Rise and Decay of Photoluminescence in Upconverting Lanthanide-Doped Nanocrystals.

Nanocrystals (NCs) doped with lanthanides are capable of efficient photon upconversion, i.e., absorbing long-wavelength light and emitting shorter-wavelength light. The internal processes that enable upconversion are a complex network of electronic transitions within and energy transfer between dopant centers. In this work, we study the rise and decay dynamics of upconversion emission from ß-NaYF4 NCs codoped with Er3+ and Yb3+. The rise dynamics of the red and green upconverted emissions are nonlinear, reflecting the nonlinear nature of upconversion and revealing the mechanisms that populate the emitting states. The excited-state decay dynamics are nonexponential. We unravel the underlying decay pathways using photonic experiments. These reveal the contributions of different upconversion pathways visually, as each pathway exhibits a distinct response to systematic variation of the local density of optical states. Moreover, the effect of the local density of optical states on core-only NCs is qualitatively different from core-shell NCs. This is due to the different balance between feeding and decay of the electronic levels that produce upconverted emission. The understanding of the upconversion dynamics provided here could lead to better imaging and sensing methods relying on upconversion lifetimes or guide the rational optimization of the dopant concentrations for brighter upconversion.

Bats as instructive animal models for studying longevity and aging.

Bats (order Chiroptera) are emerging as instructive animal models for aging studies. Unlike some common laboratory species, they meet a central criterion for aging studies: they live for a long time in the wild or in captivity, for 20, 30, and even >40 years. Healthy aging (i.e., healthspan) in bats has drawn attention to their potential to improve the lives of aging humans due to bat imperviousness to viral infections, apparent low rate of tumorigenesis, and unique ability to repair DNA. At the same time, bat longevity also permits the accumulation of age-associated systemic pathologies that can be examined in detail and manipulated, especially in captive animals. Research has uncovered additional and critical advantages of bats. In multiple ways, bats are better analogs to humans than are rodents. In this review, we highlight eight diverse areas of bat research with relevance to aging: genome sequencing, telomeres, and DNA repair; immunity and inflammation; hearing; menstruation and menopause; skeletal system and fragility; neurobiology and neurodegeneration; stem cells; and senescence and mortality. These examples demonstrate the broad relevance of the bat as an animal model and point to directions that are particularly important for human aging studies.

Early prediction and impact assessment of CYP3A4-related drug-drug interactions for small molecule anti-cancer drugs using human-CYP3A4-transgenic mouse models.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here, we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (CYP)3A4 related DDIs of small molecule anti-cancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99 to 1.31 fold from clinical trial results for inhibition with itraconazole, while exposure predictions for the induction with rifampicin were less accurate with deviations of 0.22 to 0.48 fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method. Significance Statement The described method offers an alternative for the early detection and assessment of potential clinical impact of CYP3A4-related DDIs. The model was able to adequately describe the inhibition of CYP3A4 metabolism and the subsequent magnitude of change in exposure. However, it was unable to accurately predict the magnitude of change in exposure of victim drugs in combination with an inducer.

The Trial Enrollment Diversity Dashboard for Acute Leukemia Clinical Research: Intervention Development and Cohort Analysis.

PURPOSE: Participation in acute leukemia clinical trials is inequitable across multiple sociodemographic categories. Tools that provide researchers with performance feedback on the representativeness of the patients they enroll are limited. We aimed to develop an electronic health record (EHR)-based dashboard to provide such feedback and to describe any enrollment inequities uncovered. METHODS: We created a visual dashboard linking leukemia clinical trial registration and EHR data at the Dana-Farber Cancer Institute. Accuracy of a patient inclusion and assignment algorithm was tested with a target area under the receiver-operator curve (AUROC) of >0.90 against manual review. Demographic metric identification, visualization construction, and dashboard refinement were performed through stakeholder cognitive testing. Analysis of a recent 5-year cohort generated by the final algorithm assessed bivariate associations between enrollment and demographic metrics. Multivariable logistic regression included significant bivariate results. RESULTS: The final algorithm assignment AUROC was 0.98. Metrics were identified and visualizations successfully constructed. Fourteen individuals participated in testing and identified areas for revision: category mergers, denominator filters, and data delivery preferences. In the initial cohort of 1,315 patients, 1,020 (77.6%) had enrolled in any study protocol: 553 (42.1%) in a treatment trial and 936 (71.2%) in a biobanking study. In a multivariable model, older age (odds ratio [OR], 0.83 [95% CI, 0.73 to 0.94]) and Non-Hispanic Black race-ethnicity (OR, 0.38 [95% CI, 0.18 to 0.82]) were associated with lower enrollment, and English primary language with higher enrollment (OR, 2.50 [95% CI, 1.30 to 4.79]). CONCLUSION: We developed a research participation equity performance feedback dashboard for clinical researchers, and we identified actionable inequities. Next steps include feasibility and efficacy testing as well as implementation.

