Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g. anticancer treatment, genetic disorders, and enzymatic defects) may be identified. Although hormone replacement therapy, the principal therapeutic approach for POI, helps to alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, the effective approach to manage the patients with POI is highly warranted. Several mechanisms, associated with POI, have been identified, including lack of FSH receptor functioning, alterations in the apoptosis control, mutations in Sal-like 4 genes, thymulin or basonuclin-1 deficiency etc. The above-mentioned may be good targets for gene therapy in order to correct defects, leading to POI. The goal of this review is to summarize the current experience on the POI studies, that employed gene therapy, and to discuss the possible future directions in this field.

Atherosclerosis (AS) is a chronic progressive disease caused by various factors, and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein-cholesterol (LDL-C) is the primary goal in preventing and treating AS. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a crucial role in regulating LDL-C metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20(S) -protopanaxatriol (20(S)-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20(S)-PPT were investigated in vivo and in vitro by western blotting, real time-polymerase chain reaction (RT-PCR), Enzyme-linked Immunosorbent Assay (ELISA), immunofluorescence staining, and other assays. The in vitro experiments revealed that 20(S)-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low density lipoprotein receptor (LDLR) protein levels, promoted LDL uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of FoxO3 protein and mRNA and decreasing the levels of HNF1α protein and mRNA. The in vivo experiments revealed that 20(S)-PPT upregulated aortic αSMA expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol fed in ApoE-/- mice (HCF group). Additionally, 20(S)-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the HCF group. The study revealed that 20(S)-PPT inhibited LDLR degradation via PCSK9 to alleviate AS.

The objective of this study was to investigate age-related changes in cashmere production and the population of active secondary hair follicles in cashmere goats across different age groups, as well as to explore the association between secondary hair follicle activity and oxidative stress. A total of 104 adult Inner Mongolian ewe goats, aged between 2 and 7 years old, were randomly selected as experimental subjects. Skin samples were collected in August 2020 and cashmere samples were collected in April 2021. The cashmere fiber yield, staple length, and diameter showed age-related variations in cashmere goats aged 2 to 7 years (P < 0.05). Cashmere production was higher in goats aged 2-4 years compared to those aged 5-7 years (P < 0.05). There were no significant differences in the population of primary and secondary hair follicles among goats aged 2 to 7 years. However, the population of active secondary hair follicles varied significantly with age, with the younger group (aged 2-4 years) having a higher population than those aged 5 – 7 years (P < 0.05). A moderate negative correlation was observed between cashmere fiber diameter and the population of active secondary hair follicles (P < 0.05). Age-related variations in skin antioxidant capacity and oxidative damage were observed among cashmere goats aged 2 to 7 years old (P < 0.05). Goats aged 2 to 4 years exhibited higher antioxidant capacity and lower oxidative damage (P < 0.05). Interestingly, the skin antioxidant capacity and oxidative damage exhibited significant positive and negative correlations, respectively, with the population of active secondary hair follicles (P < 0.05). This study presents a novel approach to enhance the activity of secondary hair follicles and improve cashmere production performance through the regulation of oxidative stress.

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor‐α (PPARα), with the clinically available agonist fenofibrate, attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 hours after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/CTRL group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1 levels were lower than in veh/CTRL group. Notably, MIP-1, TNF-, GRO/KC, GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, indicating the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate the consequences of MIA.

Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases with transient hypothyroidism, leading to increase of the overall incidence of primary congenital hypothyroidism (CH) in several countries. We have performed retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 hours after birth, between 2002 and 2015, using DELFIA method. A TSH value of 15 mIU/L was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The incidence of primary CH was increased from 1/2489 until to 2010 to 1/1585 thereafter (p=0.131). However, the incidence of permanent CH was slightly increased (p=0.922), while the transient CH incidence had 8-fold increasing after lowering the TSH cutoff level (p<0.001). In cases with permanent CH, we observed lower frequency for thyroid dysgenesis (82.7 vs. 66.7%) and higher frequency for normal in-situ thyroid gland (17.3 vs. 33.3%), for the period with reduced TSH cutoff value. Our findings support the impact of lower TSH cutoff on the increasing incidence of congenital hypothyroidism.

Naturally fermented dairy products are an important component of the human diet. They are a valuable source of nutrients as well as vitamins and minerals. Their importance as a source of probiotic bacterial strains should not be overlooked. A number of studies highlights the positive effects of species of the Lactobacillacea on the intestinal microbiota, the overall homeostasis of the body, as well as a complementary treatment for some diseases. However, data on the effects on intestinal epithelial cells of postmetabolites released by bacteria are incomplete. This is likely due to the fact that these effects are species and strain specific. In the present study, we investigated the effects of postmetabolites produced by a pre-selected candidate probiotic strain Limosilactobacillus fermentum on HT-29 intestinal epithelial cells. Our data showed a pronounced proliferative effect, evaluated by flow cytometry, quantification of cell population, and determination of mitotic index. This was accompanied by stabilization of the cell monolayer, measured by increase of TEER (trans epithelial electric resistance) and reorganization of actin filaments. The data obtained are a clear indication of the positive effects, that the products secreted by L. fermentum strain 53 have on the intestinal epithelial cells.

