Functional Counterpart Research Articles

Are the Criteria for the Diagnosis of Premature Ejaculation Applicable to Gay Men or Sexual Activities Other than Penile-Vaginal Intercourse?

IntroductionThe criteria for premature ejaculation (PE) have generally been limited to the diagnosis of heterosexual men engaging in penile-vaginal intercourse and therefore the applicability of PE diagnostic criteria to gay men and to activities beyond penile-vaginal intercourse has yet to be explored in depth.AimTo compare the prevalence of PE in gay and straight men and to assess whether PE-related diagnostic measures (ejaculatory control, ejaculation latency [EL], and bother/distress) can be applied with confidence to gay men or to men engaging in sexual activities other than penile-vaginal intercourse.MethodsGay and straight participants (n = 3878) were recruited to take an online survey assessing sexual orientation, sexual function/dysfunction (including specific PE-related measures), sexual relationship satisfaction, and various other sexual behaviors during partnered sex or masturbation.OutcomesComparison of ejaculatory control, EL, and bother/distress across gay and straight men, as well as across different types of sexual activities.ResultsA slightly lower PE prevalence among gay men became undetectable when other predictors of prevalence were included in a multivariate analysis (aOR = 0.87 [95% CI: 0.60–1.22]). Gay men with PE reported longer typical ELs (zU = -3.35, P < .001) and lower distress (zU = 3.68, P < .001) relative to straight men, but longer ELs and lower distress were also associated with anal sex.Clinical TranslationClinicians can feel confident about using existing criteria for the diagnosis of PE in gay men but should be aware of potentially longer ELs and lower PE-related bother/distress—probably related to the practice of anal sex—compared with straight men.Strengths and LimitationsAlthough well-powered and international in scope, this study was limited by biases inherent to online surveys, the lack of a sizable sample of bisexual men, and a lack of differentiation between men with acquired vs lifelong PE.ConclusionsIrrespective of sexual orientation, gay and straight men with PE reported shorter ELs, lower satisfaction, and greater bother/distress than functional counterparts. While PE-related diagnostic criteria (ejaculatory control, EL, and bother/distress) are applicable to gay men, accommodation for longer ELs and lower bother/distress in gay men should be considered.McNabney SM, Weseman CE, Hevesi K, et al. Are the Criteria for the Diagnosis of Premature Ejaculation Applicable to Gay Men or Sexual Activities Other than Penile-Vaginal Intercourse?. Sex Med 2022;10:100516.

Artificial Mitochondrial Transfer (AMT) for the Management of Age-related Musculoskeletal Degenerative Disorders: An Emerging Avenue for Bone and Cartilage Metabolism Regulation.

Musculoskeletal system disorders are among the most common age-related conditions worldwide. All associated with a degeneration of the supporting tissues under pro-inflammatory micro- and macro-environments, the erosion of cartilage and later of bones, are the main hallmarks of these pathologies. Affected chondrocytes, osteoblasts and synoviocytes, that are all critical actors in the bone and cartilage defects exhibit mitochondrial dysfunction that develops immediately following cartilage and bone injury, and leads to tissue residing specific cell death, cartilage degeneration, bone erosion, and ultimately post-traumatic musculoskeletal degeneration. Herein, we would like to introduce a novel concept for bone and cartilage related defects treatment based on artificial transfer of exogeneous functional mitochondria (AMT). Particularly, we believe that because mitochondrial failure critically contributes to degenerative disorders onset and progression, replacing malfunctioning mitochondria with their healthy and functional counterparts can represent a novel, and effective therapeutic solution for the management of bone and cartilage related degenerative diseases. Artificial mitochondrial transfer (AMT) may reverse the failed metabolic status of musculoskeletal tissues cells and reduce bone and cartilage tissues defects by restoring mitochondrial bioenergetics.

Recent Progress in Graphene- and Related Carbon-Nanomaterial-based Electrochemical Biosensors for Early Disease Detection.

