Breaking Bad Proteins-Discovery Approaches and the Road to Clinic for Degraders.

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.

Personalised lifestyle recommendations for type 2 diabetes: Design and simulation of a recommender system on UK Biobank Data.

Mobile health applications, which employ wireless technology for healthcare, can aid behaviour change and subsequently improve health outcomes. Mobile health applications have been developed to increase physical activity, but are rarely grounded on behavioural theory and employ simple techniques for personalisation, which has been proven effective in promoting behaviour change. In this work, we propose a theoretically driven and personalised behavioural intervention delivered through an adaptive knowledge-based system. The behavioural system design is guided by the Behavioural Change Wheel and the Capability-Opportunity-Motivation behavioural model. The system exploits the ever-increasing availability of health data from wearable devices, point-of-care tests and consumer genetic tests to issue highly personalised physical activity and sedentary behaviour recommendations. To provide the personalised recommendations, the system firstly classifies the user into one of four diabetes clusters based on their cardiometabolic profile. Secondly, it recommends activity levels based on their genotype and past activity history, and finally, it presents the user with their current risk of developing cardiovascular disease. In addition, leptin, a hormone involved in metabolism, is included as a feedback biosignal to personalise the recommendations further. As a case study, we designed and demonstrated the system on people with type 2 diabetes, since it is a chronic condition often managed through lifestyle changes, such as physical activity increase and sedentary behaviour reduction. We trained and simulated the system using data from diabetic participants of the UK Biobank, a large-scale clinical database, and demonstrate that the system could help increase activity over time. These results warrant a real-life implementation of the system, which we aim to evaluate through human intervention.

A Point-of-Care Device for Fully Automated, Fast and Sensitive Protein Quantification via qPCR.

This paper presents a fully automated point-of-care device for protein quantification using short-DNA aptamers, where no manual sample preparation is needed. The device is based on our novel aptamer-based methodology combined with real-time polymerase chain reaction (qPCR), which we employ for very sensitive protein quantification. DNA amplification through qPCR, sensing and real-time data processing are seamlessly integrated into a point-of-care device equipped with a disposable cartridge for automated sample preparation. The system's modular nature allows for easy assembly, adjustment and expansion towards a variety of biomarkers for applications in disease diagnostics and personalised medicine. Alongside the device description, we also present a new algorithm, which we named PeakFluo, to perform automated and real-time quantification of proteins. PeakFluo achieves better linearity than proprietary software from a commercially available qPCR machine, and it allows for early detection of the amplification signal. Additionally, we propose an alternative way to use the proposed device beyond the quantitative reading, which can provide clinically relevant advice. We demonstrate how a convolutional neural network algorithm trained on qPCR images can classify samples into high/low concentration classes. This method can help classify obese patients from their leptin values to optimise weight loss therapies in clinical settings.

The association between sedentary behaviour, physical activity and type 2 diabetes markers: A systematic review of mixed analytic approaches.

The negative effect of sedentary behaviour on type 2 diabetes markers is established, but the interaction with measures of physical activity is still largely unknown. Previous studies have analysed associations with single-activity models, which ignore the interaction with other behaviours. By including results from various analytical approaches, this review critically summarises the effects of sedentary behaviour on diabetes markers and the benefits of substitutions and compositions of physical activity. Ovid Medline, Embase and Cochrane Library databases were systematically searched. Studies were selected if sedentary behaviour and physical activity were measured by accelerometer in the general population, and if associations were reported with glucose, insulin, HOMA-IR, insulin sensitivity, HbA1c, diabetes incidence, CRP and IL-6. Forty-five studies were included in the review. Conclusive detrimental associations with sedentary behaviour were determined for 2-h insulin (6/12 studies found associations), fasting insulin (15/19 studies), insulin sensitivity (4/6 studies), diabetes (3/4 studies) and IL-6 (2/3 studies). Reallocating sedentary behaviour to light or moderate-to-vigorous activity has a beneficial effect for 2-h glucose (1/1 studies), fasting insulin (3/3 studies), HOMA-IR (1/1 studies) and insulin sensitivity (1/1 studies). Compositional measures of sedentary behaviour were found to affect 2-h glucose (1/1 studies), fasting insulin (2/3 studies), 2-h insulin (1/1 studies), HOMA-IR (2/2 studies) and CRP (1/1 studies). Different analytical methods produced conflicting results for fasting glucose, 2-h glucose, 2-h insulin, insulin sensitivity, HOMA-IR, diabetes, hbA1c, CRP and IL-6. Studies analysing data by quartiles report independent associations between sedentary behaviour and fasting insulin, HOMA-IR and diabetes only for high duration of sedentary time (7-9 hours/day). However, this review could not provide sufficient evidence for a time-specific cut-off of sedentary behaviour for diabetes biomarkers. While substituting sedentary behaviour with moderate-to-vigorous activity brings greater improvements for health, light activity also benefits metabolic health. Future research should elucidate the effects of substituting and combining different activity durations and modalities.