Seeds from several Ribes taxa were surveyed for phenolic compounds and in vitro antiproliferative activity against HT-29 colorectal cancer cells. Total phenolic compounds were analysed through the Folin-Ciocalteu procedure, while phenolic profiles were analysed by LC coupled to a single mass spectrometer Orbitrap using an electrospray interface (ESI). Antitumor effects were established using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Total phenolics ranged from 11.4 in R. alpinum to 94.8 mg of caffeic acid equivalents (CAE)/g in R. nigrum 'Koksa'. Concerning phenolic compounds, four were hydroxylated benzoic acids, four cinnamic acid derivatives, eight flavonoids, and nine flavonoid glycosides. The growth inhibition against HT-29 cancer cells was exercised much better by R. nigrum 'Koksa' and Ribes 'Erkeeni' (GI50 37 and 42 µg/ml). All Ribes extracts, except R. nigrum 'Hara katarlik', showed higher activity than that of R. rubrum (GI50 at 72 h: 99 µg/ml). Interestingly, the highly bioactive extract from Ribes 'Erkeeni' contains all detected phenolics, while R. nigrum 'Koksa' lacks only populnin. Therefore, the high bioactivity found for such extracts could be due to a synergy due to all detected compounds. This work constitutes a comprehensive action for expanding knowledge on the phenolic profiles and antitumor activity of GLA-rich Ribes seeds.

This study focuses on the potential medicinal properties of Campsis radicans L. extracts and its aim is to investigate the antioxidant and antiproliferative effects of these extracts on the human colon adenocarcinoma cell line (HT-29). Cytotoxic activity in the HT-29 cell line was evaluated, and the 3-dimensional structures of phenolic compounds were obtained using the GC-MS method. Docking simulations were performed with AutoDock Vina, targeting proteins that are crucial in the apoptotic pathway (Bax, Bcl-2, and Caspase-3). Drug similarities and ADMET estimates of the phenolic compounds were obtained from databases. The highest antioxidant activity of Campsis radicans L. plant was observed in ethanol and water extracts, with notable inhibition capacities. While the total phenolic content was highest in ethanol, water, and ether extracts respectively the total flavonoid content was highest in ethanol, then ether, and water extracts. Certain elements were undetectable in mineral determination, and others exceeded the toxic doses for plants. The water extract exhibited dose-dependent cytotoxic activity in the HT-29 cell line, with an IC50 value of 4.47 mg/mL. Molecular docking results revealed the binding of phenolic molecules to the active sites of apoptotic pathway proteins. The findings suggest that Campsis radicans L. plant possesses cytotoxic properties, significant phenolic and flavonoid content, and a high antioxidant capacity. These properties make it a potential candidate for treatment use, emphasizing its potential therapeutic value in the HT-29 cell line. Further research and exploration on the identified phenolic compounds could contribute to the development of novel therapeutic agents.

The development of the ovarian antral follicle is a complex, highly regulated process. Oocytes orchestrate and coordinate the development of mammalian ovarian follicles, and the rate of follicular development is governed by a developmental program intrinsic to the oocyte. Characterizing oocyte signatures during this dynamic process is critical for understanding oocyte maturation and follicular development. Although the transcriptional signature of sheep oocytes matured in vitro and preovulatory oocytes have been previously described, the transcriptional changes of oocytes in antral follicles have not. Here, we used single-cell transcriptomics (SmartSeq2) to characterize sheep oocytes from small, medium, and large antral follicles. We characterized the transcriptomic landscape of sheep oocytes during antral follicle development, identifying unique features in the transcriptional atlas, stage-specific molecular signatures, oocyte-secreted factors, and transcription factor networks. Notably, we identified specific gene and signaling pathways in each antral follicle stage that may reflect oocyte quality and in vitro maturation competency. Additionally, we discovered key biological processes that drive the transition from small to large antral follicles, revealing hub genes involved in follicle recruitment and selection. Thus, our work provides a comprehensive characterization of the single-oocyte transcriptome, filling a gap in the mapping of the molecular landscape of sheep oogenesis. We also provide key insights into the transcriptional regulation of the critical stages of antral follicular development, which is essential for understanding how the oocyte orchestrates follicular development.