Graphene- and carbon-based nanomaterials are key materials to develop advanced biosensors for the sensitive detection of many biomarkers owing to their unique properties. Biosensors have attracted increasing interest because they allow efficacious, sensitive, selective, rapid, and low-cost diagnosis. Biosensors are analytical devices based on receptors for the process of detection and transducers for response measuring. Biosensors can be based on electrochemical, piezoelectric, thermal, and optical transduction mechanisms. Early virus identification provides critical information about potentially effective and selective therapies, extends the therapeutic window, and thereby reduces morbidity. The sensitivity and selectivity of graphene can be amended via functionalizing it or conjoining it with further materials. Amendment of the optical and electrical features of the hybrid structure by introducing appropriate functional groups or counterparts is especially appealing for quick and easy-to-use virus detection. Various techniques for the electrochemical detection of viruses depending on antigen-antibody interactions or DNA hybridization are discussed in this work, and the reasons behind using graphene and related carbon nanomaterials for the fabrication are presented and discussed. We review the existing state-of-the-art directions of graphene-based classifications for detecting DNA, protein, and hormone biomarkers and summarize the use of the different biosensors to detect several diseases, like cancer, Alzheimer's disease, and diabetes, to sense numerous viruses, including SARS-CoV-2, human immunodeficiency virus, rotavirus, Zika virus, and hepatitis B virus, and to detect the recent pandemic virus COVID-19. The general concepts, mechanisms of action, benefits, and disadvantages of advanced virus biosensors are discussed to afford beneficial evidence of the creation and manufacture of innovative virus biosensors. We emphasize that graphene-based nanomaterials are ideal candidates for electrochemical biosensor engineering due to their special and tunable physicochemical properties.

An efficient extreme value moment method combining adaptive Kriging model for time-variant imprecise reliability analysis

For time-variant imprecise reliability problem with parameterized probability-box (p-box), determining the upper and lower bounds of time-variant failure probability is usually more of concern for engineers. To compute these two bounds, this paper proposes a new extreme value moment method (EVMM) combining adaptive Kriging model. In the proposed method, the adaptive Kriging models are first employed to approximate limit state function (LSF) responses and the predicted values are mapped into the extreme value function (EVF) counterparts. Then, the weighted approach based on sparse grid numerical integration (WA-SGNI) is developed to estimate the statistical moments of the approximated EVF responses. The resulting moments are further used to decouple the calculation of bounds of time-variant failure probability into two deterministic optimization problems. The accuracy and efficiency of the proposed method for time-variant imprecise reliability analysis are demonstrated through three numerical examples with LSFs involving non-Gaussian processes and finite element analysis.

Infections, Reactions of Natural Killer T Cells and Natural Killer Cells, and Kidney Injury.

Natural killer T (NKT) cells and NK cells are representative innate immune cells that perform antitumor and antimicrobial functions. The involvement of these cells in various renal diseases, including acute kidney injury (AKI), has recently become evident. Murine NKT cells are activated and cause AKI in response to various stimuli, such as their specific ligand, cytokines, and bacterial components. Both renal vascular endothelial cell injury (via the perforin-mediated pathway) and tubular epithelial cell injury (via the tumor necrosis factor-alpha/Fas ligand pathway) are independently involved in the pathogenesis of AKI. NK cells complement the functions of NKT cells, thereby contributing to the development of infection-associated AKI. Human CD56+ T cells, which are a functional counterpart of murine NKT cells, as well as a subpopulation of CD56+ NK cells, strongly damage intrinsic renal cells in vitro upon their activation, possibly through mechanisms similar to those in mice. These cells are also thought to be involved in the acute exacerbation of pre-existing glomerulonephritis triggered by infection in humans, and their roles in sepsis-associated AKI are currently under investigation. In this review, we will provide an overview of the recent advances in the understanding of the association among infections, NKT and NK cells, and kidney injury, which is much more profound than previously considered. The important role of liver macrophages in the activation of NKT cells will also be introduced.

