SGLT2 inhibitors activate pantothenate kinase in the human heart.

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.

Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis.

Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/ß5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAPoff cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/ß5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/ß5 axis as a critical effector of YAP tumor suppressor activity. SIGNIFICANCE: Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B.

Where and how to invest in greenspace for optimal health benefits: a systematic review of greenspace morphology and human health relationships.

Research on the relationship between greenspace morphology and health is a growing field that informs the spatial design of greenspace to enhance health outcomes. This study reviews the current progress, methodologies, and knowledge gaps in this area. From a database search of 272 940 English articles and 39 053 Chinese articles up to April 18, 2024, we identified 22 and 7 studies on the topic for further evaluation. Predominantly cross-sectional and neighbourhood-scale analyses were conducted using land cover maps ranging from 0·25 to 100 meters in resolution. Six primary characteristics of greenspace morphology have been studied, including size, shape, fragmentation, connectedness, aggregation, and diversity. While associations between greenspace morphology and health outcomes have been observed, both their reliability and generalisability remain suggestive due to ecological study designs and heterogeneity among studies. Future research should prioritise individual-level prospective cohorts and intervention studies. Exploring mechanisms linking greenspace morphology and health, determining optimal map resolution, and distinguishing it from greenness magnitude in statistical analysis is essential. This evidence is crucial for health-promoting greenspace planning and should be routinely integrated into urban epidemiological research.

Syntax-like Structures in Maternal Contact Calls of Chestnut-Crowned Babblers (Pomatostomus ruficeps).

The combination of meaning-bearing units (e.g., words) into higher-order structures (e.g., compound words and phrases) is integral to human language. Despite this central role of syntax in language, little is known about its evolutionary progression. Comparative data using animal communication systems offer potential insights, but only a handful of species have been identified to combine meaningful calls together into larger signals. We investigated a candidate for syntax-like structure in the highly social chestnut-crowned babbler (Pomatostomus ruficeps). Using a combination of behavioral observations, acoustic analyses, and playback experiments, we test whether the form and function of maternal contact calls is modified by combining the core "piping" elements of such calls with at least one other call element or call. Results from the acoustic analyses (236 analysed calls from 10 individuals) suggested that piping call elements can be flexibly initiated with either "peow" elements from middle-distance contact calls or adult "begging" calls to form "peow-pipe" and "beg-pipe" calls. Behavioral responses to playbacks (20 trials to 7 groups) of natural peow-pipe and beg-pipe calls were comparable to those of artificially generated versions of each call using peow elements and begging calls from other contexts. Furthermore, responses to playbacks (34 trials to 7 groups) of the three forms of maternal contact calls (piping alone, peow-pipe, beg-pipe) differed. Together these data suggest that meaning encoded in piping calls is modified by combining such calls with begging calls or peow elements used in other contexts and so provide rare empirical evidence for syntactic-like structuring in a nonhuman animal.

Current Status of the Management of Idiopathic Condylar Resorption/Progressive Condylar Resorption-A Scoping Review.

The temporomandibular joint (TMJ) is a complex synovial joint shrouded in mystery, as the etiology of many TMJ disorders are unsolved. Idiopathic/progressive condylar resorption (ICR/PCR) is one such TMJ disorder characterized by a gradually deteriorating mandibular condylar mass, resulting in severe mandibular retrognathia, which often accompanied by clockwise rotation of mandible and an anterior open bite. Since the etiology of the ICR/PCR remains unclear, no definitive prevention or management options have been established. To date, various symptomatic non-surgical, surgical, and salvage management options have been developed and reported. To understand the current status of the ICR/PCR management options, this article provides an overview of the options presently reported in the literature to reduce its TMJ symptoms and improve mandibular function and form.

Correction to: 'Unscrambling variation in avian eggshell colour and patterning in a continent-wide study' (2019), by L'Herpiniere et al.

[This corrects the article DOI: 10.1098/rsos.181269.][This corrects the article DOI: 10.1098/rsos.181269.].

Clutch Size, but Not Egg Volume, Increases with Rainfall in an Arid-dwelling Bird.

