MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes.

Oxidation processes in mitochondria and different environmental insults contribute to unwarranted accumulation of reactive oxygen species (ROS). These, in turn, rapidly damage intracellular lipids, proteins, and DNA, ultimately causing aging and several human diseases. Cells have developed different and very effective systems to control ROS levels. Among these, removal of excessive amounts is guaranteed by upregulated expression of various antioxidant enzymes, through activation of the NF-E2-Related Factor 2 (NRF2) protein. Here, we show that Mitogen Activated Protein Kinase 15 (MAPK15) controls the transactivating potential of NRF2 and, in turn, the expression of its downstream target genes. Specifically, upon oxidative stress, MAPK15 is necessary to increase NRF2 expression and nuclear translocation, by inducing its activating phosphorylation, ultimately supporting transactivation of cytoprotective antioxidant genes. Lungs are continuously exposed to oxidative damages induced by environmental insults such as air pollutants and cigarette smoke. Interestingly, we demonstrate that MAPK15 is very effective in supporting NRF2-dependent antioxidant transcriptional response to cigarette smoke of epithelial lung cells. Oxidative damage induced by cigarette smoke indeed represents a leading cause of disability and death worldwide by contributing to the pathogenesis of different chronic respiratory diseases and lung cancer. Therefore, the development of novel therapeutic strategies able to modulate cellular responses to oxidative stress would be highly beneficial. Our data contribute to the necessary understanding of the molecular mechanisms behind such responses and identify new potentially actionable targets.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Peripheral muscle oxygenation, pain, and disability indices in individuals with and without nonspecific neck pain, before and after myofascial reorganization®: A double-blind randomized controlled trial.

To investigate whether myofascial reorganization® in the trapezius muscle (MRT) improves peripheral muscle oxygenation and pain tolerance and decreases neck disability index (NDI) scores in individuals with and without nonspecific neck pain (NP) using a double-blind randomized controlled trial. Seventy-five subjects were equally and randomly assigned to three groups: the intervention groups (experimental [EG] and sham sSG]) and the control group (CG). Several inclusion criteria were applied to the intervention groups: male or female, aged 18-32 years, self-reported NP in the last 3 months without a defined cause; at least "soft" pain in session 1 of the NDI, and at least a score of 1 on the Visual Analogue Scale (VAS). The CG was required to have NDI and VAS scores of 0 at recruitment. Intervention: The EG underwent MRT for 10 min, once a week for 6 weeks. Patients with NP in the SG underwent classical massage for the same duration and frequency. Patients in the CG had no pain and underwent no intervention. Data collection was performed using the NDI Questionnaire, a pressure algometer for pain evaluation, and near-infrared spectroscopy for muscle oxygenation measurements. It was registered as NCT03882515 at ClinicalTrials.gov. The NDI score in both the EG (p<0.001) and SG (p<0.001) decreased after 6 weeks of intervention compared to the CG. The CG demonstrated a lower basal tissue saturation (TSI) index than the EG (p<0.001) and SG (p = 0.02). The EG demonstrated higher oxyhemoglobin values than the SG (p<0.001) and CG (p = 0.03). The CG had higher pain tolerance than the EG (p = 0.01) and SG (p<0.001) post-intervention. MRT increased trapezius muscle oxygenation after 6 weeks of intervention.

Factors associated with HPV-associated sexual risk behaviors among sexually active college students.

High-risk sexual behavior is the primary risk factor for the acquisition and persistence of human papillomavirus (HPV) infection and the development of HPV-associated diseases including cancer. Incidence of HPV infection is high among individuals in their late teens and early 20s. Thus, college students represent a historically high-risk group for HPV infection yet are also a group with the ability to independently access HPV vaccination for HPV prevention. To inform future interventions, we examined factors associated with HPV-associated risky sexual behaviors among sexually active college students. Data (N = 741) were from an anonymous online survey distributed to students at a public Midwestern university in 2021. The outcomes were HPV-associated sexual risk behaviors-number of oral or vaginal sexual partners [high (≥ 5) or low (< 5)] and age of oral or vaginal sexual debut [early (< 18 years) or late (≥ 18 years)]. Multivariable logistic regression models estimated the association between HPV-associated risky sexual behaviors and several predictors including age, gender, relationship status, academic level, country of birth, and rural-urban status. Among sexually active students, approximately 47% and 41% had a high number of lifetime vaginal and oral partners, respectively. Among the same group, 60% and 64% had early vaginal and oral sexual debut. Students who were single and dating (aOR = 1.93; 95% CI = 1.21, 3.08) or single and not dating (2.11; 1.28, 3.48) were more likely to have a high number of vaginal lifetime partners compared with married students. Single (vs. married) students were also about twice as likely to have a high number of oral lifetime partners. Relative to graduate students, freshmen/sophomores were more likely to have an early vaginal (2.44; 1.45, 4.11) and oral (2.14; 1.26, 3.63) sexual debut. Interventions tailored to college freshmen/sophomores and unmarried students should encourage students to receive the HPV vaccine for prevention of future HPV-associated diseases.