From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures.

Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Reconfiguration of Amorphous Complex Oxides: A Route to a Broad Range of Assembly Phenomena, Hybrid Materials, and Novel Functionalities.

Reconfiguration of amorphous complex oxides provides a readily controllable source of stress that can be leveraged in nanoscale assembly to access a broad range of 3D geometries and hybrid materials. An amorphous SrTiO3 layer on a Si:B/Si1- x Gex :B heterostructure is reconfigured at the atomic scale upon heating, exhibiting a change in volume of ≈2% and accompanying biaxial stress. The Si:B/Si1- x Gex :B bilayer is fabricated by molecular beam epitaxy, followed by sputter deposition of SrTiO3 at room temperature. The processes yield a hybrid oxide/semiconductor nanomembrane. Upon release from the substrate, the nanomembrane rolls up and has a curvature determined by the stress in the epitaxially grown Si:B/Si1- x Gex :B heterostructure. Heating to 600 °C leads to a decrease of the radius of curvature consistent with the development of a large compressive biaxial stress during the reconfiguration of SrTiO3 . The control of stresses via post-deposition processing provides a new route to the assembly of complex-oxide-based heterostructures in 3D geometry. The reconfiguration of metastable mechanical stressors enables i) synthesis of various types of strained superlattice structures that cannot be fabricated by direct growth and ii) technologies based on strain engineering of complex oxides via highly scalable lithographic processes and on large-area semiconductor substrates.

Erectile Dysfunction Is the Main Correlate of Depression in Men with Chronic Spinal Cord Injury.

Depression is the most prevalent psychological issue after a spinal cord injury (SCI) and is associated with noticeable disability, mortality and health expenditure. As SCI mainly occurs in sexually active men at a young age, and can lead to them suffering from an organic neurogenic erectile dysfunction (ED), we supposed that ED could be a major correlate of depressive status in men with SCI. As documented by a Beck Depression Inventory-II (BDI-II) score ≥14, depression was reported in 17 out of 57 men with a chronic SCI (29.8%). They exhibited a significantly higher prevalence of ED and a more severe bowel and bladder dysfunction when compared to the group without depression. At the multiple logistic regression analysis, depression showed a significant independent association with ED (OR = 19.0, 95% CI: 3.1, 203.3; p = 0.004) and, to a lesser extent, with a severe impairment of bowel and bladder function (OR = 0.84; 95% CI: 0.72, 0.94; p = 0.01). Depression was observed in 43.7% of men with ED and only in 12.0% of those without ED (p = 0.002). In conclusion, healthcare providers should give the right level of importance to the management of ED in men with SCI, as this represents a major independent correlate of depression, which, in turn, might hinder physical rehabilitation and exacerbate physical health issues related to SCI.

Testicular Germ Cell Tumors Acquire Cisplatin Resistance by Rebalancing the Usage of DNA Repair Pathways.