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.

Flexible Soft X-Ray Image Sensors based on Metal Halide Perovskites With High Quantum Efficiency.

Soft X-ray imaging is a powerful tool to explore the structure of cells, probe material with nanometer resolution, and investigate the energetic phenomena in the universe. Conventional soft X-ray image sensors are by and large Si-based charge coupled devices that suffer from low frame rates, complex fabrication processes, mechanical inflexibility, and required cooling below -60 °C. Here, a soft X-ray photodiode is reported based on low-cost metal halide perovskite with comparable performance to commercial Si-based device. Nanothrough network electrode minimized the optical loss due to the shadowing of insensitive layers, while a multidimensional perovskite heterojunction is generated to reduce the photo-generated carrier loss. This strategy promoted a record quantum efficiency of 8 × 103% without cooling, several orders of magnitude greater than the previously achieved. Flexible and curved soft X-ray imaging arrays are fabricated based on this high-performance device structure, demonstrating stable soft X-ray response and sharp imaging capabilities. This work highlights the low-cost and efficient perovskite photodiode as a strong candidate for the next-generation soft X-ray image sensors.

A chromosome phased diploid genome assembly of African hunting dog (Lycaon pictus).

The African hunting dog (Lycaon pictus, 2n=78) once ranged over most sub-Saharan ecosystems except its deserts and rainforests. However as a result of (still ongoing) population declines, today they remain only as small fragmented populations. Furthermore, the future of the species remains unclear, due to both anthropogenic pressure as well as interactions with domestic dogs, thus their preservation is a conservation priority. On the tree of life, the hunting dog is basal to Canis and Cuon and forms a crown group with them, making it a useful species for comparative genomic studies. Here, we present a diploid chromosome level assembly of an African hunting dog. Assembled according to VGP guidelines from a combination of PacBio HiFi reads and HiC data, it is phased at the level of individual chromosomes. The maternal (pseudo)haplotype (mat) of our assembly has a length of 2.38 Gbp, and 99.36 % of the sequence is encompassed by 39 chromosomal scaffolds. The rest is included in only 36 unplaced short scaffolds. At the contig level, mat consists of only 166 contigs with an N50 of 39 Mbp. BUSCO analysis showed 95.4 % completeness based on Сarnivora conservative genes (carnivora_odb10). When compared to other available genomes from subtribe Canina, the quality of the assembly is excellent, typically between the 1st and 3rd depending on the parameter used, and a significant improvement on previously published genomes for the species. We hope this assembly will play an important role in future conservation efforts and comparative studies of canid genomes.

Extracellular matrix production and oxygen diffusion regulate chemotherapeutic response in osteosarcoma spheroids.

BACKGROUND: Osteosarcoma (OS) survival rates and outcome have not improved in 50 years since the advent of modern chemotherapeutics. Thus, there is a critical need for an improved understanding of the tumor microenvironment to identify better therapies. Extracellular matrix (ECM) deposition and hypoxia are known to abrogate the efficacy of various chemical and cell-based therapeutics. Here, we aim to mechanistically investigate the combinatorial effects of hypoxia and matrix deposition with the use of OS spheroids. METHODS: We use two murine OS cell lines with differential metastatic potential to form spheroids. We form spheroids of two sizes, use ascorbate-2-phosphate supplementation to enhance ECM deposition, and study cell response under standard (21% O2) and physiologic (5% O2) oxygen tensions. Finally, we examine chemotherapeutic responses to doxorubicin treatment. RESULTS: ECM production and oxygen tension are key determinants of spheroid size through cell organization based on nutrient and oxygen distribution. Interestingly, highly metastatic OS is more susceptible to chemotherapeutics compared to less metastatic OS when matrix production increases. Together, these data suggest that dynamic interactions between ECM production and oxygen diffusion may result in distinct chemotherapeutic responses despite inherent tumor aggressiveness. CONCLUSION: This work establishes OS spheroids as a valuable tool for early OS tumor formation investigation and holds potential for novel therapeutic target and prognostic indicator discovery.

Management of bone health in idiopathic inflammatory myopathies: A two-center audit in the United Kingdom and Hong Kong.

