Investigating self-reported efficacy of lifestyle medicine approaches to tackle erectile dysfunction: a cross-sectional eSurvey based study.

BACKGROUND: Erectile dysfunction (ED) is the most common sexual dysfunction in men. Some types of ED are amenable to treatment using lifestyle medicine approaches with or without pharmacotherapy. AIM: Investigate self-reported efficacy of lifestyle medicine approaches to tackle ED. METHODS: A cross-sectional online survey of 1177 community dwelling adults explored the prevalence and methods used to tackle ED in the community setting. We examined differences between participants with and without ED. Variables associated with ED in univariable analyses were included in a multivariable logistic regression to identify variables independently associated with the condition. OUTCOMES: Self-reported measure: perceived effectiveness of lifestyle medicine interventions to tackle ED. RESULTS: Most respondents (76.5%) had experienced ED, and this was associated with having a long-term condition, taking anti-hypertensive medication, hypercholesterolaemia and obesity. Medication was the most common management strategy overall (65.9%), followed by stress management (43.5%) and weight loss (40.4%). Over half (53.9%) did not use any lifestyle modification strategies to tackle ED. Only 7.0% of ED sufferers received a mental health assessment and 29.2% received other tests (e.g., blood test, medical imaging) by GPs. Cardiovascular training was identified as the best rated strategy by its users (37.8%). Supplements (35.1%) and weight training/physical activity (32.6%) were also positively rated. CLINICAL IMPLICATIONS: Structured education to general practitioners and community dwelling adults about the impact of lifestyle behaviour modification and how this could influence the appearance or trajectory of ED could help improve personal choice when tackling ED. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first study to collect eSurvey responses from community dwelling adults to gauge their reliance and perceived effectiveness of lifestyle medicine approaches to tackle ED. The principal limitation was the lack of follow-up, and not recording other information including lifestyle factors such as nutrition, smoking, and the use of alcohol and recreational drugs, which may have enabled a fuller exploration of the factors that could influence the primary outcome measures examined. CONCLUSION: Despite the high prevalence of ED, there is not enough awareness in the community setting about effective and low-cost lifestyle medicine strategies, including cardiovascular training and the use of supplements and weight training, to help tackle this common condition.

Erectile dysfunction (ED) is the most common sexual dysfunction in men. Some types of ED can be treated using lifestyle medicine approaches with or without the use of medicines. The aim of this study was to investigate self-reported efficacy of lifestyle medicine approaches to tackle ED. We conducted a cross-sectional online survey of 1177 community dwelling adults to explore the prevalence, methods and perceived effectiveness of lifestyle medicine approaches to tackle ED in the community setting. Most respondents (76.5%) had experienced ED, and this was associated with having a long-term condition, taking anti-hypertensive medication, high blood cholesterol and obesity. After medication stress management (43.5%) and weight loss (40.4%) were most frequently cited lifestyle medicine intervention. Cardiovascular training was identified as the best rated strategy by its users (37.8%). To our knowledge, this is the first study to collect eSurvey responses from community dwelling adults to gauge their reliance and perceived effectiveness of lifestyle medicine approaches to tackle ED. Despite the high prevalence of ED, there is not enough awareness in the community setting about effective and low-cost lifestyle medicine strategies, including cardiovascular training and the use of supplements and weight training, to help tackle this common condition.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

Tibial bone forces can be monitored using shoe-worn wearable sensors during running.

Tibial bone stress injury is a common overuse injury experienced by runners, which results from repetitive tissue forces. Wearable sensor systems (wearables) that monitor tibial forces could help understand and reduce injury incidence. However, there are currently no validated wearables that monitor tibial bone forces. Previous work using simulated wearables demonstrated accurate tibial force estimates by combining a shoe-worn inertial measurement unit (IMU) and pressure insole with a trained algorithm. This study aimed assessed how accurately tibial bone forces could be estimated with existing wearables. Nine recreational runners ran at a series of different speeds and slopes, and with various stride patterns. Shoe-worn IMU and insole data were input into a trained algorithm to estimate peak tibial force. We found an average error of 5.7% in peak tibial force estimates compared with lab-based estimates calculated using motion capture and a force instrumented treadmill. Insole calibration procedures were essential to achieving accurate tibial force estimates. We concluded that a shoe-worn, multi-sensor system is a promising approach to monitoring tibial bone forces in running. This study adds to the literature demonstrating the potential of wearables to monitor musculoskeletal forces, which could positively impact injury prevention, and scientific understanding.

