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Abstract Enhancing early-stage breast cancer detection requires integrating additional screening methods with current diagnostic imaging. Omics screening, using easily collectible serum samples, could serve as an initial step. Alongside biomarker identification capabilities, omics analysis allows for a comprehensive analysis of prevalent histological types—DCIS and IDC. Employing metabolomics, metallomics, and machine learning, could yield accurate screening models with valuable insights into organism responses. Serum samples of confirmed breast cancer patients were utilized to analyze metabolite and metal ion profiles, using two distinct analysis methods, proton NMR for metabolomics and ICP-OES for metallomics. The resulting responses were then subjected to discriminant analysis, progression biomarker exploration, examination of correlations between patients’ metabolites and metal ions, and the impact of age and menopause status. Measured NMR spectra and metabolite relative integrals were used to achieve statistically significant discrimination through MVA between breast cancer and control groups. The analysis identified 24 metabolites and 4 metal ions crucial for discrimination. Furthermore, four metabolites were associated with disease progression. Additionally, there were important correlations and relationships between metabolite relative integrals, metal ion concentrations, and age/menopausal status subgroups. Quantified relative integrals allowed for discrimination between studied subgroups, validated with a holdout set. Feature importance and statistical analysis for metabolomics and metallomics extracted a set of common entities which in combination provides valuable insights into ongoing molecular disturbances and disease progression.

Abstract Cytoplasmic polyadenylation plays a vital role in gametogenesis; however, the participating enzymes and substrates in mammals remain unclear. Using knockout and knock-in mouse models, we describe the essential role of four TENT5 poly(A) polymerases in mouse fertility and gametogenesis. TENT5B and TENT5C play crucial yet redundant roles in oogenesis, with the double knockout of both genes leading to oocyte degeneration. Additionally, TENT5B-GFP knock-in females display a gain-of-function infertility effect, with multiple chromosomal aberrations in ovulated oocytes. TENT5C and TENT5D both regulate different stages of spermatogenesis, as shown by the sterility in males following the knockout of either gene. Finally, Tent5a knockout substantially lowers fertility, although the underlying mechanism is not directly related to gametogenesis. Through direct RNA sequencing, we discovered that TENT5s polyadenylate mRNAs encoding endoplasmic reticulum-targeted proteins essential for gametogenesis. Sequence motif analysis and reporter mRNA assays reveal that the presence of an endoplasmic reticulum-leader sequence represents the primary determinant of TENT5-mediated regulation.

Abstract Purpose Besides the well-established efficacy in preventing severe COVID-19, the impact of early treatments, namely antivirals and monoclonal antibodies (mAbs), on the time length to negativization of SARS-CoV-2 nasal swabs is still unclear. The aim of this study was to compare the efficacy of different early treatments in reducing the SARS-CoV-2 viral shedding, identifying a single drug that might potentially lead to a more rapid negativization of SARS-CoV-2 nasal swab. Methods This was a single-centre, retrospective, observational study conducted at Ospedale Luigi Sacco in Milan. Data of high-risk COVID-19 patients who received early treatments between 23 December 2021 and March 2023 were extracted. The comparison across treatments was conducted using the Kruskall-Wallis test for continuous variables. Dunn’s test with Bonferroni adjustment was performed for post-hoc comparisons of days to negativization. Secondly, a negative binomial regression adjusted for age, sex, number of comorbidities, immunosuppression, and SARS-CoV-2 vaccination status was implemented. Results Data from 428 patients receiving early treatments were collected. The majority were treated with Nirmatrelvir/Ritonavir and were affected by SARS-CoV-2 Omicron infection with BA.2 sublineage. The median length time to SARS-CoV-2 nasal swab negativization was 9 days [IQR 7–13 days]. We found that Nirmatrelvir/Ritonavir determined a significant decrease of the length time to SARS-CoV-2 nasal swab negativization compared to mAbs (p = 0.003), but not compared to Remdesivir (p = 0.147) and Molnupiravir (p = 0.156). Conclusion Our findings highlight the importance of promptly treating high-risk COVID-19 patients with Nirmatrelvir/Ritonavir, as it also contributes to achieving a faster time to negative SARS-CoV-2 nasal swabs.

Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor α, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence.