UMG1/CD3ε-bispecific T-cell engager redirects T-cell cytotoxicity against diffuse large B-cell lymphoma.

UMG1 is a unique epitope of CD43, not expressed by normal cells and tissues of haematopoietic and non-haematopoietic origin, except thymocytes and a minority (<5%) of peripheral blood T lymphocytes. By immunohistochemistry analysis of tissue microarray and pathology slides, we found high UMG1 expression in 20%-24% of diffuse large B-cell lymphomas (DLBCLs), including highly aggressive BCL2high and CD20low cases. UMG1 membrane expression was also found in DLBCL bone marrow-infiltrating cells and established cell lines. Targeting UMG1 with a novel asymmetric UMG1/CD3ε-bispecific T-cell engager (BTCE) induced redirected cytotoxicity against DLBCL cells and was synergistic with lenalidomide. We conclude that UMG1/CD3ε-BTCE is a promising therapeutic for DLBCLs.

Seeing emotions in the eyes: a validated test to study individual differences in the perception of basic emotions.

People are able to perceive emotions in the eyes of others and can therefore see emotions when individuals wear face masks. Research has been hampered by the lack of a good test to measure basic emotions in the eyes. In two studies respectively with 358 and 200 participants, we developed a test to see anger, disgust, fear, happiness, sadness and surprise in images of eyes. Each emotion is measured with 8 stimuli (4 male actors and 4 female actors), matched in terms of difficulty and item discrimination. Participants reliably differed in their performance on the Seeing Emotions in the Eyes test (SEE-48). The test correlated well not only with Reading the Mind in the Eyes Test (RMET) but also with the Situational Test of Emotion Understanding (STEU), indicating that the SEE-48 not only measures low-level perceptual skills but also broader skills of emotion perception and emotional intelligence. The test is freely available for research and clinical purposes.

Myofascial release strategies and technique recommendations for athletic performance: A systematic review.

OBJECTIVE: To identify the effects of instrument-assisted soft tissue mobilization (IASTM) and foam roller self-myofascial release (FRSMR) strategies and verify their results in athletic performance. METHOD: Systematic review conducted in four databases from 2017. The inclusion criteria were randomized controlled trials assessing the effects of two forms of soft tissue mobilization on athletes' performance. The risk of bias was analyzed using the Cochrane Handbook scale. RESULTS: Ten studies were included for qualitative analysis. IASTM increased range of motion, knee joint kinetic force, peak torque, and angular velocity in dorsiflexion and plantar flexion. The technique increases isometric strength and isokinetic power in vertical jumping. FRSMR was relevant in counter movement jumping between the pre- and post-intervention conditions, mainly by increasing strength in the initial jumping phase. CONCLUSIONS: IASTM should be used in sports preparation to improve muscle response and explosive force production. FRSMR increases flexibility as it tends to restore tissue elasticity, but it does not improve aerobic activity. The suggested time for strategy intervention is at least 90 s per muscle group.

Enrichment of Aerobic and Anaerobic Hydrocarbon-Degrading Bacteria from Multicontaminated Marine Sediment in Mar Piccolo Site (Taranto, Italy).