BACKGROUND: Patients with inflammatory idiopathic myopathies (IIM) face elevated risks of osteoporosis and fragility fracture. AIM: To evaluate current practice relating to bone health in adult patients with IIM in the United Kingdom and Hong Kong (HK). METHODS: Patients were identified from IIM patient lists. Demographics, osteoporosis risk factors, DXA scans, and bone protection treatment were recorded. Adherence to regional standards was evaluated for each center. Following this, in the United Kingdom, up-to-date DXA scans were performed. RESULTS: Of 136 patients identified, 51 met selection criteria (UK, n = 20, HK, n = 31). Mean age in the United Kingdom was 59 (IQR 54-66); in Hong Kong, 65 (IQR 52.5-70). Most were female (UK 70%; HK 77%), current or previous steroid treatment was common (UK 90%; HK 100%) and some had experienced fragility fracture (UK 15%; HK 9%). The mean daily dose of prednisolone that patients were prescribed during the study was 12.5 mg (UK) and 14.3 mg (HK). Some patients had had a DXA scan (UK 50%; HK 35%) though several were outdated. Among those with BMD measured (UK, n = 20; HK, n = 11), osteopenia prevalence was 35% (UK) and 36% (HK) while osteoporosis was 5% (UK) and 36% (HK). Notably, 25% (UK) and 64% (HK) exceeded treatment thresholds. Treatments included anti-osteoporotic agents (UK 55%; HK 15%), Vitamin D/calcium supplements (UK 95%; HK 52%), or no treatment (UK 5%, HK 15%). CONCLUSION: Poor compliance with guidelines exists in both centers, particularly around investigation and monitoring of bone health for IIM patients. Integrated care models and increased resource allocation to bone health are imperative to improve management of this aspect of IIM.

Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF-α and IL-6 Release.

Natural products are widely recognized as valuable starting points for the development of therapeutics, with synthetic tetracyclic triterpenoids (e.g., steroids) being the most well represented among the drugs approved by the Food and Drug Administration. Here, recently developed synthetic tools for concise, asymmetric, and convergent construction of steroidal systems are leveraged to drive a program aimed at identifying novel glucocorticoid receptor (GR) modulators. While glucocorticoids have been extensively used as anti-inflammatory agents, they are plagued by severe side effects that include bone loss, muscle wasting, and metabolic disease. Ultimately, a program targeting the unnatural enantiomers of estranes (ent-estranes) that are practically inaccessible from natural product derivatization (semisynthesis) has resulted in the identification of a new class of potent dissociated GR modulators. We identify several leads with >99% efficacy as antagonists of GR trans-activation (potency within 10-fold of that of mifepristone) and further characterize examples that also inhibit release of pro-inflammatory cytokines IL-6 and TNF-α.

The use of imputation in clinical decision support systems: a cardiovascular risk management pilot vignette study among clinicians.

Aims: A major challenge of the use of prediction models in clinical care is missing data. Real-time imputation may alleviate this. However, to what extent clinicians accept this solution remains unknown. We aimed to assess acceptance of real-time imputation for missing patient data in a clinical decision support system (CDSS) including 10-year cardiovascular absolute risk for the individual patient. Methods and results: We performed a vignette study extending an existing CDSS with the real-time imputation method joint modelling imputation (JMI). We included 17 clinicians to use the CDSS with three different vignettes, describing potential use cases (missing data, no risk estimate; imputed values, risk estimate based on imputed data; complete information). In each vignette, missing data were introduced to mimic a situation as could occur in clinical practice. Acceptance of end-users was assessed on three different axes: clinical realism, comfortableness, and added clinical value. Overall, the imputed predictor values were found to be clinically reasonable and according to the expectations. However, for binary variables, use of a probability scale to express uncertainty was deemed inconvenient. The perceived comfortableness with imputed risk prediction was low, and confidence intervals were deemed too wide for reliable decision-making. The clinicians acknowledged added value for using JMI in clinical practice when used for educational, research, or informative purposes. Conclusion: Handling missing data in CDSS via JMI is useful, but more accurate imputations are needed to generate comfort in clinicians for use in routine care. Only then can CDSS create clinical value by improving decision-making.

Colonic atresia and Hirschsprung's disease in a neonate: A case report.