Phytochemical Characterization, Antioxidant Activity, and Cytotoxicity of Methanolic Leaf Extract of Chlorophytum Comosum (Green Type) (Thunb.) Jacq.

Chlorophytum genus has been extensively studied due to its diverse biological activities. We evaluated the methanolic extract of leaves of Chlorophytum comosum (Green type) (Thunb.) Jacques, the species that is less studied compared to C. borivilianum. The aim was to identify phytoconstituents of the methanolic extract of leaves of C. comosum and biological properties of its different fractions. Water fraction was analyzed with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Nineteen compounds belonging to different chemical classes were identified in the methanolic extract of leaves of C. comosum (Green type) (Thunb.) Jacques. In addition to several fatty acids, isoprenoid and steroid compounds were found among the most abundant constituents. One of the identified compounds, 4'-methylphenyl-1C-sulfonyl-ß-d-galactoside, was not detected earlier in Chlorophytum extracts. The water fraction was toxic to HeLa cells but not to Vero cells. Our data demonstrate that methanolic extract of leaves of C. comosum can be a valuable source of bioactive constituents. The water fraction of the extract exhibited promising antitumor potential based on a high ratio of HeLa vs. Vero cytotoxicity.

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Ovarian follicular function is not altered by SARS-CoV-2 infection or BNT162b2 mRNA COVID-19 vaccination.

STUDY QUESTION: Does the immune response to coronavirus disease 2019 (COVID-19) infection or the BNT162b2 mRNA vaccine involve the ovarian follicle, and does it affect its function? SUMMARY ANSWER: We were able to demonstrate anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG in follicular fluid (FF) from both infected and vaccinated IVF patients, with no evidence for compromised follicular function. WHAT IS KNOWN ALREADY: No research data are available yet. STUDY DESIGN, SIZE, DURATION: This is a cohort study, composed of 32 consecutive IVF patients, either infected with COVID-19, vaccinated or non-exposed, conducted between 1 February and 10 March 2021 in a single university hospital-based IVF clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: A consecutive sample of female consenting patients undergoing oocyte retrieval was recruited and assigned to one of the three study groups: recovering from confirmed COVID-19 (n = 9); vaccinated (n = 9); and uninfected, non-vaccinated controls (n = 14). Serum and FF samples were taken and analyzed for anti-COVID IgG as well as estrogen, progesterone and heparan sulfate proteoglycan 2 concentration, as well as the number and maturity of aspirated oocytes and day of trigger estrogen and progesterone measurements. Main outcome measures were follicular function, including steroidogenesis, follicular response to the LH/hCG trigger, and oocyte quality biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE: Both COVID-19 and the vaccine elicited anti-COVID IgG antibodies that were detected in the FF at levels proportional to the IgG serum concentration. No differences between the three groups were detected in any of the surrogate parameters for ovarian follicle quality. LIMITATIONS, REASONS FOR CAUTION: This is a small study, comprising a mixed fertile and infertile population, and its conclusions should be supported and validated by larger studies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to examine the impact of SARS-Cov-2 infection and COVID-19 vaccination on ovarian function and these early findings suggest no measurable detrimental effect on function of the ovarian follicle. STUDY FUNDING/COMPETING INTEREST(S): The study was funded out of an internal budget. There are no conflicts of interest for any of the authors. TRIAL REGISTRATION NUMBER: CinicalTrials.gov registry number NCT04822012.

Early autologous and allogeneic peripheral blood stem cell transplantation for adult patients with acute B and T cell precursor neoplasms: a 12-year single center experience.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

Pro- and anti-inflammatory macrophages express a sub-type specific purinergic receptor profile.

