4 deficiency, providing important proof-of-concept data for future studies.

PRIMPOL ensures robust handoff between on-the-fly and post-replicative DNA lesion bypass.

The primase/polymerase PRIMPOL restarts DNA synthesis when replication is arrested by template impediments. However, we do not have a comprehensive view of how PRIMPOL-dependent repriming integrates with the main pathways of damage tolerance, REV1-dependent 'on-the-fly' lesion bypass at the fork and PCNA ubiquitination-dependent post-replicative gap filling. Guided by genome-wide CRISPR/Cas9 screens to survey the genetic interactions of PRIMPOL in a non-transformed and p53-proficient human cell line, we find that PRIMPOL is needed for cell survival following loss of the Y-family polymerases REV1 and POLη in a lesion-dependent manner, while it plays a broader role in promoting survival of cells lacking PCNA K164-dependent post-replicative gap filling. Thus, while REV1- and PCNA K164R-bypass provide two layers of protection to ensure effective damage tolerance, PRIMPOL is required to maximise the effectiveness of the interaction between them. We propose this is through the restriction of post-replicative gap length provided by PRIMPOL-dependent repriming.