Understanding how animals maximize reproductive success in variable environments is important in determining how populations will respond to increasingly extreme weather events predicted in the face of changing climates. Although temperature is generally considered a key factor in reproductive decisions, rainfall is also an important predictor of prey availability in arid environments. Here, we test the impact of weather (i.e., rainfall and temperature) on female reproductive investment in an arid-dwelling bird (i.e., clutch size and egg volume) and tradeoffs between the two. We predicted that female chestnut-crowned babblers (Pomatostomus ruficeps), endemic to the arid region of Australia, would increase clutch size at the expense of egg volume in response to variation in rainfall and temperature. We found that over 14 breeding seasons, clutch size decreased with increasing temperature, but increased following more rain. Egg volume, on the other hand, became larger as temperatures increased and, although not related to the amount of rain, was related to the number of days since the last rainfall. Finally, egg size decreased as clutch size increased, indicating a tradeoff between the two reproductive parameters. Our results suggest that chestnut-crowned babblers breed reactively in response to variable environments. We expect that clutch size variation in response to rain may reflect the impact of rain on arthropod abundance, whereas the effect of temperature may represent an established decline in clutch size observed in other seasonal breeders. As the tradeoff between clutch size and egg volume was modest, and clutch sizes were modified to a greater extent than egg volumes in response to rainfall, we suggest selection is more likely to increase offspring number than quality, at least in favorable years. Our results support the idea that reproductive investment is variable in fluctuating environments, which has implications for species living in habitats experiencing more extreme and less predictable weather as the global climate changes.

Does surgical volume correlate with outcomes in TMJ replacement surgery?

OBJECTIVE: To survey oral and maxillofacial surgeons (OMS) who perform temporomandibular joint replacement (TMJR) to determine whether length of surgery, specific TMJR protocols, or the incidence of complications are related to experience and case volume. STUDY DESIGN: An anonymous electronic survey was emailed to 407 surgeon members of the American Association of Oral and Maxillofacial Surgeons, American Society of Temporomandibular Joint Surgeons, and European Society of Temporomandibular Joint Surgeons known to have TMJR experience via publications or reputation. The descriptive survey contained multiple choice and open-ended questions. Descriptive statistics were computed for each variable for data analysis. RESULTS: Forty-nine surgeons completed the survey. The average stock TMJR cases included 54.6% unilateral and 50.5% bilateral cases. The average custom TMJR cases included 50.5% unilateral and 49.5% bilateral cases. Average procedure time for stock TMJR was 2.86 hours for unilateral, and 5.30 hours for bilateral cases. The average procedure time for a custom TMJR was 2.75 hours for unilateral, and 4.87 hours for bilateral cases. Average duration of hospital stay for stock and custom TMJR cases was 1.49 and 1.41 days (unilateral), and 1.98 and 1.95 days (bilateral). CONCLUSIONS: This study provides some pilot data that demonstrates that the length of surgery, specific TMJR surgical protocols, and the incidence of complications may be related to surgeon TMJR experience and case volume.

Selective concentration of iron, titanium, and zirconium substrate minerals within Gregory's diverticulum, an organ unique to derived sand dollars (Echinoidea: Scutelliformes).

Gregory's diverticulum, a digestive tract structure unique to a derived group of sand dollars (Echinoidea: Scutelliformes), is filled with sand grains obtained from the substrate the animals inhabit. The simple methods of shining a bright light through a specimen or testing response to a magnet can reveal the presence of a mineral-filled diverticulum. Heavy minerals with a specific gravity of >2.9 g/cm3 are selectively concentrated inside the organ, usually at concentrations one order of magnitude, or more, greater than found in the substrate. Analyses of diverticulum content for thirteen species from nine genera, using optical mineralogy, powder X-ray diffraction, scanning electron microscopy and energy dispersive X-ray spectroscopy, as well as micro-computed tomography shows the preference for selection of five major heavy minerals: magnetite (Fe3O4), hematite (Fe2O3), ilmenite (FeTiO3), rutile (TiO2), and zircon (ZrSiO4). Minor amounts of heavy or marginally heavy amphibole, pyroxene and garnet mineral grains may also be incorporated. In general, the animals exhibit a preference for mineral grains with a specific gravity of >4.0 g/cm3, although the choice is opportunistic and the actual mix of mineral species depends on the mineral composition of the substrate. The animals also select for grain size, with mineral grains generally in the range of 50 to 150 µm, and do not appear to alter this preference during ontogeny. A comparison of analytical methods demonstrates that X-ray attenuation measured using micro-computed tomography is a reliable non-destructive method for heavy mineral quantification when supported by associated analyses of mineral grains extracted destructively from specimens or from substrate collected together with the specimens. Commonalities in the electro-chemical surface properties of the ingested minerals suggest that such characteristics play an important role in the selection process.

DeepFLAIR: A neural network approach to mitigate signal and contrast loss in temporal lobes at 7 Tesla FLAIR images.

BACKGROUND AND PURPOSE: Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS: Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS: SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS: The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

Practice-Oriented Research: An Introduction to New Developments and Future Directions.

Aimed at understanding and improving psychological therapies as they are conducted in clinical routine, practice-oriented research (POR) is now a well-established approach to the scientific foundations of mental health care services. Resting on the accumulation of a wide range of practice-based evidence related to treatment outcome and process, as well as factors associated with the participants of psychotherapy and its context, POR is ripe for new developments - regarding what to investigate and how to investigate it. This paper is the introduction of a series devoted to recent advances and future directions of POR as their pertained to routine outcome monitoring, technologies and artificial intelligence, the integration of constructs and methods from program evaluation and implementation science, and the investigation of populations with limited financial resources across various regions of the world. The series also includes commentaries from two leaders of POR.