Extracellular nucleotides act as danger signals that orchestrate inflammation by purinergic receptor activation. The expression pattern of different purinergic receptors may correlate with a pro- or anti-inflammatory phenotype. Macrophages function as pro-inflammatory M1 macrophages (M1) or anti-inflammatory M2 macrophages (M2). The present study found that murine bone marrow-derived macrophages express a unique purinergic receptor profile during in vitro polarization. As assessed by real-time polymerase chain reaction (PCR), Gαs-coupled P1 receptors A2A and A2B are upregulated in M1 and M2 compared to M0, but A2A 15 times higher in M1. The ionotropic P2 receptor P2X5 is selectively upregulated in M1- and M2-polarized macrophages. P2X7 is temporarily expressed in M1 macrophages. Metabotropic P2Y receptors showed a distinct expression profile in M1 and M2-polarized macrophages: Gαq coupled P2Y1 and P2Y6 are exclusively upregulated in M2, whereas Gαi P2Y13 and P2Y14 are overexpressed in M1. This consequently leads to functional differences between M1 and M2 in response to adenosine di-phosphate stimulation (ADP): In contrast to M1, M2 showed increased cytoplasmatic calcium after ADP stimulation. In the present study we show that bone marrow-derived macrophages express a unique repertoire of purinergic receptors. We show for the first time that the repertoire of purinergic receptors is highly flexible and quickly adapts upon pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.

Ancestry, health, and lived experiences of enslaved Africans in 18th century Charleston: An osteobiographical analysis.

OBJECTIVES: In 2013, the burials of 36 individuals of putative African ancestry were discovered during renovation of the Gaillard Center in downtown Charleston, South Carolina. The Charleston community facilitated a bioarchaeological and mitogenomic study to gain insights into the lives of these unknown persons, referred to as the Anson Street Ancestors, including their ancestry, health, and lived experiences in the 18th century. METHODS: Metric and morphological assessments of skeletal and dental characteristics were recorded, and enamel and cortical bone strontium stable isotope values generated. Whole mitochondrial genomes were sequenced and analyzed. RESULTS: Osteological analysis identified adults, both females and males, and subadults at the site, and estimated African ancestry for most individuals. Skeletal trauma and pathology were infrequent, but many individuals exhibited dental decay and abscesses. Strontium isotope data suggested these individuals mostly originated in Charleston or sub-Saharan Africa, with many being long-term residents of Charleston. Nearly all had mitochondrial lineages belonging to African haplogroups (L0-L3, H1cb1a), with two individuals sharing the same L3e2a haplotype, while one had a Native American A2 mtDNA. DISCUSSION: This study generated detailed osteobiographies of the Anson Street Ancestors, who were likely of enslaved status. Our results indicate that the Ancestors have diverse maternal African ancestries and are largely unrelated, with most being born locally. These details reveal the demographic impact of the trans-Atlantic slave trade. Our analysis further illuminates the lived experiences of individuals buried at Anson Street, and expands our understanding of 18th century African history in Charleston.

Structure, Dynamics, and Accurate Laboratory Rotational Frequencies of the Acrylonitrile-Methanol Complex.

The hydrogen-bonded complex between acrylonitrile (CH2═CHCN) and methanol has been characterized spectroscopically in the millimeter wave range (59.6-74.4 GHz) using a free jet absorption millimeter wave spectrometer. Precise values of the rotational and centrifugal distortion constants were obtained from the measured frequencies of the complex of acrylonitrile with CH3OH and CD3OD. The analysis of the splittings of the rotational lines due to the hindered internal rotation of the methanol methyl group led to the determination of a V3 value of 221.9(7) and 218(5) cm-1 for the complexes of CH3OH and CD3OD, respectively, and these values are about 40% lower than that of free methanol. The structure of the observed conformation is in agreement with the global minimum determined at the MP2/aug-cc-pVTZ level of calculation, and the counterpoise corrected intermolecular binding energy, obtained at the same theoretical level, is De = 26.3 kJ mol-1.

Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

A method for the quantitative determination of glycerophospholipid regioisomers by UPLC-ESI-MS/MS.

Diacyl glycerophospholipids (GPs) belong to the most abundant lipid species in living organisms and consist of a glycerol backbone with fatty acyl groups in sn-1 and sn-2 and a polar head group in the sn-3 position. Regioisomeric mixed diacyl GPs have the same fatty acyl composition but differ in their allocation to sn-1 or sn-2 of the glycerol unit. In-depth analysis of regioisomeric mixed diacyl GP species composed of fatty acyl moieties that are similar in length and degree of saturation typically requires either chemical derivatization or sophisticated analytical instrumentation, since these types of regioisomers are not well resolved under standard ultra-performance liquid chromatography (UPLC) conditions. Here, we introduce a simple and fast method for diacyl GP regioisomer analysis employing UPLC tandem mass spectrometry (MS/MS). This GP regioisomer analysis is based both on minor chromatographic retention time shifts and on major differences in relative abundances of the two fatty acyl anion fragments observed in MS/MS. To monitor these differences with optimal precision, MS/MS spectra are recorded continuously over the UPLC elution profile of the lipid species of interest. Quantification of relative abundances of the regioisomers was performed by algorithms that we have developed for this purpose. The method was applied to commercially available mixed diacyl GP standards and to total lipid extracts of Escherichia coli (E. coli) and bovine liver. To validate our results, we determined regioisomeric ratios of phosphatidylcholine (PC) standards using phospholipase A2-specific release of fatty acids from the sn-2 position of the glycerol backbone. Our results show that most analyzed mixed diacyl GPs of biological origin exhibit significantly higher regioisomeric purity than synthetic lipid standards. In summary, this method can be implemented in routine LC-MS/MS-based lipidomics workflows without the necessity for additional chemical additives, derivatizations, or instrumentation.

Atmospherically relevant acrolein-water complexes: spectroscopic evidence of aldehyde hydration and oxygen atom exchange.

Direct spectroscopic evidence of a reaction occurring between acrolein and water and involving the exchange of an oxygen atom has been obtained by characterizing the non-covalently bound water complexes and their isotopic forms, via rotational spectroscopy. The experimental geometries of the binary and ternary water complexes have been determined, and other stationary points on the reaction path have been characterized using ab initio quantum chemical methods at the MP2/6-311++G(d,p) level. These results can enhance the understanding of the water-mediated atmospherically important reactions involving acrolein.

[Immunity and inflammation in atherosclerosis]. / Immunität und Entzündung bei Arteriosklerose.

There is now overwhelming experimental and clinical evidence that arteriosclerosis is a chronic inflammatory disease. Lessons learned from genome-wide association studies, advanced in vivo imaging techniques, transgenic lineage tracing mice models and clinical interventional studies have shown that both innate and adaptive immune mechanisms can accelerate or curb arteriosclerosis. This article summarizes and discusses the pathogenesis of arteriosclerosis with a focus on the role of the adaptive immune system. Some limitations of animal models are discussed and the need for models that are tailored to better translate to human atherosclerosis and ultimately progress in prevention and treatment are emphasized.

Phosphorylation-dependent regulation of the F-BAR protein Hof1 during cytokinesis.

Spatial and timely coordination of cytokinesis is crucial for the maintenance of organelle inheritance and genome integrity. The mitotic exit network (MEN) pathway controls both the timely initiation of mitotic exit and cytokinesis in budding yeast. Here we identified the conserved F-BAR protein Hof1 as a substrate of the MEN kinase complex Dbf2-Mob1 during cytokinesis. We show that polo-like kinase Cdc5 first phosphorylates Hof1 to allow subsequent phosphorylation by Dbf2-Mob1. This releases Hof1 from the septin ring and facilitates Hof1 binding to the medial actomyosin ring (AMR), where Hof1 promotes AMR contraction and membrane ingression. Domain structure analysis established that the central, unstructured, region of Hof1, named the ring localization sequence (RLS), is sufficient to mediate Hof1's binding to the medial ring in a cell cycle-dependent manner. Genetic and functional data support a model in which Dbf2-Mob1 regulates Hof1 by inducing domain rearrangements, leading to the exposure of the Hof1 RLS domain during telophase.

