Towards implementation of cognitive bias modification in mental health care: State of the science, best practices, and ways forward.

Cognitive bias modification (CBM) has evolved from an experimental method testing cognitive mechanisms of psychopathology to a promising tool for accessible digital mental health care. While we are still discovering the conditions under which clinically relevant effects occur, the dire need for accessible, effective, and low-cost mental health tools underscores the need for implementation where such tools are available. Providing our expert opinion as Association for Cognitive Bias Modification members, we first discuss the readiness of different CBM approaches for clinical implementation, then discuss key considerations with regard to implementation. Evidence is robust for approach bias modification as an adjunctive intervention for alcohol use disorders and interpretation bias modification as a stand-alone intervention for anxiety disorders. Theoretical predictions regarding the mechanisms by which bias and symptom change occur await further testing. We propose that CBM interventions with demonstrated efficacy should be provided to the targeted populations. To facilitate this, we set a research agenda based on implementation frameworks, which includes feasibility and acceptability testing, co-creation with end-users, and collaboration with industry partners.

Multiple paths to rumination within a network analytical framework.

Theories of rumination have proposed different psychological factors to place one at risk for repetitive negative thinking. A comprehensive empirical test that captures the most relevant contributors to rumination is lacking. Building on influential self-regulatory and metacognitive frameworks, we modeled how key constructs in this context relate to ruminative thinking. 498 participants completed online questionnaires including indicators of rumination, metacognition, promotion goal orientation, effortful control, and depression. We estimated regularized partial correlation networks to investigate unique associations between the different constructs and followed these analyses up with directed acyclic graphs to identify potential pathways towards rumination. Results demonstrated that: (1) both self-regulatory and metacognitive factors were directly linked to rumination, amongst these were (2) positive beliefs, negative beliefs about uncontrollability and harm, cognitive self-consciousness, depression, effortful control, perfectionism, and (lack of) cognitive confidence, and (3) we identified multiple directed pathways, suggesting three direct contributors to rumination while controlling for the influence of all other variables: diminished effortful control, positive beliefs, and cognitive self-consciousness. This study is the first to comprehensively assess metacognitive and self-regulatory frameworks of rumination in a data-driven manner. Our findings suggest that there are multiple pathways towards rumination, which should be incorporated in clinical case conceptualization of rumination and related disorders.

Computerized cognitive control training to reduce rumination in major depression: A randomized controlled trial.

OBJECTIVE: Rumination is a major risk factor for the onset and recurrence of depressive episodes and has been associated with deficits in updating working memory content. This randomized controlled trial examines whether training updating-specific cognitive control processes reduces daily ruminative thoughts in clinically depressed individuals. METHODS: Sixty-five individuals with a current major depressive episode were randomized to 10 sessions of either cognitive control training (N = 31) or placebo training (N = 34). The frequency and negativity of individuals' daily ruminative thoughts were assessed for seven days before training, after training, and at a 3-month follow-up using experience sampling methodology. Secondary outcomes were depressive symptoms, depressed mood, and level of disability. RESULTS: Cognitive control training led to stronger improvements in the trained task than placebo training. However, cognitive control training did not lead to greater reductions in the frequency or negativity of daily ruminative thoughts than placebo training. There were no training-specific effects on participants' depressive symptoms or level of disability. CONCLUSIONS: The robustness of the present null-findings, combined with the methodological strengths of the study, suggest that training currently depressed individuals to update emotional content in working memory does not affect the frequency or negativity of their daily ruminative thoughts.

Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.

Treatment Response Following Adaptive PASAT Training for Depression Vulnerability: a Systematic Review and Meta-Analysis.