Alloplastic TMJ replacement in the skeletally immature patient - A systematic review.

This study assessed the current evidence for the use of TMJR reconstruction in skeletally immature patients. A systematic review was conducted according to PRISMA guidelines. An electronic search in PubMed and Embase was performed. Meta-analysis randomized controlled trials (RCTs), cohort studies, observational studies, case series, and case reports were eligible for inclusion. Case reports were also included due to the limited number of publications identified with the predefined terms. Exclusion criteria were: (1) studies written in a language other than English; (2) full-text unavailability (i.e., posters and conference abstracts). The selected studies were assessed for risk of bias. A meta-analysis was not performed as it necessitates a substantial between-study design homogeneity; hence, a descriptive synthesis of data was performed. There were 9 TMJR device reconstruction studies involving 14 subjects 13 years of age or younger. Follow-up ranged from 7 months to 120 months. All papers reported significant decrease in pain and improvement of diet. All prostheses were functional. No material failures of the prosthesis components were observed. The mandible continued to show limited growth following TMJR and most of the cases required no secondary or revision surgery even when the patient reached skeletal maturity. This systematic review had some limitations. The studies included had a low level of evidence and a high risk of bias. Most of the studies had a small patient sample, and no study had a control group. The literature reviewed supports the use of TMJR devices in the restoration of mandibular function and form in skeletally immature patients.

Predator selection on multicomponent warning signals in an aposematic moth.

Aposematic prey advertise their unprofitability with conspicuous warning signals that are often composed of multiple color patterns. Many species show intraspecific variation in these patterns even though selection is expected to favor invariable warning signals that enhance predator learning. However, if predators acquire avoidance to specific signal components, this might relax selection on other aposematic traits and explain variability. Here, we investigated this idea in the aposematic moth Amata nigriceps that has conspicuous black and orange coloration. The size of the orange spots in the wings is highly variable between individuals, whereas the number and width of orange abdominal stripes remains consistent. We produced artificial moths that varied in the proportion of orange in the wings or the presence of abdominal stripes. We presented these to a natural avian predator, the noisy miner (Manorina melanocephala), and recorded how different warning signal components influenced their attack decisions. When moth models had orange stripes on the abdomen, birds did not discriminate between different wing signals. However, when the stripes on the abdomen were removed, birds chose the model with smaller wing spots. In addition, we found that birds were more likely to attack moths with a smaller number of abdominal stripes. Together, our results suggest that bird predators primarily pay attention to the abdominal stripes of A. nigriceps, and this could relax selection on wing coloration. Our study highlights the importance of considering individual warning signal components if we are to understand how predation shapes selection on prey warning coloration.

Surgical complications of vagus nerve stimulation surgery: A 14-years single-center experience.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810.

Nanodroplet formation is important to achieve supersaturation of active pharmaceutical ingredients (APIs) in an amorphous solid dispersion. The aim of the current study was to explore how polymer composition, architecture, molar mass, and surfactant concentration affect polymer-drug nanodroplet morphology with the breast cancer API, GDC-0810. The impact of nanodroplet size and morphology on dissolution efficacy and drug loading capacity was explored using polarized light microscopy, dynamic light scattering, and cryogenic transmission electron microscopy. Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) was synthesized as two linear derivatives and two bottlebrush derivatives with carboxylated or PEGylated end-groups. Hydroxypropyl methylcellulose acetate succinate grade MF (HPMCAS-MF) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) were included as commercial polymer controls. We report the first copolymerization synthesis of a PVPVA bottlebrush copolymer, which was the highest performing excipient in this study, maintaining 688 µg/mL GDC-0810 concentration at 60 wt % drug loading. This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies.

Theoretical relationships between axoneme distortion and internal forces and torques in ciliary beating.

The axoneme is an intricate nanomachine responsible for generating the propulsive oscillations of cilia and flagella in an astonishing variety of organisms. New imaging techniques based on cryoelectron-tomography (cryo-ET) and subtomogram averaging have revealed the detailed structures of the axoneme and its components with sub-nm resolution, but the mechanical function of each component and how the assembly generates oscillations remains stubbornly unclear. Most explanations of oscillatory behavior rely on the dynamic regulation of dynein by some signal, but this may not be necessary if the system of dynein-driven slender filaments is dynamically unstable. Understanding the possibility of instability-driven oscillations requires a multifilament model of the axoneme that accounts for distortions of the axoneme as it bends. Active bending requires forces and bending moments that will tend to change the spacing and alignment of doublets. We hypothesize that components of the axoneme resist and respond to these loads in ways that are critical to beating. Specifically, we propose (i) that radial spokes provide torsional stiffness by resisting misalignment (as well as spacing) between the central pair and outer doublets, and (ii) that the kinematics of dynein arms affect the relationships between active forces and bending moments on deforming doublets. These proposed relationships enhance the ability of theoretical, multifilament models of axonemal beating to generate propulsive oscillatory waveforms via dynamic mechanical instability.

Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.

The goal of precision medicine is to utilize our knowledge of the molecular causes of disease to better diagnose and treat patients. However, there is a substantial mismatch between the small number of food and drug administration (FDA)-approved drugs and annotated coding variants compared to the needs of precision medicine. This review introduces the concept of physics-based precision medicine, a scalable framework that promises to improve our understanding of sequence-function relationships and accelerate drug discovery. We show that accounting for the ensemble of structures a protein adopts in solution with computer simulations overcomes many of the limitations imposed by assuming a single protein structure. We highlight studies of protein dynamics and recent methods for the analysis of structural ensembles. These studies demonstrate that differences in conformational distributions predict functional differences within protein families and between variants. Thanks to new computational tools that are providing unprecedented access to protein structural ensembles, this insight may enable accurate predictions of variant pathogenicity for entire libraries of variants. We further show that explicitly accounting for protein ensembles, with methods like alchemical free energy calculations or docking to Markov state models, can uncover novel lead compounds. To conclude, we demonstrate that cryptic pockets, or cavities absent in experimental structures, provide an avenue to target proteins that are currently considered undruggable. Taken together, our review provides a roadmap for the field of protein science to accelerate precision medicine.

PopShift: A Thermodynamically Sound Approach to Estimate Binding Free Energies by Accounting for Ligand-Induced Population Shifts from a Ligand-Free Markov State Model.

Obtaining accurate binding free energies from in silico screens has been a long-standing goal for the computational chemistry community. However, accuracy and computational cost are at odds with one another, limiting the utility of methods that perform this type of calculation. Many methods achieve massive scale by explicitly or implicitly assuming that the target protein adopts a single structure, or undergoes limited fluctuations around that structure, to minimize computational cost. Others simulate each protein-ligand complex of interest, accepting lower throughput in exchange for better predictions of binding affinities. Here, we present the PopShift framework for accounting for the ensemble of structures a protein adopts and their relative probabilities. Protein degrees of freedom are enumerated once, and then arbitrarily many molecules can be screened against this ensemble. Specifically, we use Markov state models (MSMs) as a compressed representation of a protein's thermodynamic ensemble. We start with a ligand-free MSM and then calculate how addition of a ligand shifts the populations of each protein conformational state based on the strength of the interaction between that protein conformation and the ligand. In this work we use docking to estimate the affinity between a given protein structure and ligand, but any estimator of binding affinities could be used in the PopShift framework. We test PopShift on the classic benchmark pocket T4 Lysozyme L99A. We find that PopShift is more accurate than common strategies, such as docking to a single structure and traditional ensemble docking─producing results that compare favorably with alchemical binding free energy calculations in terms of RMSE but not correlation─and may have a more favorable computational cost profile in some applications. In addition to predicting binding free energies and ligand poses, PopShift also provides insight into how the probability of different protein structures is shifted upon addition of various concentrations of ligand, providing a platform for predicting affinities and allosteric effects of ligand binding. Therefore, we expect PopShift will be valuable for hit finding and for providing insight into phenomena like allostery.

Empirical Analysis of Drug Targets for Nervous System Disorders.

The discovery and development of drugs to treat diseases of the nervous system remains challenging. There is a higher attrition rate in the clinical stage for nervous system experimental drugs compared to other disease areas. In the preclinical stage, additional challenges arise from the considerable effort required to find molecules that penetrate the blood-brain barrier (BBB) coupled with the poor predictive value of many preclinical models of nervous system diseases. In the era of target-based drug discovery, the critical first step of drug discovery projects is the selection of a therapeutic target which is largely driven by its presumed pathogenic involvement. For nervous system diseases, however, the feasibility of identifying potent molecules within the stringent range of molecular properties necessary for BBB penetration should represent another important factor in target selection. To address the latter, the present review analyzes the distribution of human protein targets of FDA-approved drugs for nervous system disorders and compares it with drugs for other disease areas. We observed a substantial difference in the distribution of therapeutic targets across the two clusters. We expanded on this finding by analyzing the physicochemical properties of nervous and non-nervous system drugs in each target class by using the central nervous system multiparameter optimization (CNS MPO) algorithm. These data may serve as useful guidance in making more informed decisions when selecting therapeutic targets for nervous system disorders.