The endometrium is an important part of the uterus. The human endometrium is a complex and dynamic tissue that goes through phases of growth and regression during any menstrual cycle. A thin endometrium might be relevant to a lower rate of implantation as well as a higher rate of miscarriage. Several treatments have been developed for thin endometrium, such as granulocyte colony-stimulating factor, stem cell therapy, acupuncture and physical therapy, among others. These approaches have been shown to have effects on the endometrium related to reducing the area of fibrosis, increasing the number of glands, promoting angiogenesis, increasing endometrial thickness, improving tissue structure, and increasing pregnancy rates. This review summarizes the key role of these treatments in repairing thin endometrium and improving clinical pregnancy rates

Ovarian hypofunction or primary ovarian insufficiency (POI) is a common cause in the etiology of female infertility. It is a heterogeneous disorder, affecting approximately 1% of women before the age of 40. The characteristics of POI are menstrual disorders, including amenorrhea and delayed menstruation, accompanied by a raised gonadotrophin level and decreased estradiol level. In recent years, electrophysiology (EP) technology has been advancing rapidly in the diagnosis and treatments of numerous diseases. According to studies, bioelectrical stimulation (BES) therapy is an electrophysiology technology that plays significant roles in numerous diseases, including on the thin endometrium in patients with POI. In this review, the overall research progress of this electrophysiological technology has been discussed in relation to the advancement of primary ovarian insufficiency.

Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16–18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

Endotoxins are toxic substances that widely exist in the environment and can enter the intestine with food and other substances. Intestinal epithelial cells are protected by a mucus layer that contains MUC2 as its main structural component. However, a detailed understanding of the mechanisms involved in the function of the mucus barrier in endotoxin penetration is lacking. Here, we established the most suitable proportion of Caco-2/HT-29 co-culture cells as a powerful tool to evaluate the intestinal mucus layer. Our findings significantly advance current knowledge as focal adhesion and ECM-receptor interaction were identified as the two most significantly implicated pathways in MUC2 small interfering RNA (siRNA)-transfected Caco-2/HT-29 co-culture cells after 24 h of LPS stimulation. When the mucus layer was not intact, LPS was found to damage the tight junctions of Caco-2/HT29 co-cultured cells. Furthermore, LPS was demonstrated to inhibit the integrin-mediated focal adhesion structure and damage the matrix network structure of the extracellular and actin microfilament skeletons. Ultimately, LPS inhibited the interactive communication between the extracellular matrix and the cytoskeleton for 24 h in the siMUC2 group compared with the LPS(+) and LPS(-) groups. Overall, we recognized the potential of MUC2 as a tool for barrier function in several intestinal bacterial diseases.

Keywords: pelvic ultrasound, follicle number per ovary, FNPO, ovarian volume, PCOM, upper normal limits, referral population

Studies have shown that nearly half of rural toddlers in China have cognitive delays due to an absence of stimulating parenting practices, such as early childhood reading, during the critical first three years of life. However, few studies have examined the reasons behind these low levels of stimulating parenting, and no studies have sought to identify the factors that limit caregivers from providing effective early childhood reading practices (EECRP). This mixed-methods study investigates the perceptions, prevalence and correlates of EECRP in rural China, as well as associations with child cognitive development. We use quantitative survey results from 1,720 caregiver-child dyads across 100 rural villages/townships in northwestern China and field observation and interview data with 60 caregivers from these same sites. The quantitative results show significantly low rates of EECRP despite positive perceptions of early reading and positive associations between EECRP and cognitive development. Qualitative results suggest that low rates of EECRP in rural China are not due to the inability to access books, financial or time constraints, or the absence of aspirations. Rather, the low rate of book ownership and absence of reading to young children is driven by the insufficient and inaccurate knowledge of EECRP among caregivers, which leads to their delayed, misinformed reading decisions with their young children, ultimately contributing to developmental delays.

To date, radiation adaptation response has been reported as a low-dose related phenomenon and has been associated with radiation hormesis. Well-known cancers are caused by non-radiation active reactants, in addition to radiation. A model of suppression for radiation-specific cancers was previously reported, but the model did not target radiation-nonspecific cancers. In this paper, we describe kinetic models of radiation-induced suppressors for general radiation non-specific cancers, estimating the dose that induces the maximum hormesis effect while satisfying the condition that the risk is approximately proportional to dose above 100 mSv. It was found that the radiation hormesis effect is maximal at about 20 mSv when the rate constant for generation is the same as the rate constant for decomposition. When the two rate constants are different, the dose at which the radiation hormesis effect is maximized depends on both rate constants, but the dose increases as the two rate constants approach each other, reaching a maximum of about 20 mSv. This conclusion may lead to the discovery of unknown cancer suppressors at low doses and the development of cancer suppression methods in the future.