The Artemisinin Derivative Artemisone Is a Potent Inhibitor of Human Cytomegalovirus Replication.

Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neurosensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The antimalarial artemisinin derivative artesunate was shown to inhibit HCMV in vitro yet has demonstrated limited antiviral efficacy in vivo, prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the innovative artemisinin derivative artemisone, which has been screened for its activity against malaria parasites in human clinical studies, is a potent and noncytotoxic inhibitor of HCMV. Artemisone exhibited an antiviral efficacy comparable to that of ganciclovir (50% effective concentration, 1.20 ± 0.46 µM) in human foreskin fibroblasts, with enhanced relative potency in lung fibroblasts and epithelial cells. Significantly, the antiviral efficacy of artemisone was consistently ≥10-fold superior to that of artesunate in all cells. Artemisone effectively inhibited both laboratory-adapted and low-passage-number clinical strains, as well as drug-resistant HCMV strains. By using quantitative viral kinetics and gene expression studies, we show that artemisone is a reversible inhibitor targeting an earlier phase of the viral replication cycle than ganciclovir. Importantly, artemisone most effectively inhibited HCMV infection ex vivo in a clinically relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings encourage preclinical and clinical studies of artemisone as a new inhibitor against HCMV.

A timeline of stable isotopes and mass spectrometry in the life sciences.

This review retraces the role of stable isotopes and mass spectrometry in the life sciences. The timeline is divided into four segments covering the years 1920-1950, 1950-1980, 1980-2000, and 2000 until today. For each period methodic progress and typical applications are discussed. Application of stable isotopes is driven by improvements of mass spectrometry, chromatography, and related fields in sensitivity, mass accuracy, structural specificity, complex sample handling ability, data output, and data evaluation. We currently experience the vision of omics-type analyses, that is, the comprehensive identification and quantification of a complete compound class within one or a few analytical runs. This development is driven by stable isotopes without competition by radioisotopes. In metabolic studies as classic field of isotopic tracer experiments, stable isotopes and radioisotopes were competing solutions, with stable isotopes as the long-term junior partner. Since the 1990s the number of metabolic studies with radioisotopes decreases, whereas stable isotope studies retain their slow but stable upward tendency. Unique fields of stable isotopes are metabolic tests in newborns, metabolic experiments in healthy controls, newborn screening for inborn errors, quantification of drugs and drug metabolites in doping control, natural isotope fractionation in geology, ecology, food authentication, or doping control, and more recently the field of quantitative omics-type analyses. There, cells or whole organisms are systematically labeled with stable isotopes to study proteomic differences or specific responses to stimuli or genetic manipulation. The duo of stable isotopes and mass spectrometry will probably continue to grow in the life sciences, since it delivers reference-quality quantitative data with molecular specificity, often combined with informative isotope effects. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:58-85, 2017.

Induction Mapping of the 3D-Modulated Spin Texture of Skyrmions in Thin Helimagnets.

Envisaged applications of Skyrmions in magnetic memory and logic devices crucially depend on the stability and mobility of these topologically nontrivial magnetic textures in thin films. We present for the first time quantitative maps of the magnetic induction that provide evidence for a 3D modulation of the Skyrmionic spin texture. The projected in-plane magnetic induction maps as determined from in-line and off-axis electron holography carry the clear signature of Bloch Skyrmions. However, the magnitude of this induction is much smaller than the values expected for homogeneous Bloch Skyrmions that extend throughout the thickness of the film. This finding can only be understood if the underlying spin textures are modulated along the out-of-plane z direction. The projection of (the in-plane magnetic induction of) helices is further found to exhibit thickness-dependent lateral shifts, which show that this z modulation is accompanied by an (in-plane) modulation along the x and y directions.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.