Marine sediments act as a sink for the accumulation of various organic contaminants such as polychlorobiphenyls (PCBs). These contaminants affect the composition and activity of microbial communities, particularly favoring those capable of thriving from their biodegradation and biotransformation under favorable conditions. Hence, contaminated environments represent a valuable biological resource for the exploration and cultivation of microorganisms with bioremediation potential. In this study, we successfully cultivated microbial consortia with the capacity for PCB removal under both aerobic and anaerobic conditions. The source of these consortia was a multicontaminated marine sediment collected from the Mar Piccolo (Taranto, Italy), one of Europe's most heavily polluted sites. High-throughput sequencing was employed to investigate the dynamics of the bacterial community of the marine sediment sample, revealing distinct and divergent selection patterns depending on the imposed reductive or oxidative conditions. The aerobic incubation resulted in the rapid selection of bacteria specialized in oxidative pathways for hydrocarbon transformation, leading to the isolation of Marinobacter salinus and Rhodococcus cerastii species, also known for their involvement in aerobic polycyclic aromatic hydrocarbons (PAHs) transformation. On the other hand, anaerobic incubation facilitated the selection of dechlorinating species, including Dehalococcoides mccartyi, involved in PCB reduction. This study significantly contributes to our understanding of the diversity, dynamics, and adaptation of the bacterial community in the hydrocarbon-contaminated marine sediment from one sampling point of the Mar Piccolo basin, particularly in response to stressful conditions. Furthermore, the establishment of consortia with biodegradation and biotransformation capabilities represents a substantial advancement in addressing the challenge of restoring polluted sites, including marine sediments, thus contributing to expanding the toolkit for effective bioremediation strategies.

Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations.

Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells. These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of long-range interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells. TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.

The social relevance and the temporal constraints of motor resonance in humans.

In humans, motor resonance effects can be tracked by measuring the enhancement of corticospinal excitability by action observation. Uncovering factors driving motor resonance is crucial for optimizing action observation paradigms in experimental and clinical settings. In the present study, we deepen motor resonance properties for grasping movements. Thirty-five healthy subjects underwent an action observation task presenting right-hand grasping movements differing from their action goal. Single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex at 100, 200, or 300 ms from the onset of the visual stimulus depicting the action. Motor-evoked potentials were recorded from four muscles of the right hand and forearm. Results show a muscle-specific motor resonance effect at 200 ms after movement but selectively for observing a socially relevant grasp towards another human being. This effect correlates with observers' emotional empathy scores, and it was followed by inhibition of motor resonance at 300 ms post-stimulus onset. No motor resonance facilitation emerged while observing intransitive hand movement or object grasping. This evidence highlights the social side of motor resonance and its dependency on temporal factors.

The impact of laparoscopic gynecological surgery training on the technicity index of a developing country center.

PURPOSE: To compare laparoscopic gynecological surgery training between a developed country's reference center (host center) and a public reference service in a developing country (home center), and use the technicity index (TI) to compare outcomes and to determine the impact of laparoscopic gynecological surgery fellowship training on the home center's TI. METHODS: The impact of training on the home center was assessed by comparing surgical performance before and after training. TI was assessed in 2017 in the host center, and before and after training in the home center. Epidemiological and clinical data, and information on reason for surgery, preoperative images, estimated intraoperative bleeding, operative time, surgical specimen weight, hospital stay length, complication and reintervention rates were collected from both institutions. Home center pre-training data were retrospectively collected between 2010 and 2013, while post-training data were prospectively collected between 2015 and 2017. A two-tail Z-score was used for TI comparison. RESULTS: The analysis included 366 hysterectomies performed at the host center in 2017, and 663 hysterectomies performed at the home center between 2015 and 2017. TI in the host center was 82.5%, while in the home center it was 6% before training and 22% after training. There were no statistical differences in length of hospital stay, preoperative uterine volume, surgical specimen weight and complication rate between centers. However, significantly shorter mean operative time and lower blood loss during surgery were observed in the host center. CONCLUSIONS: High-quality laparoscopic training in a world-renowned specialized center allowed standardizing laparoscopic hysterectomy procedures and helped to significantly improve TI in the recipient's center with comparable surgical outcomes.

Back in Person: Frontiers in Medicinal Chemistry 2023.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3rd to 5th 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021-2022) of entirely virtual meetings, due to the COVID-19 pandemic, the FiMC could be held in a face-to-face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GÖCH), the Austrian Pharmaceutical Society (ÖPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries. The program included 38 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 102 posters were presented in two highly interactive poster sessions.

In Vitro Evaluation of Photodynamic Activity of Plant Extracts from Senna Species against Microorganisms of Medical and Dental Interest.