Hyperplastic dental follicles (HDFs) represent odontogenic hamartomatous lesions originating from pericoronal tissues and are often associated with impacted or embedded teeth. These lesions may occasionally feature unique calcifying bodies, known as calcifying whorled nodules (CWN), characterized by stromal cells arranged in a whorled or spiral fashion. CWNs are typically observed in multiple calcifying hyperplastic dental follicles or regional odontodysplasia. In our study, we examined 40 cases of HDFs, including nine instances with characteristics of CWNs, which were infrequently accompanied by odontodysplasia. Histological examination was conducted on all 40 cases, with immunohistochemical analysis performed on 21 of them. Among the cases with CWN, nine affected a single embedded tooth, with one exception. CWNs exhibited diverse calcifications featuring sparse or entirely deposited psammoma bodies, and some displayed dentinoid formation. Immunohistochemically, stromal cells of HDFs were frequently positive for CD56 and nestin. In contrast, CWNs were negative for CD56 but positive for nestin and HES1, with a few DSP-positive calcified bodies. Our results revealed that hamartomatous calcifying HFDs can impact multiple and single-embedded teeth. CWNs composed of nestin and HES1-positive ectomesenchymal cells demonstrated the potential to differentiate into odontoblasts and contribute to dentin matrix formation under the influence of HES1. This study is the first report documenting odontoblastic differentiation in HDFs.

The objective of this study was to investigate the effects of body weight gain during the cashmere non-growing period on cashmere production performance and secondary hair follicle activity, to provide a theoretical basis for appropriate supplementary feeding of cashmere goats. Fifty Inner Mongolian cashmere goats aged 2-4 years old were randomly selected and weighed in May and September 2019, respectively. Based on body weight gain between the two weights, the experi-mental ewe goats were divided into two groups: 0-5.0 kg group (n = 30) and 5.0-10.0 kg group (n = 20). Skin samples and cashmere samples were collected. Results of Pearson correlation analysis showed that body weight gain during the cashmere non-growing period had a moderate and strong positive correlation with cashmere yield (P = 0.021) and cashmere staple length (P = 0.002) respectively, but did not correlate with cashmere diameter (P = 0.254). Compared with cashmere goats with a body weight gain of 0-5.0 kg, cashmere goats with a body weight gain of 5.0-10.0 kg had a 17.10% increment in cashmere yield (P = 0.037), 8.09% increase in cashmere staple length (P=0.045) and had no significant difference in cashmere diameter (P = 0.324). Results of Pearson correlation analysis showed that there was a strong positive correlation between body weight gain and the population of active secondary hair follicles in the skin of cashmere goats (P < 0.01). Compared with cashmere goats with a body weight gain of 0-5.0 kg, cashmere goats with a body weight gain of 5.0-10.0 kg had an increase in the population of active secondary hair follicles (P < 0.05). In conclusion, the body weight gain during the cashmere non-growing period had a sig-nificant effect on secondary hair follicle activity and cashmere production performance in cash-mere goats. Since body weight gain reflects nutritional level to a certain extent, this study suggests that nutritional manipulations such as supplementary feeding during cashmere non-growing periods can increase cashmere production performance. However, specific nutritional manipula-tions during the cashmere non-growing period need further research to increase cashmere pro-duction performance.

Accurately diagnosing specific variants of alopecia remains challenging for pathologists, potentially delaying appropriate therapeutic decisions by dermatologists. Issues such as limited knowledge on optimal biopsy types and processing methods add complexity. Understanding the normal histology of hair follicles and their changes throughout the follicular cycle further complicates microscopic evaluation. This paper aims to summarize these characteristics and highlight essential diagnostic clues for pathologists to confidently suggest a diagnosis, therefore playing a key role in alopecia diagnosis. Ongoing education, collaboration with dermatologists, and staying updated on advancements is crucial for accurate diagnosis and effective management of different types of alopecia.

The visual appearance of humans derives significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly in the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). Localization of a second ‘immature’ SOX10 negative melanocyte population, which was c-KIT/MITF double positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. These studies describe an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells destined to synthesize mela-nin ultimately or could they contribute to the hair follicle in non-melanogenic ways.

Keywords: Wall-like RC columns; Strengthening; FRP; NSM rebars; Steel plates; Testing; FE modeling; Preloading.