In recent years, cognitive control training (CCT) has gained momentum as an intervention to remediate cognitive impairments and decrease depressive symptoms. One promising operationalization to train cognitive control is the adaptive Paced Auditory Serial Addition Task (aPASAT). In this systematic review and meta-analysis of aPASAT training, the efficacy of the intervention and potential moderators were examined. The PsycINFO, MEDLINE, Embase, Web of Science and Cochrane Library electronic databases were searched for studies examining aPASAT training for depressive symptomatology or rumination. Nineteen studies (n = 1255) were included, comprising of depressed patients, remitted depressed patients, at-risk, and healthy participants. We found small significant effects directly after training for both depressive symptomatology and rumination, with similar effect sizes at follow-up. Subgroup analyses suggest a significantly higher mean effect of aPASAT training in non-healthy populations for rumination immediately following training, but not for depressive symptomatology. The amount of training sessions did not moderate effects of CCT. aPASAT has a small but significant effect on depressive symptoms, with direct effects immediately after training, as well as sustained long-term effects. It is currently unclear how many sessions are required for sustained effects due to heterogeneity in training dosage and absence of sufficient trials. Our results suggest that aPASAT training may be most effective for at-risk, remitted- and clinically depressed populations. The effect sizes resulting from this meta-analysis could be used to adequately power future research, which could investigate a dose-response relationship and examine potential treatment gains when combining CCT with other antidepressant interventions.

Light Sheet-Based Laser Patterning Bioprinting Produces Long-Term Viable Full-Thickness Skin Constructs.

Tissue engineering holds great promise for biomedical research and healthcare, offering alternatives to animal models and enabling tissue regeneration and organ transplantation. 3D bioprinting stands out for its design flexibility and reproducibility. Here, an integrated fluorescent light sheet bioprinting and imaging system is presented that combines high printing speed (0.66 mm3 /s) and resolution (9 µm) with light sheet-based imaging. This approach employs direct laser patterning and a static light sheet for confined voxel crosslinking in photocrosslinkable materials. The developed bioprinter enables real-time monitoring of hydrogel crosslinking using fluorescent recovery after photobleaching (FRAP) and brightfield imaging as well as in situ light sheet imaging of cells. Human fibroblasts encapsulated in a thiol-ene click chemistry-based hydrogel exhibited high viability (83% ± 4.34%) and functionality. Furthermore, full-thickness skin constructs displayed characteristics of both epidermal and dermal layers and remained viable for 41 days. The integrated approach demonstrates the capabilities of light sheet bioprinting, offering high speed, resolution, and real-time characterization. Future enhancements involving solid-state laser scanning devices such as acousto-optic deflectors and modulators will further enhance resolution and speed, opening new opportunities in light-based bioprinting and advancing tissue engineering.

Thirty years with three-dimensional structures of lipoxygenases.

The X-ray crystal structures of soybean lipoxygenase (LOX) and rabbit 15-LOX were reported in the 1990s. Subsequent 3D structures demonstrated a conserved U-like shape of the substrate cavities as reviewed here. The 8-LOX:arachidonic acid (AA) complex showed AA bound to the substrate cavity carboxylate-out with C10 at 3.4 Å from the iron metal center. A recent cryo-electron microscopy (EM) analysis of the 12-LOX:AA complex illustrated AA in the same position as in the 8-LOX:AA complex. The 15- and 12-LOX complexes with isoenzyme-specific inhibitors/substrate mimics confirmed the U-fold. 5-LOX oxidizes AA to leukotriene A4, the first step in biosynthesis of mediators of asthma. The X-ray structure showed that the entrance to the substrate cavity was closed to AA by Phe and Tyr residues of a partly unfolded α2-helix. Recent X-ray analysis revealed that soaking with inhibitors shifted the short α2-helix to a long and continuous, which opened the substrate cavity. The α2-helix also adopted two conformations in 15-LOX. 12-LOX dimers consisted of one closed and one open subunit with an elongated α2-helix. 13C-ENDOR-MD computations of the 9-MnLOX:linoleate complex showed carboxylate-out position with C11 placed 3.4 ± 0.1 Å from the catalytic water. 3D structures have provided a solid ground for future research.

Next generation marker-based vector concepts for rapid and unambiguous identification of single and double homozygous transgenic organisms.