Background: Bacterial resistance requires new treatments for infections. In this context, antimicrobial photodynamic therapy (aPDT) is an effective and promising option. Objectives: Three plant extracts (Senna splendida, Senna alata, and Senna macranthera) were evaluated as photosensitizers for aPDT. Methods: Cutibacterium acnes (ATCC 6919), Streptococcus mutans (ATCC 35668), Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 90028) were evaluated. Reactive oxygen species production was also verified. Oral keratinocytes assessed cytotoxicity. LC-DAD-MS analysis identified the chemical components of the evaluated extracts. Results: Most species cultured in the planktonic phase showed total microbial reduction (>6 log10 CFU/mL/p < 0.0001) for all extracts. C. albicans cultured in biofilm showed total microbial reduction (7.68 log10 CFU/mL/p < 0.0001) for aPDT mediated by all extracts. Extracts from S. macranthera and S. alata produced the highest number of reactive oxygen species (p < 0.0001). The S. alata extract had the highest cell viability. The LC-DAD-MS analysis of active extracts showed one naphthopyrone and seven anthraquinones as potential candidates for photoactive compounds. Conclusion: This study showed that aPDT mediated by Senna spp. was efficient in microbial suspension and biofilm of microorganisms of medical and dental interest.

College Students' Awareness of the Link Between Human Papillomavirus (HPV) and HPV-Associated Cancers.

We describe the level of awareness of the link between HPV and HPV-associated cancers and identify demographic and lifestyle factors associated with awareness. This was a cross-sectional study of college students (n = 862) at a public Midwestern university conducted between February and May 2021. The outcomes were student's awareness-accessed by asking students if they knew whether HPV was causally link with anal, cervical, vaginal, oropharyngeal, vulvar, and penile cancers. Logistic regression models estimated the association between sociodemographic and sexual behavior and awareness of the link between HPV and HPV-associated cancers. Approximately 70% were aware that HPV causes cervical, 53% were aware HPV causes vaginal, 40% were aware HPV causes vulvar cancers, 39% were aware HPV causes oropharyngeal, 38% were aware HPV causes penile, and 34% were aware HPV causes anal cancers. In multivariable analyses, men were less likely to be aware that HPV causes vaginal (aOR = 0.42, 95% CI 0.30-0.59) or vulvar cancers (aOR = 0.54, 95% CI 0.38-0.77) compared to women. Compared with sexually naïve students, those who had have oral and vaginal sex were more likely to be aware that HPV causes anal (aOR = 1.98, 95% CI 1.17-3.34), penile (aOR = 1.82, 95% CI 1.11-2.97), vaginal (aOR = 1.81, 95% CI 1.14-2.88), or vulvar (aOR = 2.05, 95% CI 1.24-3.40) cancers. Awareness of the link between HPV and HPV-associated cancers was low, except cervical. This underscores the need for more tailored interventions to increase knowledge about HPV and its association with cancer. Increasing students' levels of awareness may impact HPV vaccine uptake.

Flavonoids composition, antioxidant, anticholinesterase, and cytotoxic activities of flowers extract of Senna cearensis Afr. Fern.

The Senna genus has a wide diversity of species, with an interesting chemical composition of secondary metabolites and applications as medicine. The folk medicine, mainly in developing countries, uses species of Senna to treat seizures, epilepsy and constipation. Though the recognized bioactivity, some Brazilian native species of Senna remain unexplored, such as Senna cearensis, a native species of Caatinga. This is the first report about the bioactivity of the flowers of S. cearensis Afr. Fern., a native species of northeast Brazil. In this communication, flavonoids and catechins are identified in S. cearensis flowers and the chemical composition is linked with its antioxidant, anticholinesterase, and cytotoxic activities. By UPLC-QTOF, some compounds that belong to the class of flavonoids were identified. They are: catechin, epigallocatechin, guibourtinidol-(4α-8)-catechin, and cassiaflavan-(Cat)-epicatechin. The cytotoxic activity is more noticeable for the HL60 (leukemia) cell line with a cell growth inhibition (GI%) of 81.65 ± 5.65.

Association between Sexual Activity and Human Papillomavirus (HPV) Vaccine Initiation and Completion among College Students.