Despite germ cell tumors (GCTs) responding to cisplatin-based chemotherapy at a high rate, a subset of patients does not respond to treatment and have significantly worse prognosis. The biological mechanisms underlying the resistance remain unknown. In this study, by using two TGCT cell lines that have acquired cisplatin resistance after chronic exposure to the drug, we identified some key proteins and mechanisms of acquired resistance. We show that cisplatin-resistant cell lines had a non-homologous end-joining (NHEJ)-less phenotype. This correlated with a reduced basal expression of TP53-binding protein 1 (53BP1) and DNA-dependent protein kinase (DNA-PKcs) proteins and reduced formation of 53BP1 foci after cisplatin treatment. Consistent with these observations, modulation of 53BP1 protein expression altered the cell line's resistance to cisplatin, and inhibition of DNA-PKcs activity antagonized cisplatin cytotoxicity. Dampening of NHEJ was accompanied by a functional increase in the repair of DNA double-strand breaks (DSBs) by the homologous recombination repair pathway. As a result, cisplatin-resistant cells were more resistant to PARP inhibitor (PARPi) monotherapy. Moreover, when PARPi was given in combination with cisplatin, it exerted an additive/synergistic effect, and reduced the cisplatin dose for cytotoxicity. These results suggest that treatment of cisplatin-refractory patients may benefit from low-dose cisplatin therapy combined with PARPi.

Aptasensor for Quantification of Leptin Through PCR Amplification of Short DNA-Aptamers.

Protein quantification is traditionally performed through enzyme-linked immunosorbent assay (ELISA), which involves long preparation times. To overcome this, new approaches use aptamers as an alternative to antibodies. In this paper, we present a new approach to quantify proteins with short DNA aptamers through polymerase chain reaction (PCR) resulting in shorter protocol times with comparatively improved limits of detection. The proposed method includes a novel way to quantify both the target protein and the corresponding short DNA-aptamers simultaneously, which also allows us to fully characterize the performance of aptasensors. Human leptin is used as a target protein to validate this technique, because it is considered an important biomarker for obesity-related studies. In our experiments, we achieved the lowest limit of detection of 100 pg/mL within less than 2 h, a limit affected by the dissociation constant of the leptin aptamer, which could be improved by selecting a more specific aptamer. Because of the simple and inexpensive approach, this technique can be employed for Lab-On-Chip implementations and for rapid "on-site" quantification of proteins.

Self-Winding Helices as Slow-Wave Structures for Sub-Millimeter Traveling-Wave Tubes.

We present a transformative route to obtain mass-producible helical slow-wave structures for operation in beam-wave interaction devices at THz frequencies. The approach relies on guided self-assembly of conductive nanomembranes. Our work coordinates simulations of cold helices (i.e., helices with no electron beam) and hot helices (i.e., helices that interact with an electron beam). The theoretical study determines electromagnetic fields, current distributions, and beam-wave interaction in a parameter space that has not been explored before. These parameters include microscale diameter, pitch, tape width, and nanoscale surface finish. Parametric simulations show that beam-wave interaction devices based on self-assembled and electroplated helices will potentially provide gain-bandwidth products higher than 2 dBTHz at 1 THz. Informed by the simulation results, we fabricate prototype helices for operation as slow-wave structures at THz frequencies, using metal nanomembranes. Single and intertwined double helices, as well as helices with one or two chiralities, are obtained by self-assembly of stressed metal bilayers. The nanomembrane stiffness and built-in stress control the diameter of the helices. The in-plane geometry of the nanomembrane determines the pitch, the chirality, and the formation of single vs intertwined double helices.

Assessing Homologous Recombination and Interstrand Cross-Link Repair in Embryonal Carcinoma Testicular Germ Cell Tumor Cell Lines.

Testicular germ cell tumors (TGCTs) are typically exquisitely sensitive to DNA interstrand cross-link (ICLs) agents. ICLs covalently link both strands of the DNA duplex, impeding fundamental cellular processes like DNA replication to cause cell death. A leading drug used for the treatment of TGCTs is cisplatin, which introduces ICLs and leads to formation of double strand breaks (DSBs), a DNA lesion that can be repaired in the S/G2 phases of the cell cycle by homologous recombination (HR, also termed homology-direct repair). Although most TGCTs respond to cisplatin-induced ICLs, a fraction is resistant to treatment. One proposed mechanism of TGCT resistance to cisplatin is an enhanced ability to repair DSBs by HR. Other than HR, repair of the ICL-lesions requires additional DNA repair mechanisms, whose action might also be implemented in therapy-resistant cells. This chapter describes GFP assays to measure (a) HR proficiency following formation of a DSB by the endonuclease I-SceI, and (b) HR repair induced by site-specific ICL formation involving psoralen. These experimental approaches can be used to determine the proficiency of TGCT cell lines in DSB repair by HR in comparison to HR repair of ICLs, providing tools to better characterize their recombination profile. Protocols of these assays have been adapted for use in Embryonal Carcinoma (EC) TGCT cell lines. Assays only require transient introduction of plasmids within cells, affording the advantage of testing multiple cell lines in a relatively short time.