Abstract Background Hemp (Cannabis sativa) is a crop with a wide range of uses, from the production of fiber and seeds to the secondary metabolites for medicinal purposes. In addition, it is characterized by high biomass yield and the ability to accumulate heavy metals, which makes this plant convenient for phytoremediation purposes. In this study, the effect of applying exogenous biodegradable chelating agents, citric acid (CA) and nitrilotriacetic acid (NTA), to zinc-contaminated soil on zinc (Zn) uptake by two industrial hemp varieties ‘Felina 32’ and ‘Monoica’ was studied. The effect of CA and NTA on available Zn in soils was investigated using an ‘in pot’ experiment under controlled conditions. The effect of both tested compounds on soil microbial activity was simultaneously evaluated. Results After the application of NTA at a concentration of 5 mmol L−1, a > threefold increased accumulation of Zn in the above-ground parts was recorded in the ‘Felina 32’ variety. In the ‘Monoica’ variety, the levels of Zn in the above-ground parts were increased > twofold. NTA affected the soil microbiome negatively, causing decreased enzyme activity (in ‘Monoica’ planted soil) and induced respiration (in ‘Monoica’ and especially in ‘Felina 32’ planted soil). On the other hand, CA application did not lead to significantly increased Zn levels in any of the studied hemp varieties. Together with CA’s negative effects on some soil enzymes, CA enhanced urease activity, dehydrogenase and several respiration types for the ‘Felina 32’ variety and exerted less detrimental effect on the soil microbiome. No toxic effects from increased Zn uptake and accumulation in experimental plants were detected, accounting for the unchanged physiological stress markers (levels of photosynthetic pigments and proline in leaves, chlorophyll fluorescence parameters) and selected growth traits of the above-ground organs and root system. Conclusions From the studied varieties, ‘Felina 32’ seems to be more suitable for Zn-phytoextraction because of its higher tolerance to increased Zn levels, higher biomass production and Zn accumulation capacity. Our results indicate the potential of using the ‘Felina 32’ variety in NTA-assisted Zn phytoextraction from contaminated soils. Graphical Abstract

Abstract Background One of the levers towards alternative solutions to pesticides is to improve seed defenses against pathogens, but a better understanding is needed on the type and regulation of existing pathways during germination. Dormant seeds are able to defend themselves against microorganisms during cycles of rehydration and dehydration in the soil. During imbibition, seeds leak copious amounts of exudates. Here, we developed a nephelometry method to assay antimicrobial activity (AA) in tomato seed exudates as a proxy to assess level of defenses. Results A protocol is described to determine the level of AA against the nonhost filamentous fungus Alternaria brassicicola in the exudates of tomato seeds and seedlings. The fungal and exudate concentrations can be adjusted to modulate the assay sensitivity, thereby providing a large window of AA detection. We established that AA in dormant seeds depends on the genotype. It ranged from very strong AA to complete absence of AA, even after prolonged imbibition. AA depends also on the stages of germination and seedling emergence. Exudates from germinated seeds and seedlings showed very strong AA, while those from dormant seeds exhibited less activity for the same imbibition time. The exudate AA did not impact the growth of a pathogenic fungus host of tomato, Alternaria alternata, illustrating the adaptation of this fungus to its host. Conclusions We demonstrate that our nephelometry method is a simple yet powerful bioassay to quantify AA in seed exudates. Different developmental stages from dormant seed to seedlings show different levels of AA in the exudate that vary between genotypes, highlighting a genetic diversity x developmental stage interaction in defense. These findings will be important to identify molecules in the exudates conferring antifungal properties and obtain a better understanding of the regulatory and biosynthetic pathways through the lifecycle of seeds, from dormant seeds until seedling emergence.