Integrating multiple dimensions of ecological stability into a vulnerability framework

AbstractEcological stability encompasses multiple dimensions of functional and compositional responses to environmental change. Though no single stability dimension used in isolation can fully reflect the overall response to environmental change, a common vulnerability assessment that integrates simultaneously across multiple stability components is highly desirable for ecological risk assessment.We develop both functional and compositional counterparts of a novel, integrative metric of overall ecological vulnerability (OEV). We test the framework with data from a modularized experiment replicated in five lakes over two seasons, examining functional and compositional responses to both pulse and press disturbances across three trophic groups. OEV is measured as the area under the curve integrated over the entire observation period, with the curve delimiting the difference between the disturbance treatment and undisturbed parallel controls, expressed either as the log response ratio of biomass (functional OEV) or community dissimilarity index (compositional OEV).Both, functional and compositional OEV correlated negatively with functional and compositional ‘resistance’, ‘temporal stability’ and ‘final/extent of recovery’ following both pulse and press disturbances, though less so with ‘resilience’ following a pulse disturbance. We also found a positive correlation between functional and compositional OEV, which reveals the potential to also evaluate the intricate linkage between biodiversity and functional change.Our findings demonstrate that OEV comprises a robust framework to: (a) capture simultaneously multiple functional and compositional stability components, and (b) quantify the functional consequences of biodiversity change. Our results provide the basis for an overarching framework for quantifying the overall vulnerability of ecosystems to environmental change, opening new possibilities for ecological risk assessment and management.Synthesis. Ecological stability comprises multiple dimensions that together encapsulate how ecosystems respond to environmental change. Considering these multiple aspects of stability simultaneously often poses a problem in environmental assessments, which frequently require overarching indicators of risk or vulnerability. While an analysis of multiple dimensions allows for deeper exploration of mechanisms, here we develop and test a new univariate indicator that integrates stability aspects under a broad range of disturbance regimes. Using a modularized experiment in Swedish lakes, we show that this integrative measure captures multiple stability dimensions reflecting compositional and functional vulnerability and their relationships between them.

Regulation of Plant Immunity by Nuclear Membrane-Associated Mechanisms.

Unlike animals, plants do not have specialized immune cells and lack an adaptive immune system. Instead, plant cells rely on their unique innate immune system to defend against pathogens and coordinate beneficial interactions with commensal and symbiotic microbes. One of the major convergent points for plant immune signaling is the nucleus, where transcriptome reprogramming is initiated to orchestrate defense responses. Mechanisms that regulate selective transport of nuclear signaling cargo and chromatin activity at the nuclear boundary play a pivotal role in immune activation. This review summarizes the current knowledge of how nuclear membrane-associated core protein and protein complexes, including the nuclear pore complex, nuclear transport receptors, and the nucleoskeleton participate in plant innate immune activation and pathogen resistance. We also discuss the role of their functional counterparts in regulating innate immunity in animals and highlight potential common mechanisms that contribute to nuclear membrane-centered immune regulation in higher eukaryotes.

Cell Wall Stress Stimulates the Activity of the Protein Kinase StkP of Streptococcus pneumoniae, Leading to Multiple Phosphorylation