INTRODUCTION: Colonic atresia is a rare form of intestinal atresia that can be encountered in neonates. Although uncommon, other disease processes can be found simultaneously including malrotation, additional atresias, gastroschisis, and Hirschsprung's disease. CASE PRESENTATION: A 2-day-old female neonate with known maternal polysubstance use was found to have colonic atresia on contrast enema after emesis and failure to pass meconium. Abdominal exploration revealed a blind ending cecum with evidence of ischemia along with an atretic transverse colon. An ileocecectomy with end ileostomy and transverse colon mucous fistula creation were performed. After eventual ileostomy reversal at 5 weeks of age, she struggled with intermittent oral intolerance and inconsistent bowel function. Re-exploration with ileostomy and gastrostomy tube placement was performed with additional biopsies revealing Hirschsprung's disease. CLINICAL DISCUSSION: Concomitant colonic atresia and Hirschsprung's disease is a rare clinical entity that provides challenges in diagnosis and definitive surgical management. The suspected source of atresia in this case was presumed to be due to an intra-uterine vascular accident given maternal polysubstance use. Delays in diagnosis can lead to increased patient morbidity. CONCLUSION: Even with a clear suspected etiology for colonic atresia, surgeons must maintain a high clinical suspicion for additional pathologies including but not limited to Hirschsprung's disease. Rectal suction biopsies should be performed if clinical suspicion arises for Hirschsprung's disease.

Using priorities between human and livestock bacterial antimicrobial resistance (AMR) to identify data gaps in livestock AMR surveillance.

BACKGROUND: Bacterial antimicrobial resistance (AMR) is a global threat to both humans and livestock. Despite this, there is limited global consensus on data-informed, priority areas for intervention in both sectors. We compare current livestock AMR data collection efforts with other variables pertinent to human and livestock AMR to identify critical data gaps and mutual priorities. METHODS: We globally synthesized livestock AMR data from open-source surveillance reports and point prevalence surveys stratified for six pathogens (Escherichia coli, Staphylococcus aureus, non-typhoidal Salmonella, Campylobacter spp., Enterococcus faecalis, Enterococcus faecium) and eleven antimicrobial classes important in human and veterinary use, published between 2000 and 2020. We also included all livestock species represented in the data: cattle, chickens, pigs, sheep, turkeys, ducks, horses, buffaloes, and goats. We compared this data with intended priorities calculated from: disability-adjusted life years (DALYs), livestock antimicrobial usage (AMU), livestock biomass, and a global correlation exercise between livestock and human proportion of resistant isolates. RESULTS: Resistance to fluoroquinolones and macrolides in Staphylococcus aureus were identified as priorities in many countries but, less than 10% of these reported livestock AMR data. Resistance data for Escherichia coli specific to cattle, chickens, and pigs, which we prioritized, were also well collected. AMR data collection on non-typhoidal Salmonella and other livestock species were often not prioritized. Of 232 categories prioritized by at least one country, data were only collected for 48% (n = 112). CONCLUSIONS: The lack of livestock AMR data globally for broad resistance in Staphylococcus aureus could underplay their zoonotic threat. Countries can bolster livestock AMR data collection, reporting, and intervention setting for Staphylococcus aureus as done for Escherichia coli. This framework can provide guidance on areas to strengthen AMR surveillance and decision-making for humans and livestock, and if done routinely, can adapt to resistance trends and priorities.

Hypervalent zinc(I) complexes with an NNNN-macrocycle: C-H bond activation across the zinc(I)-zinc(I) bond.

Hetero- and homoleptic dinuclear zinc(I) complexes containing the macrocycle Me4TACD (N,N',N'',N'''-1,4,7,10-tetramethylcyclododecane) were prepared; the heteroleptic complex [(Me4TACD)Zn-ZnCp*]+ reacted with activated hydrocarbons R-H (R = CH2CN, CCPh) to give the corresponding hydrocarbyl zinc(II) complexes [(Me4TACD)ZnR]+.

Focal adhesion kinase regulates tendon cell mechanoresponse and physiological tendon development.