For diploid model organisms, the actual transgenesis processes require subsequent periods of transgene management, which are challenging in emerging model organisms due to the lack of suitable methodology. We used the red flour beetle Tribolium castaneum, a stored-grain pest, to perform a comprehensive functional evaluation of our AClashOfStrings (ACOS) and the combined AGameOfClones/AClashOfStrings (AGOC/ACOS) vector concepts, which use four clearly distinguishable markers to provide full visual control over up to two independent transgenes. We achieved comprehensive statistical validation of our approach by systematically creating seventeen novel single and double homozygous sublines intended for fluorescence live imaging, including several sublines in which the microtubule cytoskeleton is labeled. During the mating procedures, we genotyped more than 20,000 individuals in less than 80 working hours, which corresponds to about 10 to 15 s per individual. We also confirm the functionality of our combined concept in two double transgene special cases, i.e. integration of both transgenes in close proximity on the same chromosome and integration of one transgene on the X allosome. Finally, we discuss our vector concepts regarding performance, genotyping accuracy, throughput, resource saving potential, fluorescent protein choice, modularity, adaptation to other diploid model organisms and expansion capability.

A Legionella toxin exhibits tRNA mimicry and glycosyl transferase activity to target the translation machinery and trigger a ribotoxic stress response.

A widespread strategy employed by pathogens to establish infection is to inhibit host-cell protein synthesis. Legionella pneumophila, an intracellular bacterial pathogen and the causative organism of Legionnaires' disease, secretes a subset of protein effectors into host cells that inhibit translation elongation. Mechanistic insights into how the bacterium targets translation elongation remain poorly defined. We report here that the Legionella effector SidI functions in an unprecedented way as a transfer-RNA mimic that directly binds to and glycosylates the ribosome. The 3.1 Å cryo-electron microscopy structure of SidI reveals an N-terminal domain with an 'inverted L' shape and surface-charge distribution characteristic of tRNA mimicry, and a C-terminal domain that adopts a glycosyl transferase fold that licenses SidI to utilize GDP-mannose as a sugar precursor. This coupling of tRNA mimicry and enzymatic action endows SidI with the ability to block protein synthesis with a potency comparable to ricin, one of the most powerful toxins known. In Legionella-infected cells, the translational pausing activated by SidI elicits a stress response signature mimicking the ribotoxic stress response, which is activated by elongation inhibitors that induce ribosome collisions. SidI-mediated effects on the ribosome activate the stress kinases ZAKα and p38, which in turn drive an accumulation of the protein activating transcription factor 3 (ATF3). Intriguingly, ATF3 escapes the translation block imposed by SidI, translocates to the nucleus and orchestrates the transcription of stress-inducible genes that promote cell death, revealing a major role for ATF3 in the response to collided ribosome stress. Together, our findings elucidate a novel mechanism by which a pathogenic bacterium employs tRNA mimicry to hijack a ribosome-to-nuclear signalling pathway that regulates cell fate.

Health Economic Evaluation of Cognitive Control Training for Depression: Key Considerations.

Depression is a serious and burdensome psychiatric illness that contributes heavily to health expenditures. These costs are partly related to the observation that depression is often not limited to a single episode but can recur or follow a chronic pathway. In terms of risk factors, it is acknowledged that cognitive impairments play a crucial role in vulnerability to depression. Within this context, cognitive control training (CCT) has shown its effectiveness in reducing the risk for recurrence of depression. CCT is low cost intensive and can be provided as a web-based intervention, which makes it easy to disseminate. Despite increasing interest in the field, studies examining the cost-effectiveness of CCT in the context of depression are largely missing. Health economic evaluation (HEE) allows to inform decision makers with evidence-based insights about how to spend limited available (financial) resources in the most efficient way. HEE studies constitute a crucial step in the implementation of a new intervention in clinical practice. Approaching preventive measures for depression such as CCT from an HEE perspective is informative to health policy, fostering optimal use of health expenditures. The aim of this paper was to inform and guide researchers during the phase of designing HEE studies in the context of CCT for depression. A clear view of CCT's cost-effectiveness is paramount for its clinical implementation.