Streptococcus pneumoniae is an opportunistic human pathogen that encodes a single eukaryotic-type Ser/Thr protein kinase StkP and its functional counterpart, the protein phosphatase PhpP. These signaling enzymes play critical roles in coordinating cell division and growth in pneumococci. In this study, we determined the proteome and phosphoproteome profiles of relevant mutants. Comparison of those with the wild-type provided a representative dataset of novel phosphoacceptor sites and StkP-dependent substrates. StkP phosphorylates key proteins involved in cell division and cell wall biosynthesis in both the unencapsulated laboratory strain Rx1 and the encapsulated virulent strain D39. Furthermore, we show that StkP plays an important role in triggering an adaptive response induced by a cell wall-directed antibiotic. Phosphorylation of the sensor histidine kinase WalK and downregulation of proteins of the WalRK core regulon suggest crosstalk between StkP and the WalRK two-component system. Analysis of proteomic profiles led to the identification of gene clusters regulated by catabolite control mechanisms, indicating a tight coupling of carbon metabolism and cell wall homeostasis. The imbalance of steady-state protein phosphorylation in the mutants as well as after antibiotic treatment is accompanied by an accumulation of the global Spx regulator, indicating a Spx-mediated envelope stress response. In summary, StkP relays the perceived signal of cell wall status to key cell division and regulatory proteins, controlling the cell cycle and cell wall homeostasis.

Brain Structural and Functional Connectivity: A Review of Combined Works of Diffusion Magnetic Resonance Imaging and Electro-Encephalography.

Implications of structural connections within and between brain regions for their functional counterpart are timely points of discussion. White matter microstructural organization and functional activity can be assessed in unison. At first glance, however, the corresponding findings appear variable, both in the healthy brain and in numerous neuro-pathologies. To identify consistent associations between structural and functional connectivity and possible impacts for the clinic, we reviewed the literature of combined recordings of electro-encephalography (EEG) and diffusion-based magnetic resonance imaging (MRI). It appears that the strength of event-related EEG activity increases with increased integrity of structural connectivity, while latency drops. This agrees with a simple mechanistic perspective: the nature of microstructural white matter influences the transfer of activity. The EEG, however, is often assessed for its spectral content. Spectral power shows associations with structural connectivity that can be negative or positive often dependent on the frequencies under study. Functional connectivity shows even more variations, which are difficult to rank. This might be caused by the diversity of paradigms being investigated, from sleep and resting state to cognitive and motor tasks, from healthy participants to patients. More challenging, though, is the potential dependency of findings on the kind of analysis applied. While this does not diminish the principal capacity of EEG and diffusion-based MRI co-registration, it highlights the urgency to standardize especially EEG analysis.

A functional genetic toolbox for human tissue-derived organoids.

Human organoid systems recapitulate key features of organs offering platforms for modelling developmental biology and disease. Tissue-derived organoids have been widely used to study the impact of extrinsic niche factors on stem cells. However, they are rarely used to study endogenous gene function due to the lack of efficient gene manipulation tools. Previously, we established a human foetal lung organoid system (Nikolić et al., 2017). Here, using this organoid system as an example, we have systematically developed and optimised a complete genetic toolbox for use in tissue-derived organoids. This includes 'Organoid Easytag', our efficient workflow for targeting all types of gene loci through CRISPR-mediated homologous recombination followed by flow cytometry for enriching correctly targeted cells. Our toolbox also incorporates conditional gene knockdown or overexpression using tightly inducible CRISPR interference and CRISPR activation which is the first efficient application of these techniques to tissue-derived organoids. These tools will facilitate gene perturbation studies in tissue-derived organoids facilitating human disease modelling and providing a functional counterpart to many ongoing descriptive studies, such as the Human Cell Atlas Project.

A Live Olfactory Mouse Cytomegalovirus Vaccine, Attenuated for Systemic Spread, Protects against Superinfection.