Tendons enable locomotion by transmitting high tensile mechanical forces between muscle and bone via their dense extracellular matrix (ECM). The application of extrinsic mechanical stimuli via muscle contraction is necessary to regulate healthy tendon function. Specifically, applied physiological levels of mechanical loading elicit an anabolic tendon cell response, while decreased mechanical loading evokes a degradative tendon state. Although the tendon response to mechanical stimuli has implications in disease pathogenesis and clinical treatment strategies, the cell signaling mechanisms by which tendon cells sense and respond to mechanical stimuli within the native tendon ECM remain largely unknown. Therefore, we explored the role of cell-ECM adhesions in regulating tendon cell mechanotransduction by perturbing the genetic expression and signaling activity of focal adhesion kinase (FAK) through both in vitro and in vivo approaches. We determined that FAK regulates tendon cell spreading behavior and focal adhesion morphology, nuclear deformation in response to applied mechanical strain, and mechanosensitive gene expression. In addition, our data reveal that FAK signaling plays an essential role in in vivo tendon development and postnatal growth, as FAK-knockout mouse tendons demonstrated reduced tendon size, altered mechanical properties, differences in cellular composition, and reduced maturity of the deposited ECM. These data provide a foundational understanding of the role of FAK signaling as a critical regulator of in situ tendon cell mechanotransduction. Importantly, an increased understanding of tendon cell mechanotransductive mechanisms may inform clinical practice as well as lead to the discovery of diagnostic and/or therapeutic molecular targets.

The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism-An Unconventional Ally in Cancer Treatment.

The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a "ceramide neutralizer", an unwelcome event, highlighting yet another facet of P-gp's versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp "neutralizes" ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer.

Preclinical toxicity studies supporting 2DG for treatment of status epilepticus.

2-deoxy-D-glucose (2DG) has been proposed as a potential antiseizure treatment based on seizure suppressive actions in multiple acute and chronic seizure models, including models of status epilepticus (SE). Here we summarize recently completed preclinical toxicological studies of single doses of an intravenous formulation of 2DG supporting potential safety of 2DG for acute treatment of SE and acute repetitive seizures (ARS).

Spatial and Bidirectional Work Function Modulation of Monolayer Graphene with Patterned Polymer "Fluorozwitterists".

Understanding the electronic properties resulting from soft-hard material interfacial contact has elevated the utility of functional polymers in advanced materials and nanoscale structures, such as in work function engineering of two-dimensional (2D) materials to produce new types of high-performance devices. In this paper, we describe the electronic impact of functional polymers, containing both zwitterionic and fluorocarbon components in their side chains, on the work function of monolayer graphene through the preparation of negative-tone photoresists, which we term "fluorozwitterists." The zwitterionic and fluorinated groups each represent dipole-containing moieties capable of producing distinct surface energies as thin films. Kelvin probe force microscopy revealed these polymers to have a p-doping effect on graphene, which contrasts the work function decrease typically associated with polymer-to-graphene contact. Copolymerization of fluorinated zwitterionic monomers with methyl methacrylate and a benzophenone-substituted methacrylate produced copolymers that were amenable to photolithographic fabrication of fluorozwitterist structures. Consequently, spatial alteration of zwitterion coverage across graphene yielded stripes that resemble a lateral p-i-n diode configuration, with local increase or decrease of work function. Overall, this polymeric fluorozwitterist design is suitable for enabling simple, solution-based surface patterning and is anticipated to be useful for spatial work function modulation of 2D materials integrated into electronic devices.

The genome sequence of the Mauritius kestrel, Falco punctatus (Temminck, 1821).

We present a genome assembly from an individual male Falco punctatus (the Mauritius kestrel; Chordata; Aves; Falconiformes; Falconidae). The genome sequence is 1,279.3 megabases in span. Most of the assembly is scaffolded into 23 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 17.34 kilobases in length.

The promise of molecular science in brain health. What breakthroughs are anticipated in the next 20 years?

Brain health means optimal physiological brain function across the normal life-course. It encompasses not only healthy brain aging but also brain diseases, their diagnosis and treatment. In all these areas, molecular science has advanced our understanding. This multi-disciplinary review combines viewpoints from laboratory science, clinical medicine and the bioscience industry. First, we review the advances that molecular science has brought to brain health in the past twenty years. These include therapeutic antibodies for CNS diseases (multiple sclerosis, Alzheimer disease) and the dramatic introduction of RNA-targeted therapeutics. Second, we highlight areas where greater molecular understanding is needed. Salient examples are the relation of brain structure to cognitive symptoms, and molecular biomarkers for diagnosis, target discovery and testing of interventions. Finally, we speculate on aspects of molecular science that are likely to advance brain health in the next twenty years. These include: cell senescence and chronobiology; gene editing (notably, CRISPR) and RNA targeting (RNA interference, miRNA manipulation); brain-immune interactions; novel drug targets (AQP4, HIF1, Toll-like receptors); and novel chemistry to make new drugs (molecular machines, quantum molecular modelling and "click" chemistry). Early testing of the relationships between molecular pathways and clinical manifestations will drive much-needed breakthroughs in neurology and psychiatry.