The strategy of any organization is based on the growth of its customer base, and one of 5 its principles is that selling a product to an existing customer is much more profitable than acquiring 6 a new customer. However, this approach has several opportunities for improvement, since it usu- 7 ally has a totally reactive approach, which does not give opportunity to the areas specialized in 8 customer experience and recovery, to give an effective response for that moment, since the customer 9 is gone at the time of the intervention. This happens because usually a diagnostic analysis of cus- 10 tomers who have stopped buying products or services in a defined period, commonly three (3) pe- 11 riods or months, is performed. This thesis work challenges the way to face this problem, and pro- 12 poses the development of a complete solution, which does not focus exclusively on the prediction 13 of churn, as is usually done in the state of the art research, but to intervene in different interactions 14 that can be carried out with customers. The above focused not only to prevent customer churn, but 15 to generate an added value of continuous improvement in sales processes, increase customer pene- 16 tration, leading to an improvement in customer experience and consequently, an increase in cus- 17 tomer loyalty.

The strategy of any organization is based on the growth of its customer base, and one of 5 its principles is that selling a product to an existing customer is much more profitable than acquiring 6 a new customer. However, this approach has several opportunities for improvement, since it usu- 7 ally has a totally reactive approach, which does not give opportunity to the areas specialized in 8 customer experience and recovery, to give an effective response for that moment, since the customer 9 is gone at the time of the intervention. This happens because usually a diagnostic analysis of cus- 10 tomers who have stopped buying products or services in a defined period, commonly three (3) pe- 11 riods or months, is performed. This paper challenges the way to face this problem, and proposes 12 the development of a complete solution, which does not focus exclusively on the prediction of 13 churn, as is usually done in the state of the art research, but to intervene in different interactions 14 that can be carried out with customers. The above focused not only to prevent customer churn, but 15 to generate an added value of continuous improvement in sales processes, increase customer pene- 16 tration, leading to an improvement in customer experience and consequently, an increase in cus- 17 tomer loyalty.

Запропонована методика спрямована на визначення та прогнозування технічного стану елементів мосту, що може слугувати прогресивним інженерним інструментом для оцінки надійності та довговічності. Розроблено на основі фундаментальних досліджень, які узагальнюють досвід вивчення фізико-механічних і фізико-хімічних властивостей матеріалів мостових конструкцій, що експлуатуються в реальних умовах. Теоретичною основою методики є модель надійності та прогнозування залишкового ресурсу елементів мосту на основі теорії Маркова. Розроблена методика призначена для оцінки технічного стану окремих елементів мосту з подальшою комплексною оцінкою всієї конструкції. За показник технічного стану прийнята надійність при експлуатації. Цей кількісний показник надійності в моделі є критерієм для: оцінки рівня безпеки елементів мосту; ранжування елементів мосту за необхідністю для конкретних видів ремонту, реконструкції або заміни; стратегічне планування витрат на ремонт або реконструкцію в умовах обмеженого фінансування; прогнозування залишкового ресурсу елементів. Для застосування розробленої методики запропоновано алгоритм оцінки та прогнозування технічного стану мостів. Було проведено математичний експеримент розробленої методики, який підтвердив адекватність висунутої гіпотези, тобто використання моделі надійності та прогнозування залишкового ресурсу елементів мосту. По-перше, запропоновано триступеневий механізм уточнення технічного стану мосту, суттєво підвищення точності розрахунків. Тому розроблена методика має практичне значення і може слугувати основою для інформаційно-аналітичних систем управління станом мостів.

The timely diagnosis of defects at their incipient stage of formation is crucial to extend the life-cycle of technical appliances. This is the case of mechanical-related stress, either due to long aging degradation processes (e.g., corrosion) or in-operation forces (e.g., impact events), which might provoke detrimental damages, such as cracks, disbonding or delaminations, most commonly followed by the release of acoustic energy. The localization of these sources can be successfully fulfilled via adoption of Acoustic Emission (AE)-based inspection techniques through the computation of the Time of Arrival (ToA), namely the time at which the induced mechanical wave released at the occurrence of the acoustic event arrives to the acquisition unit. However, the accurate estimation of the ToA may be hampered by poor Signal-to-Noise ratios (SNRs). In these conditions, standard statistical methods typically fail. In this work, two alternative Deep Learning methods are proposed for ToA retrieval, namely a Dilated Convolutional Neural Network (DilCNN) and a Capsule Neural Network for ToA (CapsToA). These methods have the additional benefit of being portable on resource-constrained microprocessors. Their performance has been extensively studied on both synthetic and experimental data, focusing on the problem of ToA identification for the case of a metallic plate. Results show that the two novel methods can achieve localization errors which are up to 70% more precise than those yielded by conventional strategies, even when the SNR is severely compromised (i.e., down to 2 dB). Moreover, DilCNN and CapsNet have been implemented in a tiny machine learning environment and then deployed on microcontroller units, showing a negligible loss of performance with respect to offline realizations.