Vaccination against the betaherpesvirus, human cytomegalovirus (HCMV) is a public health goal. However, HCMV has proved difficult to vaccinate against. Vaccination against single HCMV determinants has not worked, suggesting that immunity to a wider antigenic profile may be required. Live attenuated vaccines provide the best prospects for protection, but the question remains as to how to balance vaccine virulence with safety. Animal models of HCMV infection provide insights into identifying targets for virus attenuation and understanding how host immunity blocks natural, mucosal infection. Here, we evaluated the vaccine potential of a mouse cytomegalovirus (MCMV) vaccine deleted of a viral G protein-coupled receptor (GPCR), designated M33, that renders it attenuated for systemic spread. A single noninvasive olfactory ΔM33 MCMV vaccine replicated locally, but as a result of the loss of the M33 GPCR, it failed to spread systemically and was attenuated for latent infection. Vaccination did not prevent host entry of a superinfecting MCMV but spread from the mucosa was blocked. This approach to vaccine design may provide a viable alternative for a safe and effective betaherpesvirus vaccine. IMPORTANCE Human cytomegalovirus (HCMV) is the most common cause of congenital infection for which a vaccine is not yet available. Subunit vaccine candidates have failed to achieve licensure. A live HCMV vaccine may prove more efficacious, but it faces safety hurdles which include its propensity to persist and to establish latency. Understanding how pathogens infect guide rational vaccine design. However, HCMV infections are asymptomatic and thus difficult to capture. Animal models of experimental infection provide insight. Here, we investigated the vaccine potential of a mouse cytomegalovirus (MCMV) attenuated for systemic spread and latency. We used olfactory vaccination and virus challenge to mimic its natural acquisition. We provide proof of concept that a single olfactory MCMV that is deficient in systemic spread can protect against wild-type MCMV superinfection and dissemination. This approach of deleting functional counterpart genes in HCMV may provide safe and effective vaccination against congenital HCMV disease.

A conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration.

PROPPINs are phosphoinositide-binding β-propeller proteins that mediate membrane recruitment of other proteins and are involved in different membrane remodeling processes. The main role of PROPPINs is their function in autophagy, where they act at different steps in phagophore formation. The human PROPPIN WIPI4 (WDR45) forms a complex with ATG2 involved in phagophore elongation, and mutations in this gene cause β-propeller protein-associated neurodegeneration (BPAN). The yeast functional counterpart of WIPI4 is Atg18, although its closest sequence homolog is another member of the PROPPIN family, Hsv2, whose function remains largely undefined. Here, we provide evidence that Hsv2, like WIPI4 and Atg18, interacts with Atg2. We show that Hsv2 and a pool of Atg2 colocalize on endosomes under basal conditions and at the pre-autophagosomal structure (PAS) upon autophagy induction. We further show that Hsv2 drives the recruitment of Atg2 to endosomes while Atg2 mediates Hsv2 recruitment to the PAS. HSV2 overexpression results in mis-sorting and secretion of carboxypeptidase CPY, suggesting that the endosomal function of this protein is related to the endosome-to-Golgi recycling pathway. Furthermore, we show that the Atg2 binding site is conserved in Hsv2 and WIPI4 but not in Atg18. Notably, two WIPI4 residues involved in ATG2 binding are mutated in patients with BPAN, and there is a correlation between the inhibitory effect of these mutations on ATG2 binding and the severity of the disease.

Hybrid Atomic Orbital Basis from First Principles: Bottom-Up Mapping of Self-Energy Correction to Large Covalent Systems.

Construction of hybrid atomic orbitals is proposed as the approximate common eigenstates of finite first moment matrices. Their hybridization and orientation can be a priori tuned as per their anticipated neighborhood. Their Wannier function counterparts constructed from the Kohn-Sham (KS) single particle states constitute an orthonormal multiorbital tight binding (TB) basis resembling hybrid atomic orbitals locked to their immediate atomic neighborhood, while spanning the subspace of KS states. The proposed basis thus renders predominantly single TB parameters from first principles for each nearest neighbor bond involving no more than two orbitals irrespective of their orientation and also facilitates an easy route for the transfer of such TB parameters across isostructural systems exclusively through mapping of neighborhoods and projection of orbital charge centers. With hybridized 2s, 2p and 3s, 3p valence electrons, the spatial extent of the self-energy correction (SEC) to TB parameters in the proposed basis is found to be localized mostly within the third nearest neighborhood, thus allowing effective transfer of self-energy-corrected TB parameters from smaller reference systems to much larger target systems, with nominal additional computational cost beyond that required for explicit computation of SEC in the reference systems. The proposed approach promises inexpensive estimation of the quasi-particle structures of large covalent systems with workable accuracy.