HPV vaccination is most effective if received before initiation of sexual activity. Previous studies suggested that young adult women who were not sexually active were not interested in receiving the vaccine because they did not think it was necessary. Whether this misperception is still prevalent today-and also shared by men-is unknown. This study examined whether sexual activity was associated with HPV vaccine uptake (initiation and completion) among university students. A cross-sectional study was conducted between February and May 2021 among students (n = 951) at a public Midwestern University. Sexual activity was categorized as "never" or "ever" had oral and/or vaginal sex. Outcome variables were HPV vaccine initiation, defined as receipt of ≥1 dose, and completion, defined as receipt of ≥3 doses. Multivariable logistic regression models estimated the association between sexual activity and HPV vaccine uptake, adjusting for sociodemographic factors. Approximately 18% of students reported never engaging in sexual activity. Overall, 45.5% initiated the HPV vaccine, and 16.5% completed the vaccine series. After adjusting for covariates, compared to students that reported never engaging in sexual activity, those that had ever engaged in sexual activity were more likely to have initiated the vaccine series (aOR = 2.06, 95% CI: 1.34-3.17); however, no difference was observed for completion. HPV vaccination was low; sexually naïve students were less likely to initiate the HPV vaccine. Since sexually naïve students may benefit from receiving the HPV vaccination, targeted interventions should be implemented towards this population to help increase vaccination rates and prevent HPV-associated diseases.

Hydrophilic Versus Hydrophobic Coupling in the Pressure Dependence of the Chemical Potential of Alkali Metal and Halide Ions in Water.

We computed the chemical potential for some alkali metal ions (K+, Rb+, and Cs+) and two halide ions (Br- and I-) in aqueous solution at ambient T and various pressures in the range 1-8000 atm. Results were obtained from classic Monte Carlo simulations in the NPT ensemble by means of the free energy perturbation method. Here, the chemical potential is computed as the sum of a term relative to a Lennard-Jones solute and a term relative to the process in which this solute is transformed into the ion. Hydrophobic and hydrophilic features of these two components of the chemical potential show opposite behaviors under isothermal compression. The increase in pressure determines an increase in the hydrophobic component, which becomes more positive with a stronger effect for larger ions. Correspondingly, the values of the hydrophilic component become more negative for alkali ions, whereas they are only slightly affected by compression for halide ions. Hydrophobic-hydrophilic quasi-compensation in the slopes is observed for Rb+. For a smaller ion, such as K+, the dependence on pressure of the hydrophilic component is slightly dominant. For a larger ion, as observed in the cases of Cs+, Br-, and I-, the hydrophobic component assumes the determinant role. Pressure dependence of the chemical potential is little affected by corrections introduced for molecular potential truncation. This view can change for possible boundary artifacts that could have affected the static electrostatic potential. Some inference is obtained from comparison with experimental data at 1 atm on the free energy of hydration. Discrepancies show the characteristic asymmetry between cations and anions. The further addition of a correction based on the static potential significantly reduces these discrepancies with important error cancellation on the sum of chemical potentials of ions of opposite charge. The correction is applied also at higher pressures, and results are compared with those obtained by adding an alternative correction that is based on the water number density. Regardless of the ion, changes of the chemical potential induced by an increase in pressure appear to be dominated by the hydrophobic component, in particular when using the alternative correction. For bromide and iodide electrolytes, the two corrections give chemical potentials in good agreement.

The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development.

Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is universally enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein-Barr virus (EBV) LMP1, Kaposi's sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) Tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate on recent findings on virus-telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer-causing viruses.

Frontiers in Medicinal Chemistry 2022 Goes Virtual.

The Frontiers in Medicinal Chemistry (FiMC) meeting, which represents the largest international medicinal chemistry conference in Germany, took place from March 14th to 16th 2022 in a fully virtual format. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh) together with the Division of Pharmaceutical & Medicinal Chemistry of the German Pharmaceutical Society (DPhG) and a "local" organization committee from the University of Freiburg headed by Manfred Jung, the meeting brought together 271 participants from around 20 countries. The program included 33 lectures by leading scientists from industry and academia as well as early career investigators. 67 posters were presented in two poster sessions and with over 20.000 poster abstract downloads. The general organization and the time-shift function were very much appreciated as demonstrated by almost 600 on-demand contents retrieved. The online format fitted perfectly to bring together medicinal chemists from academia and industry across the globe.