High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons.

BACKGROUND: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26-28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams-Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. METHODS: We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. RESULTS: We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. LIMITATIONS: In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. CONCLUSIONS: These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism.

Phylogenetic variation in cortical layer II immature neuron reservoir of mammals.

The adult mammalian brain is mainly composed of mature neurons. A limited amount of stem cell-driven neurogenesis persists in postnatal life and is reduced in large-brained species. Another source of immature neurons in adult brains is cortical layer II. These cortical immature neurons (cINs) retain developmentally undifferentiated states in adulthood, though they are generated before birth. Here, the occurrence, distribution and cellular features of cINs were systematically studied in 12 diverse mammalian species spanning from small-lissencephalic to large-gyrencephalic brains. In spite of well-preserved morphological and molecular features, the distribution of cINs was highly heterogeneous, particularly in neocortex. While virtually absent in rodents, they are present in the entire neocortex of many other species and their linear density in cortical layer II generally increased with brain size. These findings suggest an evolutionary developmental mechanism for plasticity that varies among mammalian species, granting a reservoir of young cells for the cerebral cortex.

To acquire new skills or recover after injuries, the mammalian brain relies on plasticity, the ability for the brain to change its architecture and its connections during the lifetime of an animal. Creating new nerve cells is one way to achieve plasticity, but this process is rarer in humans than it is in mammals with smaller brains. In particular, it is absent in the human cortex: this region is enlarged in species with large brains, where it carries out complex tasks such as learning and memory. Producing new cells in the cortex would threaten the stability of the structures that retain long-term memories. Another route to plasticity is to reshape the connections between existing, mature nerve cells. This process takes place in the human brain during childhood and adolescence, as some connections are strengthened and others pruned away. An alternative mechanism relies on keeping some nerve cells in an immature, 'adolescent' state. When needed, these nerve cells emerge from their state of arrested development and 'grow up', connecting with the appropriate brain circuits. This mechanism does not involve producing new nerve cells, and so it would be suitable to maintain plasticity in the cortex. Consistent with this idea, in mice some dormant nerve cells are present in a small, primitive part of the cortex. La Rosa et al. therefore wanted to determine if the location and number of immature cells in the cortex differed between mammals, and if so, whether these differences depended on brain size. The study spanned 12 mammal species, from small-brained species like mice to larger-brained animals including sheep and non-human primates. Microscopy imaging was used to identify immature nerve cells in brain samples, which revealed that the cortex in larger-brained species contained more adolescent cells than its mouse counterpart. The difference was greatest in a region called the neocortex, which has evolved most recently. This area is most pronounced in primates ­ especially humans ­ where it carries out high-level cognitive tasks. These results identify immature nerve cells as a potential mechanism for plasticity in the cortex. La Rosa et al. hope that the work will inspire searches for similar reservoirs of young cells in humans, which could perhaps lead to new treatments for brain disorders like dementia.

Single-Cell Response to the Rigidity of Semiconductor Nanomembranes on Compliant Substrates.