Pneumatically Controlled Reconfigurable Bistable Bionic Flower for Robotic Gripper.

Beyond their colorful appearances and versatile geometries, flowers can self-shape-morph by adapting to environmental changes. Nature-inspired artificial systems that mimic their natural counterparts in function, flexibility, and adaptation find an emerging application in mobile robotics. In this study, a novel reconfigurable bionic flower made of petal-shaped bistable carbon fiber-reinforced composites and actuated by soft pneumatic actuators is presented. A robotic gripper based on the bionic flower was then developed for transportation tasks. First, a bionic petal based on a hybridization of bistable composites was designed and a theoretical model was established to analyze its bistable characteristic. Second, experiments and simulations were performed to analyze the out-of-plane deformation and morphing processes of the bionic petal. Curvature analysis of the closing state and blooming state shows a good match with the theoretical results. Finally, a flower-inspired robotic gripper made of the bionic petal is demonstrated to evaluate its gripping performances, including gripping force, response time, and reliability. The functional tests confirmed that the proposed soft gripper can grip objects of various shapes, sizes, and weights within milliseconds response time. The stable gripping configuration was maintained through the bistability of the bionic petal without continuous pressure consumption. The high reliability of the gripper is very useful for gripping tasks under unstructured environments, where precise control over the robot is not possible.

SoxD transcription factor deficiency in Schwann cells delays myelination in the developing peripheral nervous system

The three SoxD proteins, Sox5, Sox6 and Sox13, represent closely related transcription factors with important roles during development. In the developing nervous system, SoxD proteins have so far been primarily studied in oligodendroglial cells and in interneurons of brain and spinal cord. In oligodendroglial cells, Sox5 and Sox6 jointly maintain the precursor state, interfere with terminal differentiation, and thereby ensure the proper timing of myelination in the central nervous system. Here we studied the role of SoxD proteins in Schwann cells, the functional counterpart of oligodendrocytes in the peripheral nervous system. We show that Schwann cells express Sox5 and Sox13 but not Sox6. Expression was transient and ceased with the onset of terminal differentiation. In mice with early Schwann cell-specific deletion of both Sox5 and Sox13, embryonic Schwann cell development was not substantially affected and progressed normally into the promyelinating stage. However, there was a mild and transient delay in the myelination of the peripheral nervous system of these mice. We therefore conclude that SoxD proteins—in stark contrast to their action in oligodendrocytes—promote differentiation and myelination in Schwann cells.

One-Pot Highly Efficient Synthesis of N-Enrich Graphene Quantum Dots as a Photocatalytic Platform for NAD+/NADP+ Reduction.

An efficient photocatalytic regeneration of nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH) has been carried out by two-electron reduction and protonation of NAD+ /NADP+ , induced by photons in the visible light region. This functional artificial photosynthetic counterpart of the complete energy-trapping occurring in natural photosystem I (PS I) is achieved with nitrogen-enrich graphene quantum dot (N-EGQD) as the light-harvesting photocatalyst. In buffer aqueous solution, this compound photo catalytically recycles a rhodium hydride complex of the type [Cp*Rh(bpy)H]+ (Cp* = pentamethylcyclopentadienyl, bpy = 2,2'-bipyridine) which can mediate hydride transfer processes leading to nucleotide co-factor reduction. Very promising yields of 73.31%/78.45% of NADH/NADPH with the excellent thermal stability of N-EGQD photocatalyst is observed. Thus, in this work, an efficient light-harvesting photocatalyst is synthesized for the regeneration of nicotinamide cofactor that has pharmaceuticals application.

Life after Cell Death-Survival and Survivorship Following Chemotherapy.