During the last trimester of gestation and for the first 18 months after birth, both docosahexaenoic acid,22:6n-3 (DHA) and arachidonic acid,20:4n-6 (ARA) are preferentially deposited within the cerebral cortex at a rapid rate. Although, the structural and functional roles of DHA in brain development are well investigated, similar roles of ARA are not well documented. The mode of action of these two fatty acids and their derivatives at different structural-functional roles and their levels in the gene expression and signaling pathways of the brain have been continuously emanating. In addition to DHA, importance of ARA has been much discussed in recent years for fetal and postnatal brain development and the maternal supply of ARA and DHA. These fatty acids are also involved in various brain developmental processes; however, their mechanistic cross talks are not clearly known yet. This review describes the importance of ARA, in addition to DHA to support the optimal brain development and growth and functional roles in the brain.

Statistical denoising techniques have been well studied, however many challenges still remain. This 9 article focuses on determining the least necessary number of significant samples in a statistical pop-10 ulation sampling, while minimizing the impact on the statistical detection of the fiber Bragg grating 11 (FBG) power spectra. This is achieved by using Bayesian decision making, small population statis-12 tics while excluding false detection. First, we investigate the impact of two-sided sliding window 13 technique applied near the cell under the test. The window size varies from 8 to 60 samples. The 14 considered maximum size of population sampling is connected with the number of wavelength 15 samples within the bandwidth of the symmetrical FBG power spectra peaks. Regarding the sym-16 metry of FBG power spectra peaks and the possible reduction of computational demands, we inves-17 tigate the impact of a one-sided sliding window. This enables to achieve less processing latency for 18 real time applications thus brings benefits to FBG-based fiber optical sensing. Both, two- and one-19 sided small population sampling techniques are then experimentally verified. Detection results are 20 analyzed in depth via calculating detection thresholds by using the small size window sliding along-21 side the waveband. From results achieved, it was found that the normality three-sigma rule does 22 not need to be followed while using the small population sampling. Experimental demonstrations 23 and analyses showed that the proposed concept of denoising and statistical threshold detection 24 based on the sliding window does not depend on the prior knowledge of probability distribution 25 functions of the FBG power spectra peaks level and background noise. We have also found that the 26 thresholds’ adaptability mainly depends on the statistical numerical characteristics of the above ad-27 ditive mixture of the FBG power spectra peaks signals and background noise.

Thirteen benzylethylenearyl ureas and one carbamate have been designed, synthesized and biologically evaluated as regards their antiproliferative activity on tumor cell lines HEK-293 and A-549 and on the immune and endothelial Jurkat T cells and HMEC-1, respectively. A relationship between the structure of the synthetic compounds and their antiproliferative activity has been established. Compounds C.1, C.3, C.12 and C.14 were chosen for further biological studies in order to determine their potential as oncoimmunomodulating agents. Some compounds exhibited significant inhibitory effects on both total PD-L1 and VEGFR-2 in HT-29 cell line, showing urea C.12 active against both targets. Some compounds could reduce more than 50% of cancer living cells, compared to non-treated ones, when assessed in co-cultures using HT-29 and THP-1 cells. In addition, these compounds showed no effect on the immune cell viability and significantly reduce CD11b expression, which is a promising target for immune modulation in anti-cancer therapies.

The first detection of gypsum (CaSO4.2H2O) by the Mars Science Laboratory (MSL) rover Curiosity in the Gale Crater, Mars created a profound impact on planetary science and exploration. The unique capability of plasma spectroscopy involving in situ elemental analysis in extraterrestrial environments, suggesting the presence of water in the red planet based on phase characterization and providing a clue to Martian paleoclimate. The key to gypsum as an ideal paleoclimate proxy lies in its textural variants, and in this study terrestrial gypsum samples from varied locations and textural types have been analyzed by Laser Induced Breakdown Spectroscopy (LIBS) technique. Petrographic, sub-microscopic and powder X-ray diffraction characterizations confirm the presence of gypsum (hydrated calcium sulphate; CaSO4.2H2O), bassanite (semi-hydrated calcium sulphate; CaSO4.1/2H2O) and anhydrite (anhydrous calcium sulphate; CaSO4) along with accessory phases (quartz and jarosite). The principal component analysis of LIBS spectra from texturally varied gypsums can be differentiated from one another because of the chemical variability in their elemental concentrations. The concentration of gypsum is determined from the partial least-square regressions model. Rapid characterization of gypsum samples with LIBS is expected to work well in extraterrestrial environments.