How enhancers regulate wavelike gene expression patterns.

A key problem in development is to understand how genes turn on or off at the right place and right time during embryogenesis. Such decisions are made by non-coding sequences called 'enhancers.' Much of our models of how enhancers work rely on the assumption that genes are activated de novo as stable domains across embryonic tissues. Such a view has been strengthened by the intensive landmark studies of the early patterning of the anterior-posterior (AP) axis of the Drosophila embryo, where indeed gene expression domains seem to arise more or less stably. However, careful analysis of gene expression patterns in other model systems (including the AP patterning in vertebrates and short-germ insects like the beetle Tribolium castaneum) painted a different, very dynamic view of gene regulation, where genes are oftentimes expressed in a wavelike fashion. How such gene expression waves are mediated at the enhancer level is so far unclear. Here, we establish the AP patterning of the short-germ beetle Tribolium as a model system to study dynamic and temporal pattern formation at the enhancer level. To that end, we established an enhancer prediction system in Tribolium based on time- and tissue-specific ATAC-seq and an enhancer live reporter system based on MS2 tagging. Using this experimental framework, we discovered several Tribolium enhancers, and assessed the spatiotemporal activities of some of them in live embryos. We found our data consistent with a model in which the timing of gene expression during embryonic pattern formation is mediated by a balancing act between enhancers that induce rapid changes in gene expression patterns (that we call 'dynamic enhancers') and enhancers that stabilize gene expression patterns (that we call 'static enhancers'). However, more data is needed for a strong support for this or any other alternative models.

Online Contingent Attention Training (OCAT): transfer effects to cognitive biases, rumination, and anxiety symptoms from two proof-of-principle studies.

The aim of the present research was to develop and test the efficacy of a novel online contingent attention training (i.e., OCAT) to modify attention and interpretation biases, improve emotion regulation, and reduce emotional symptom levels in the face of major stressors. Two proof-of-principle studies were carried out. In study 1, 64 undergraduates who were about to start a major stressful period (i.e., final exams) were randomized to undergo 10 days of active OCAT or a sham-control training. Emotion regulation (habitual use of rumination and reappraisal) and symptom levels (depression and anxiety) were assessed before and after the intervention. In study 2, the same 2 × 2 mixed design was used with 58 individuals from the general population undergoing a major stressful situation (the lockdown period at the beginning of the COVID-19 pandemic in 2020). In both studies, the OCAT group showed significant improvements on attention towards negative information and interpretation biases in comparison to the sham-control group. Additionally, changes in cognitive biases transferred to reductions of participants' use of rumination and anxiety symptom levels. These results show preliminary evidence regarding the efficacy of the OCAT to target attention and interpretation biases as well as to improve emotion regulation processes and to buffer against the effects of major stressors.

Nanocomposites with ZrO2@S-Doped g-C3N4 as an Enhanced Binder-Free Sensor: Synthesis and Characterization.

This study describes new electrocatalyst materials that can detect and reduce environmental pollutants. The synthesis and characterization of semiconductor nanocomposites (NCs) made from active ZrO2@S-doped g-C3N4 is presented. Electrochemical impedance spectroscopy (EIS) and Mott-Schottky (M-S) measurements were used to examine electron transfer characteristics of the synthesized samples. Using X-ray diffraction (XRD) and high-resolution scanning electron microscopy (HR-SEM) techniques, inclusion of monoclinic ZrO2 on flower-shaped S-doped-g-C3N4 was visualized. High-resolution X-ray photoelectron spectroscopy (XPS) revealed successful doping of ZrO2 into the lattice of S-doped g-C3N4. The electron transport mechanism between the electrolyte and the fluorine tin-oxide electrode (FTOE) was enhanced by the synergistic interaction between ZrO2 and S-doped g-C3N4 as co-modifiers. Development of a platform with improved conductivity based on an FTOE modified with ZrO2@S-doped g-C3N4 NCs resulted in an ideal platform for the detection of 4-nitrophenol (4-NP) in water. The electrocatalytic activity of the modified electrode was evaluated through determination of 4-NP by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) under optimum conditions (pH 5). ZrO2@S-doped g-C3N4 (20%)/FTOE exhibited good electrocatalytic activity with a linear range from 10 to 100 µM and a low limit of detection (LOD) of 6.65 µM. Typical p-type semiconductor ZrO2@S-doped g-C3N4 NCs significantly impact the superior detection of 4-NP due to its size, shape, optical properties, specific surface area and effective separation of electron-hole pairs. We conclude that the superior electrochemical sensor behavior of the ZrO2@S-doped g-C3N4 (20%)/FTOE surfaces results from the synergistic interaction between S-doped g-C3N4 and ZrO2 surfaces that produce an active NC interface.

Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13.

Mycobacterium tuberculosis is currently the leading cause of death by any bacterial infection1. The mycolic acid layer of the cell wall is essential for viability and virulence, and the enzymes responsible for its synthesis are therefore front line targets for antimycobacterial drug development2,3. Polyketide synthase 13 (Pks13) is a module comprised of a closely symmetric parallel dimer of chains, each encoding several enzymatic and transport functions, that carries out the condensation of two different very long chain fatty acids to produce mycolic acids that are essential components of the mycobacterial cell wall. Consequently individual enzymatic domains of Pks13 are targets for antimycobacterial drug development4. To understand this machinery, we sought to determine the structure and domain trajectories of the dimeric multi-enzyme Pks13, a 2×198,426 Dalton complex, from protein purified endogenously from mycobacteria under normal growth conditions, to capture it with normal substrates bound trapped 'in action'. Structures of the multi-domain assembly revealed by cryogenic electron microscopy (cryoEM) define the ketosynthase (KS), linker, and acyltransferase (AT) domains, each at atomic resolution (1.8Å), with bound substrates defined at 2.4Å and 2.9Å resolution. Image classification reveals two distinct structures with alternate locations of the N-terminal acyl carrier protein (termed ACP1a, ACP1b) seen at 3.6Å and 4.6Å resolution respectively. These two structures suggest plausible intermediate states, related by a ~60Å movement of ACP1, on the pathway for substrate delivery from the fatty acyl-ACP ligase (FadD32) to the ketosynthase domain. The linking sequence between ACP1 and the KS includes an 11 amino acid sequence with 6 negatively charged side chains that lies in different positively charged grooves on the KS in ACP1a versus ACP1b structures. This charge complementarity between the extended chain and the grooves suggests some stabilization of these two distinct orientations. Other domains are visible at lower resolution and indicate flexibility relative to the KS-AT core. The chemical structures of three bound endogenous long chain fatty acid substrates with their proximal regions defined in the structures were determined by electrospray ionization mass spectrometry. The domain proximities were probed by chemical cross-linking and identified by mass spectrometry. These were incorporated into integrative structure modeling to define multiple domain configurations that transport the very long fatty acid chains throughout the multistep Pks13 mediated synthetic pathway.

Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13.

The mycolic acid layer of the Mycobacterium tuberculosis cell wall is essential for viability and virulence, and the enzymes responsible for its synthesis are targets for antimycobacterial drug development. Polyketide synthase 13 (Pks13) is a module encoding several enzymatic and transport functions that carries out the condensation of two different long-chain fatty acids to produce mycolic acids. We determined structures by cryogenic-electron microscopy of dimeric multi-enzyme Pks13 purified from mycobacteria under normal growth conditions, captured with native substrates. Structures define the ketosynthase (KS), linker and acyl transferase (AT) domains at 1.8 Å resolution and two alternative locations of the N-terminal acyl carrier protein. These structures suggest intermediate states on the pathway for substrate delivery to the KS domain. Other domains, visible at lower resolution, are flexible relative to the KS-AT core. The chemical structures of three bound endogenous long-chain fatty acid substrates were determined by electrospray ionization mass spectrometry.