Simple SummaryTreatment of aggressive cancers often relies on chemotherapy. This treatment has improved survival rates, but while effective at killing cancer cells, inevitably it also kills or alters the function of others. While many of the known effects are transient and resolve after treatment, as survival rates increase, so does our understanding of the long-term health costs that accompany cancer survivors. Here we provide an overview of common long-term morbidities known to be caused by conventional chemotherapy, including the risk of relapse, but more importantly, the cost of quality of life experienced, especially by those who have cancer in early life. We aim to highlight the importance of the development of targeted therapies to replace the use of conventional chemotherapy, but also that of treating the patients along with the disease to enable not only longer but also healthier life after cancer.To prevent cancer cells replacing and outnumbering their functional somatic counterparts, the most effective solution is their removal. Classical treatments rely on surgical excision, chemical or physical damage to the cancer cells by conventional interventions such as chemo- and radiotherapy, to eliminate or reduce tumour burden. Cancer treatment has in the last two decades seen the advent of increasingly sophisticated therapeutic regimens aimed at selectively targeting cancer cells whilst sparing the remaining cells from severe loss of viability or function. These include small molecule inhibitors, monoclonal antibodies and a myriad of compounds that affect metabolism, angiogenesis or immunotherapy. Our increased knowledge of specific cancer types, stratified diagnoses, genetic and molecular profiling, and more refined treatment practices have improved overall survival in a significant number of patients. Increased survival, however, has also increased the incidence of associated challenges of chemotherapy-induced morbidity, with some pathologies developing several years after termination of treatment. Long-term care of cancer survivors must therefore become a focus in itself, such that along with prolonging life expectancy, treatments allow for improved quality of life.

Activation of Prp28 ATPase by phosphorylated Npl3 at a critical step of spliceosome remodeling

Splicing, a key step in the eukaryotic gene-expression pathway, converts precursor messenger RNA (pre-mRNA) into mRNA by excising introns and ligating exons. This task is accomplished by the spliceosome, a macromolecular machine that must undergo sequential conformational changes to establish its active site. Each of these major changes requires a dedicated DExD/H-box ATPase, but how these enzymes are activated remain obscure. Here we show that Prp28, a yeast DEAD-box ATPase, transiently interacts with the conserved 5′ splice-site (5′SS) GU dinucleotide and makes splicing-dependent contacts with the U1 snRNP protein U1C, and U4/U6.U5 tri-snRNP proteins, Prp8, Brr2, and Snu114. We further show that Prp28’s ATPase activity is potentiated by the phosphorylated Npl3, but not the unphosphorylated Npl3, thus suggesting a strategy for regulating DExD/H-box ATPases. We propose that Npl3 is a functional counterpart of the metazoan-specific Prp28 N-terminal region, which can be phosphorylated and serves as an anchor to human spliceosome.

Persistence of hierarchical network organization and emergent topologies in models of functional connectivity

Functional networks provide a topological description of activity patterns in the brain, as they stem from the propagation of neural activity on the underlying anatomical or structural network of synaptic connections. This latter is well known to be organized in hierarchical and modular way. While it is assumed that structural networks shape their functional counterparts, it is also hypothesized that alterations of brain dynamics come with transformations of functional connectivity. In this computational study, we introduce a novel methodology to monitor the persistence and breakdown of hierarchical order in functional networks, generated from computational models of activity spreading on both synthetic and real structural connectomes. We show that hierarchical connectivity appears in functional networks in a persistent way if the dynamics is set to be in the quasi-critical regime associated with optimal processing capabilities and normal brain function, while it breaks down in other (supercritical) dynamical regimes, often associated with pathological conditions. Our results offer important clues for the study of optimal neurocomputing architectures and processes, which are capable of controlling patterns of activity and information flow. We conclude that functional connectivity patterns achieve optimal balance between local specialized processing (i.e. segregation) and global integration by inheriting the hierarchical organization of the underlying structural architecture.

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured invitro and invivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.