Antibodies are proteins produced by our immune system that have been harnessed as biotherapeutics. The discovery of antibody-based therapeutics relies on analyzing large volumes of diverse sequences coming from phage display or animal immunizations. Identification of suitable therapeutic candidates is achieved by grouping the sequences by their similarity and subsequent selection of a diverse set of antibodies for further tests. Such groupings are typically created using sequence-similarity measures alone. Maximizing diversity in selected candidates is crucial to reducing the number of tests of molecules with near-identical properties. With the advances in structural modeling and machine learning, antibodies can now be grouped across other diversity dimensions, such as predicted paratopes or three-dimensional structures. Here we benchmarked antibody grouping methods using clonotype, sequence, paratope prediction, structure prediction, and embedding information. The results were benchmarked on two tasks: binder detection and epitope mapping. We demonstrate that on binder detection no method appears to outperform the others, while on epitope mapping, clonotype, paratope, and embedding clusterings are top performers. Most importantly, all the methods propose orthogonal groupings, offering more diverse pools of candidates when using multiple methods than any single method alone. To facilitate exploring the diversity of antibodies using different methods, we have created an online tool-CLAP-available at (clap.naturalantibody.com) that allows users to group, contrast, and visualize antibodies using the different grouping methods.

Antibody-based therapeutics must not undergo chemical modifications that would impair their efficacy or hinder their developability. A commonly used technique to de-risk lead biotherapeutic candidates annotates chemical liability motifs on their sequence. By analyzing sequences from all major sources of data (therapeutics, patents, GenBank, literature, and next-generation sequencing outputs), we find that almost all antibodies contain an average of 3-4 such liability motifs in their paratopes, irrespective of the source dataset. This is in line with the common wisdom that liability motif annotation is over-predictive. Therefore, we have compiled three computational flags to prioritize liability motifs for removal from lead drug candidates: 1. germline, to reflect naturally occurring motifs, 2. therapeutic, reflecting chemical liability motifs found in therapeutic antibodies, and 3. surface, indicative of structural accessibility for chemical modification. We show that these flags annotate approximately 60% of liability motifs as benign, that is, the flagged liabilities have a smaller probability of undergoing degradation as benchmarked on two experimental datasets covering deamidation, isomerization, and oxidation. We combined the liability detection and flags into a tool called Liability Antibody Profiler (LAP), publicly available at lap.naturalantibody.com. We anticipate that LAP will save time and effort in de-risking therapeutic molecules.

Objectives The aim of the research was to explore the potential of the concept of work in the activity-based working (ABW) environment, including its impact on stress, back pain and psychomedical parameters of employees subjected to and not subject to relocation. Material and Methods The data of 396 employees of both sexes were analyzed. The study used standardized psychological questionnaires to measure the level of perceived stress ( Perceived Stress Scale ), the level of readiness for change ( Readiness for Change Questionnaire ), the severity of health behaviors ( Health Behavior Inventory ) and the level of general self-efficacy ( General Self-Efficacy Scale ). The set included questionnaires measuring the level of knowledge of occupational health and safety rules and the frequency of back pain. Results In the group of people whose workplace was moved to another building (in accordance with the concept), the relationship between the level of stress and selected variables: age, sense of generalized self-efficacy was checked. A significant negative correlation between the level of stress and age was confirmed (ρ = –0.16, p = 0.023), meaning a decrease in the level of stress with age. The level of stress correlated positively with the sense of efficacy (ρ = 0.21, p = 0.003), which means, the higher the sense of effectiveness, the higher the level of stress. In addition, it was confirmed that the level of stress in the group of people changing their location differed significantly from the general population. Conclusions Work in the ABW concept can contribute to the improvement of interpersonal communication and facilitate the social integration of employees and better evaluation of work in this model. Work in concept has not been shown to be a protective factor against back pain in people with obesity. It was confirmed that in people relocated from traditional office to office in the concept, relocation was associated with stress, but also with a greater sense of self-efficacy. Int J Occup Med Environ Health. 2023;36(4):526–40

Abstract The field of plant hormonomics focuses on the qualitative and quantitative analysis of the hormone complement in plant samples, akin to other omics sciences. Plant hormones, alongside primary and secondary metabolites, govern vital processes throughout a plant's lifecycle. While active hormones have received significant attention, studying all related compounds provides valuable insights into internal processes. Conventional single-class plant hormone analysis employs thorough sample purification, short analysis and triple quadrupole tandem mass spectrometry. Conversely, comprehensive hormonomics analysis necessitates minimal purification, robust and efficient separation and better-performing mass spectrometry instruments. This review summarizes the current status of plant hormone analysis methods, focusing on sample preparation, advances in chromatographic separation and mass spectrometric detection, including a discussion on internal standard selection and the potential of derivatization. Moreover, current approaches for assessing the spatiotemporal distribution are evaluated. The review touches on the legitimacy of the term plant hormonomics by exploring the current status of methods and outlining possible future trends.