Single-crystalline semiconductor nanomembranes (NMs) bonded to compliant substrates are increasingly used for biomedical research and in health care. Nevertheless, there is a limited understanding of how individual cells sense the unique mechanical properties of these substrates and adjust their behavior in response to them. In this work, we performed proliferation assays, cytoskeleton analysis, and focal adhesion (FA) studies for NIH-3T3 fibroblasts on 220 and 20 nm single-crystalline Si on polydimethylsiloxane (PDMS) substrates with an elastic modulus of ∼31 kPa. We also characterized cell response on bulk Si as a reference. Our in vitro studies show that varying the thickness of the NM between 20 and 220 nm affects the proliferation rate of the cells, their cytoskeleton, fiber organization, spread area, and degree of FA. For example, cultured cells on 220 nm Si/PMDS exhibit the same response as on bulk Si, that is, they are well-spread with a pentagonal (or dendritic) shape and show a good organization of stress fibers and FAs. On the other hand, the cells on 20 nm Si/PDMS are spherical, with fiber organization and FAs in undetectable levels. We explained the results of our in vitro studies through a shear-lag mechanical model. The calculated FA-substrate contact stiffnesses for fibroblasts on bulk Si and 220 nm Si/PDMS closely match, and they are significantly higher than the stiffness of the integrin clutches and the plaque. Conversely, focal contacts with 20 nm Si/PDMS have comparable lateral compliance to adhesion-mediating intracellular organisms. In conclusion, our work relies on recent advances in NM technology to fill a critical knowledge gap about how individual cells sense and react to the mechanical properties of NM-based substrates. Our findings will have a major impact on the design of flexible electronic materials for applications in biomedical science and health care.

Independent Association of Erectile Dysfunction and Low Testosterone Levels With Life Dissatisfaction in Men With Chronic Spinal Cord Injury.

BACKGROUND: The loss of global functional independence, along with bladder, bowel, and sexual dysfunctions, may contribute to psychological distress and life dissatisfaction after spinal cord injury (SCI). AIM: To explore the relationship of erectile function and androgenic status with life satisfaction, independently from confounders recognizable in spinal cord-injured men. METHODS: 100 consecutive men (49 ± 17 years) admitted to a rehabilitation program because of chronic SCI (≥1 year) underwent clinical/biochemical evaluations, including the assessment of life and sexual satisfaction using the Life-Satisfaction Questionnaire-9 (LiSat-9), erectile function using the International Index of Erectile Function-5 (IIEF-5), global and bowel-bladder functional independence using the Spinal Cord Independence Measure (SCIM) and measurement of total testosterone (TT) levels. The free testosterone level was calculated using the Vermeulen formula. OUTCOMES: The outcomes include the relationship between sexual health and life satisfaction in men with SCI. RESULTS: A LiSat-9 score <4, suggestive for life dissatisfaction, was exhibited by 49% of men. When compared with the life-satisfied group, a significantly higher percentage of them had sexual dissatisfaction and erectile dysfunction (ED); they also exhibited significantly lower levels of TT and calculated free testosterone (cFT) and a more severe impairment of bowel-bladder function. The life satisfaction degree correlated with sexual satisfaction degree, IIEF-5 score, TT, cFT, and bowel-bladder function degree. At the logistic regression model, including sexual LiSat-9 subscore and bowel-bladder SCIM subscore, only the former exhibited a significant negative association with life dissatisfaction. In a further logistic regression model, including the putative key determinants of sexual satisfaction, erectile function, and cFT levels, a higher odd of life dissatisfaction was independently associated both with a lower IIEF-5 score (OR: 0.93; 95% CI: 0.88, 0.98) and lower cFT levels (OR: 0.98; 95% CI: 0.98, 0.99). CLINICAL IMPLICATIONS: In men with chronic SCI, assessment of erectile function and testosterone levels can help to predict life satisfaction. STRENGTHS & LIMITATIONS: This is the first demonstration of the independent association of androgen deficiency and ED with life satisfaction in men with SCI. Prospective studies are warranted to clarify the cause-effect relationships. CONCLUSIONS: In men with SCI, ED and low testosterone levels exhibit a significant independent association with life dissatisfaction; longitudinal intervention studies could explore possible effects of their treatment in improving sexual and life satisfaction in this population. D'Andrea S, Minaldi E, Castellini C, et al. Independent Association of Erectile Dysfunction and Low Testosterone Levels With Life Dissatisfaction in Men With Chronic Spinal Cord Injury. J Sex Med 2020;17:911-918.

Erectile Dysfunction and Premature Ejaculation in Homosexual and Heterosexual Men: A Systematic Review and Meta-Analysis of Comparative Studies.