Delay in data transmission is one of key performance indicators (KPIs) of a network. The planning and project value of delay in network management is of crucial importance for the optimal allocation of network resources and their performance focuses. To create optimal solutions, predictive models, which are currently most often based on machine learning (ML), are used. This paper aims to investigate the training, testing and selection of the best predictive delay model for a VoIP service in an Long Term Evolution (LTE) network using three ML techniques - Neural Networks (NN), Support Vector Machines (SVM) and k-Nearest Neighbors (k-NN). The space of model input variables is optimized by dimensionality reduction techniques: RReliefF algorithm, Backward selection via the recursive feature elimination algorithm and the Pareto 80/20 rule. A three-segment road in the geo-space between the cities of Banja Luka (BL) and Doboj (Db) in the Republic of Srpska (RS), Bosnia and Herzegovina (BiH), covered by the cellular network (LTE) of the M:tel BL operator was chosen for the case study. The results show that, in all three optimization approaches, the k-NN model is selected as the best solution. For the RReliefF optimization algorithm, the best model has 6 inputs and minimum relative error (RE), RE=0.109; for the Backward selection via the recursive feature elimination algorithm, the best model has 4 inputs and RE=0.041; and for the Pareto 80/20 rule, the best model has 11 inputs and RE= 0.049. The comparative analysis of the results concludes that according to observed criteria for the selection of the final model, the best solution is an approach to optimizing the number of predictors based on the Backward selection via the recursive feature elimination algorithm.

This contribution is an attempt to reconstruct the favorable atmosphere that prevailed in Lau-sanne in 1986-87 and provided the backdrop of our invention of two-dimensional ion cyclotron resonance mass spectroscopy (2D ICR-MS). To avoid a self-centered histoire d’ancien combattant, we shall try to emphasize the context, the contributions of key players within our nascent research group at UNIL and the established group of Tino Gäumann at EPFL, the role of external speakers, and the open atmosphere that was not yet polluted by bibliometrics, obsessive concern with im-pact factors, and top-down management of research. We shall also explain why the idea of 2D ICR-MS has been ignored for many years and still has a limited impact: different scientific cul-tures in the ICR and NMR communities, different concerns with fundamental vs. applied research, different status of theory and numerical simulations, different levels of commitment of instrument manufacturers, not to mention many theoretical problems that appear to be at least as challenging in ICR as in NMR.

This paper presents work done as part of a transformation effort towards a greener and more sustainable Aluminium manufacturing plant. The effort includes reducing the carbon footprint by minimising waste and increasing operational efficiency. The contribution of this work includes the reduction of waste through the implementation of autonomous, real-time quality measurement and classification at an Aluminium casthouse. Data is collected from the MV20/20 which uses ultrasound pulses to detect molten Aluminium inclusions, which degrade the quality of the metal and cause subsequent metal waste. The sensor measures cleanliness, inclusion counts and distributions from 20 - 160 microns. The contribution of this work is in the development of business analytics to implement condition-based monitoring through anomaly detection, and to classify inclusion types for samples that failed. For anomaly detection, multivariate K-Means and DBSCAN algorithms are compared as they have been proven to work in a wide range of datasets. For classification, a two-stage classifier is implemented. The first stage classifies the success or failure of the sample, while the second stage classifies the inclusion responsible for the failed sample. The algorithms considered include logistic regression, support vector machine, multi-layer perceptron and radial basis function network. The multi-layer perceptron offers the best performance using k-fold cross-validation, and is further tuned using grid search to explore the possibility of an even better performance. The results reveal that the model has achieved a global maximum in performance. Recommendations include the integration of additional sensor systems and the improvements in quality assurance practices.

A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74, 76-81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site. If these sites are spatially separated in the receptor, then the pharmacophores in the bitopic ligand must be connected with a flexible linker, the length of which exactly corresponds to the distance between the orthosteric and allosteric sites. At the same time, it is important that the linker does not significantly affect the conformational rearrangements in the receptor caused by its activation by orthosteric and (or) allosteric agonists [74, 79].

This study investigates the spatio-temporal variability of the onset, offset, and Length of the rainy season in Senegal over the 1981-2018 period. The onset, offset dates, and length of the rainy season are crucial parameters for agricultural planning in West Africa, which exhibits high interannual and spatial variability in rainfall. The objective is to detect and spatially classify these phenological parameters across Senegal using different approaches. Daily precipitation data from the Climate Hazards group InfraRed Precipitation with Stations (CHIRPS) dataset over the study period and ERA5 reanalysis were used. The method of was applied to detect the onset, offset dates, and length of the rainy season. The Kohonen algorithm was then used to spatially classify these parameters on topological maps. A hierarchical ascendant classification was also performed to reduce the number of classes obtained. Finally, a composite analysis of moisture transport before the onset and end of the 1984 and 2007 seasons was conducted with ERA5 data. The results show a meridional gradient of the start of the season, progressively later from southeast to northwest, while the end follows a north-south gradient. The duration of the rainy season ranges from 45 days in northern Senegal to 150 days in the south. The maximum number of dry days also decreases from north to south. The Kohonen self-organizing maps allow spatial prediction of the onset, end date, and duration of the rainy season across Senegal. The dynamics analysis reveals that early onset years are associated with stronger and earlier northward moisture transport over West Africa, underscoring the role of this parameter in triggering the rainy season. These promising results can provide an early warning to policymakers and farmers on the start and end dates of the season in each area of Senegal.