The research was carried out in calcareous fen habitats which share coverage with Natura 2000 sites designated under the EU Habitats and the Birds Directive. A total of 27 taxa of molluscs were recorded: 23 gastropod and 4 bivalve species. Anisus vorticulus, one of the species of Community interest whose conservation requires designation of special conservation areas within the Habitats Directive Natura 2000, was subrecedent and accedent in mollusc communities. Calcareous fen habitats offer the aquatic organisms harsh environmental conditions including a relatively high temperature of the water up to 33.29 °C (undrained fens), oxygen deficits in the water, high pH of up to 11.08 (fen pools) and conductivity above 3000 μS cm−1 (fen ditches). Therefore molluscs have to face extreme environmental conditions. Temperature of the water, pH, dissolved oxygen and conductivity were the parameters most associated with the distribution of mollusc species in the calcareous fen habitats. The abundance of submerged and floating macrophytes, the degree of habitat persistence and the fish predation pressure on molluscs also exerted a significant effect on their distribution. The calcareous fen habitats that are listed in Annex I of the European Union Habitats Directive create a unique valuable ecosystem that contributes to the natural diversity of aquatic organisms.

Abstract Introduction Cancer patients are frail individuals, thus the prevention of SARS‐CoV‐2 infection is essential. To date, vaccination is the most effective tool to prevent COVID‐19. In a previous study, we evaluated the immunogenicity of two doses of mRNA‐based vaccines (BNT162b2 or mRNA‐1273) in solid cancer patients. We found that seroconversion rate in cancer patients without a previous exposure to SARS‐CoV‐2 was lower than in healthy controls (66.7% vs. 95%, p = 0.0020). The present study aimed to evaluate the clinical efficacy of the vaccination in the same population. Methods This is a single‐institution, prospective observational study. Data were collected through a predefined questionnaire through phone call in the period between the second and third vaccine dose. The primary objective was to describe the clinical efficacy of the vaccination, defined as the percentage of vaccinated subjects who did not develop symptomatic COVID‐19 within 6 months after the second dose. The secondary objective was to describe the clinical features of patients who developed COVID‐19. Results From January to June 2021, 195 cancer patients were enrolled. Considering that 7 (3.59%) patients tested positive for SARS‐CoV‐2 and 5 developed symptomatic disease, the clinical efficacy of the vaccination was 97.4%. COVID‐19 disease in most patients was mild and managed at home; only one hospitalization was recorded and no patient required hospitalization in the intensive care unit. Discussion Our study suggests that increasing vaccination coverage, including booster doses, could improve the prevention of infection, hospitalization, serious illness, and death in the frail population of cancer patients.

Vulvovaginal candidiasis (VVC) is a real gynecological problem among women of reproductive age from 15 to 49. A recent analysis showed that 75% of women will have an occurrence at least once per year, while 5% are observed to have recurrent vaginal mycosis—these patients may become unwell four or more times a year. This pathology is caused in 85–90% of cases by fungi of the Candida albicans species. It represents an intractable medical problem for female patients due to pain and pruritus. Due to the observation of an increasing number of strains resistant to standard preparations and an increase in the recurrence of this pathology when using local or oral preferential therapy, such as fluconazole, an analysis was launched to develop alternative methods of treating VVC using herbs such as dill, turmeric, and berberine. An in-depth analysis of databases that include scientific articles from recent years made it possible to draw satisfactory conclusions supporting the validity of herbal therapy for the pathology in question. Although phytotherapy has not yet been approved by the Food and Drug Administration, it appears to be a promising therapeutic solution for strains that are resistant to existing treatments. There is research currently undergoing aimed at comparing classical pharmacotherapy and herbal therapy in the treatment of vaginal candidiasis for the purpose of increasing medical competence and knowledge for the care of the health and long-term comfort of gynecological patients.