INTRODUCTION: Comparative studies on differences in sexual function outcomes between homosexual and heterosexual men are sparse and inconclusive. AIM: To systematically evaluate whether, and to what extent, a statistically significant difference exists in the odds of erectile dysfunction (ED) and premature ejaculation (PE) between homosexual and heterosexual men. METHODS: A thorough search of Medline, SCOPUS, CINAHL, and Web of Science databases was carried out to identify case-control studies comparing the prevalence of ED and PE in homosexual and heterosexual men. Methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Odds ratios (ORs) of reporting ED and PE were combined using random effect models. The Cochrane Q and I2 tests were carried out to analyze the between-studies heterogeneity. Funnel plots and trim-and-fill analysis were used to assess publication bias. MAIN OUTCOME MEASURES: The relationship between sexual orientation and odds of ED and PE was assessed by calculating pooled ORs with a 95% CI. RESULTS: 4 studies included in the quantitative analysis collectively provided information on 1,807 homosexual and 4,055 heterosexual men. The pooled ORs indicated that homosexual orientation was associated with 1.5-fold higher odds of reporting ED (OR = 1.49, 95% CI = 1.03-2.16; P = .04) and 28.0% lower odds of reporting PE in comparison to the heterosexual orientation (OR = 0.72, 95% CI = 0.52-1.00; P = .05). However, a significant heterogeneity among the studies was observed. Funnel plots revealed a possible publication bias only for the ED analysis, where the trim-and-fill test detected a putative missing study. Nevertheless, even when the pooled estimate was adjusted for publication bias, there was a significantly higher risk of ED in the homosexual group (adjusted OR = 1.60, 95% CI = 1.10-2.30; P = .01). CLINICAL IMPLICATIONS: These findings can drive future studies on sexual needs and concerns of homosexual men, which might not exactly match those of heterosexual individuals. STRENGTH & LIMITATIONS: This is the first meta-analysis exploring the differences in the prevalence of ED and PE between homosexual and heterosexual men. However, the results should be interpreted with caution, because their generalization could be hindered by the non-probabilistic nature of the samples, and a measurement bias could result from the use of different non-standardized indicators of sexual dysfunctions. CONCLUSION: Homosexual orientation is associated with higher odds of ED and lower odds of PE compared with heterosexual orientation. Further studies are warranted to elucidate the clinical significance of these findings and whether they reflect differences in patterns of sexual lifestyle. Barbonetti A, D'Andrea S, Cavallo F, et al. Erectile Dysfunction and Premature Ejaculation in Homosexual and Heterosexual Men: A Systematic Review and Meta-Analysis of Comparative Studies. J Sex Med 2019;16:624-632.

Emotion dysregulation, impulsivity and personality disorder traits: A community sample study.

The present study was designed to test an emotion regulation framework to understand individual differences in personality disorder (PD) traits in a non-clinical sample. Specifically, we tested whether: selected dimensions of emotion dysregulation were differentially related to PD traits; and whether emotion dysregulation and impulsivity had independent associations with PD traits. A community sample of 399 individuals (mean age = 37.91; 56.6% males) completed self-report measures of PDs, emotion dysregulation and impulsivity. Emotion dysregulation facets and impulsivity had uniform bivariate associations with PD traits, but also evidenced unique associations in multiple regression analyses. Nonacceptance of emotional responses was the emotion dysregulation dimension underlying a wide array of PD. A limited repertoire of effective emotion regulation strategies was characteristic of cluster C PD, whereas emotional unawareness distinctly predicted schizoid PD. Antisocial PD traits were uniquely related to difficulties controlling impulsive behavior when upset. Finally, histrionic, narcissistic, and obsessive-compulsive PD were related to better self-reported emotion regulation. Impulsivity further explained a significant amount of variance in schizotypal, antisocial, borderline (positively), and obsessive-compulsive PD traits (negatively). If replicated in clinical samples, our findings will support the usefulness of targeting both emotional dysregulation and impulsivity in PDs psychotherapy.

Strain engineering, efficient excitonic photoluminescence, and exciton funnelling in unmodified MoS2 nanosheets.

We established locally varying strain fields in unmodified MoS2 nanosheets. The approach relies on dry release in place of multilayer MoS2 on textured Si substrates. By this process we demonstrated intense photoluminescence, a ∼70 meV decrease of the transition energy, and exciton funneling in ∼4 nm-thick MoS2 films.