The literature on the causation of multiple sclerosis (MS), both genetic and environmental, extends over hundreds of years, with no firm conclusions on the exact role of autoimmunity and lifestyle. The epidemiology of MS was the basis for this review, but with a new, extensive examination of genes pertaining to each disorder, and disease of first, and second, degree relatives of those with MS. The author’s motivation was to discover some relationship between MS, and notable familial conditions, as the heredity of MS is concluded to be 30%, and the disorders had a chronic and/or idiopathic nature. This investigation hoped to further understand the randomness of MS- who acquires it, and what symptoms develop- after the author’s decades of observing several incidences of multiple members developing MS in a single family. Online databases for the human genome were used to link genes to MS, and symptoms, including excessive depression, fatigue and suicide rates, in coordination with linking genes for specific familial conditions including seizures, stroke, mental illness, bowel disorders, and thyroid conditions. Interesting associations were found, notably a cluster of Th2 cytokines, known to cure the animal model of MS, important receptors for neurotransmitters and hormones, a gene specific to Epstein Barr Virus, and potential genes for mitochondrial dysfunction. The results surprised the author, showing polygenic regions of chromosome 2 and 5, especially a cluster at loci 5q31-q33, may be dysregulated. The conclusion agrees with past hypotheses MS results not from a single gene, but from various genes, including those expressed in glial cells. The individual theories to the causation of MS, starting with Charcot may be explained by multiple pathways converging into a single disease outcome. In coordination with a sunlight factor, chromosome 2 appears to mediate the immune system, and inflammation, through ultraviolet radiation producing vitamin D3 in the skin, but additionally through peptides formed in the melanocyte stimulating and concentrating hormone class. The impact of stress in MS could be primary, given the loci of several stress-related and stress-modulated genes on these chromosomes, and calls for more appreciation of, and greater care for, the MS patients’ state of mind.

This study investigates the long-term stability of the Suomi National Polar-orbiting Partnership (S-NPP) Visible Infrared Imaging Radiometer Suite (VIIRS) moderate-resolution Thermal Emissive Bands (M TEBs; M12 – M16) covering a period from February 2012 to August 2020. It also assesses inter-sensor consistency of the VIIRS M TEBs among three satellites-S-NPP, NOAA-20, and NOAA-21 over eight months spanning from March 18 to November 30, 2023. The field of interesting is limited to the ocean surface between 60°S and 60°N, specifically under clear-sky conditions. Taking radiative transfer modeling (RTM) as the transfer reference, we employed the Community Radiative Transfer Model (CRTM) to simulate VIIRS TEB brightness temperature (BTs), incorporating European Centre for Medium-range Weather Forecasts (ECMWF) reanalysis data as inputs. Our results reveal two key findings. Firstly, the reprocessed S-NPP VIIRS TEBs exhibit a robust long-term stability, as demonstrated through analyses of the observation minus background BT differences (O-B ∆BTs) between VIIRS measurements (O) and CRTM simulations (B). The drifts of the O-B BT differences are consistently less than 0.105 K/Decade across all S-NPP VIIRS M TEB bands. Notably, observations from VIIRS M14 and M16 stand out with drifts well within 0.04 K/Decade, reinforcing their exceptional reliability for climate change studies. Secondly, excellent inter-sensor consistency among these three VIIRS instruments is confirmed through the double-difference analysis method (O-O). This method relies on the O-B BT differences obtained from daily data. The mean inter-VIIRS O-O BT differences remain within 0.08 K for all M TEBs, except for M13. Even in the case of M13, the O-O BT differences between NOAA-21 and NOAA-20/S-NPP have values of 0.312 K and 0.234 K, respectively, which are comparable to the 0.2 K difference between some TEBs among VIIRS and MODIS. These disparities are primarily attributed to the significant differences in the Spectral Response Function (SRF) of NOAA-21 compared to NOAA-20 and S-NPP. Our study confirms the RTM-based TEB quality evaluation method’s versatility and effectiveness in assessing long-term sensor stability and inter-sensor consistency. The double-difference approach effectively mitigates uncertainties and biases inherent to CRTM simulations, establishing itself a robust mechanism for assessing inter-sensor consistency. In addition, we’ve observed that, except for M13, M12 always exhibits larger spatial variations of O-O BT differences with greater uncertainties compared to the other M TEBs. The influence of solar contribution through sea surface reflection on the Top of Atmosphere (TOA) radiance measurements during daytime in M12 should not be underestimated.