Underground hydrogen storage in geological structures is considered appropriate for storing large amounts of hydrogen. Using the geological Konary structure in the deep saline aquifers, an analysis of the influence of depth on hydrogen storage was carried out. Hydrogen injection and withdrawal modeling was performed using TOUGH2 software, assuming different structure depths. Changes in the relevant parameters for the operation of an underground hydrogen storage facility, including the amount of H2 injected in the initial filling period, cushion gas, working gas, and average amount of extracted water, are presented. The results showed that increasing the depth to approximately 1500 m positively affects hydrogen storage (flow rate of injected hydrogen, total capacity, and working gas). Below this depth, the trend was reversed. The cushion gas-to-working gas ratio did not significantly change with increasing depth. Its magnitude depends on the length of the initial hydrogen filling period. An increase in the depth of hydrogen storage is associated with a greater amount of extracted water. Increasing the duration of the initial hydrogen filling period will reduce the water production but increase the cushion gas volume.

Underground hydrogen storage facilities require cushion gas to operate, which is an expensive one-time investment. Only some of this gas is recoverable after the end of UHS operation. A significant percentage of the hydrogen will remain in underground storage as non-recoverable cushion gas. Efforts must be made to reduce it. This article presents the results of modeling the cushion gas withdrawal after the end of cyclical storage operation. It was found that the amount of non-recoverable cushion gas is fundamentally influenced by the duration of the initial hydrogen filling period, the hydrogen flow rate, and the timing of the upconing occurrence. Upconing is one of the main technical barriers to hydrogen storage in deep saline aquifers. The ratio of non-recoverable cushion gas to cushion gas (NRCG/CG) decreases with an increasing amount of cushion gas. The highest ratio, 0.63, was obtained in the shortest 2-year initial filling period. The lowest ratio, 0.35, was obtained when utilizing the longest initial filling period of 4 years and employing the largest amount of cushion gas. The presented cases of cushion gas recovery can help investors decide which storage option is the most advantageous based on the criteria that are important to them.

IntroductionEndometriosis is a common gynecological disorder affecting approximately 10–15% of women of reproductive age. The main complaints of patients with endometriosis are pain and fertility problems. Symptoms of endometriosis can impact the psychological functioning of the patients and significantly compromise their mental health.Methods The aim of this review was to assess the prevalence of depressive and anxiety symptoms and quality of life in endometriosis patients. For this systematic review, we searched the PubMed, MEDLINE, ProQuest, EMBASE, Cochrane, CINAHL, Google Scholar, Scopus, and ScienceDirect electronic databases up to March 2023 to identify potentially relevant studies. The systematic review in the present paper is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance.ResultsOf four records identified, 18 were eligible to be reviewed on the association between endometriosis and symptoms of depression and anxiety. Of 8,901 records identified, 28 were reviewed on the association between endometriosis and quality of life. The reviewed articles showed a prevalence ranging from 9.8 to 98.5% for depressive symptoms and 11.5 to 87.5% for anxiety. The quality of life in patients with endometriosis was significantly impaired, regardless of the tool used for evaluation.DiscussionThis systematic review shows that endometriosis is associated with depressive and anxiety symptoms and impaired HRQoL. Broad correlating factors modulate mental health outcomes, indicating the complex relationship between the disease and the psychological health of the patients.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

W artykule przedstawiono wyniki badań, w których uczestniczyło 37 dzieci ze spektrum autyzmu oraz 12 dzieci z afazją rozwojową wieku od 2,6 do 8,1 lat. Zostały one ocenione za pomocą Testu Rozumienia Zdań, Przesiewowego Testu Logopedycznego oraz Skali Inte­ligencji Stanford‑Binet. Okazało się, że badane dzieci autystyczne oraz dzieci afatyczne mają inteligencję na pograniczu niepełnosprawności intelektualnej oraz są opóźnione w rozwoju mowy. Nie stwierdzono między nimi istotnych statystycznie różnic w zakresie rozumienia języka. Dzieci autystyczne uzyskały znacznie wyższe wyniki niż dzieci afatyczne w próbach oceniających słownik, gramatykę i wymowę. Stwierdzono także wysoką zależność między wynikami w Teście Rozumienia Zdań oraz Przesiewowym Teście Logopedycznym. Nato­miast korelacja między rozumieniem języka a inteligencją niewerbalną okazała się nieistot­na statystycznie.