Regaining control of your emotions? Investigating the mechanisms underlying effects of cognitive control training for remitted depressed patients.

Studies suggest that cognitive control training shows potential as a preventive intervention for depression. At the same time, little is known regarding the mechanisms underlying effects of cognitive control training. Informed by theoretical frameworks of cognitive risk for recurrent depression (De Raedt & Koster, 2010; Siegle et al., 2007), the current study sought to model direct effects of cognitive control training on the complex interplay between affect, emotion regulation, residual symptomatology, and resilience in a sample of remitted depressed patients (n = 92). Combining a 4-week experience sampling procedure with an experimental manipulation of cognitive control, we observed beneficial effects of cognitive control training on deployment of rumination. In addition, we obtained evidence for the causal involvement of cognitive control in efficacy of emotion regulation. In contrast to our expectations, cognitive control training did not exert immediate effects on residual symptomatology or resilience when compared with an active control condition, nor did cognitive control training impact the complex interplay between these variables. Overall, immediate effects of cognitive control training on functioning in daily life were limited. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Synthesis and characterization of CuO@S-doped g-C3N4 based nanocomposites for binder-free sensor applications.

This study presents the simultaneous exfoliation and modification of heterostructured copper oxide incorporated sulfur doped graphitic carbon nitride (CuO@S-doped g-C3N4) nanocomposites (NCs) synthesized via chemical precipitation and pyrolysis techniques. The results revealed that the approach is feasible and highly efficient in producing 2-dimensional CuO@S-doped g-C3N4 NCs. The findings also showed a promising technique for enhancing the optical and electrical properties of bulk g-C3N4 by combining CuO nanoparticles (NPs) with S-doped g-C3N4. The crystallite and the average size of the NCs were validated using X-ray diffraction (XRD) studies. Incorporation of the cubical structured CuO on flower shaped S-doped-g-C3N4 was visualized and characterized through XRD, HR-SEM/EDS/SED, FT-IR, BET, UV-Vis/DRS, PL, XPS and impedance spectroscopy. The agglomerated NCs had various pore sizes, shapes and nanosized crystals, while being photo-active in the UV-vis range. The synergistic effect of CuO and S-doped g-C3N4 as co-modifiers greatly facilitates the electron transfer process between the electrolyte and the bare glassy carbon electrode. Specific surface areas of the NCs clearly revealed modification of bulk S-doped g-C3N4 when CuO NPs are incorporated with S-doped g-C3N4, providing a suitable environment for the binder-free decorated electrode with sensing behavior for hazardous pollutants. This was tested for the preparation of a 4-nitrophenol sensor.

Diversity of the manganese lipoxygenase gene family - A mini-review.

Analyses of fungal genomes of escalate from biological and evolutionary investigations. The biochemical analyses of putative enzymes will inevitably lag behind and only a selection will be characterized. Plant-pathogenic fungi secrete manganese-lipoxygenases (MnLOX), which oxidize unsaturated fatty acids to hydroperoxides to support infection. Six MnLOX have been characterized so far including the 3D structures of these enzymes of the Rice blast and the Take-all fungi. The goal was to use this information to evaluate MnLOX-related gene transcripts to find informative specimens for further studies. Phylogenetic analysis, determinants of catalytic activities, and the C-terminal amino acid sequences divided 54 transcripts into three major subfamilies. The six MnLOX belonged to the same "prototype" subfamily with conserved residues in catalytic determinants and C-terminal sequences. The second subfamily retained the secretion mechanism, presumably necessary for uptake of Mn2+, but differed in catalytic determinants and by cysteine replacement of an invariant Leu residue for positioning ("clamping") of fatty acids. The third subfamily contrasted with alanine in the Gly/Ala switch for regiospecific oxidation and a minority contained unprecedented C-terminal sequences or lacked secretion signals. With these exceptions, biochemical analyses of transcripts of the three subfamilies appear to have reasonable prospects to find active enzymes.

Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.

Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.