Sex differences in 3- to 5-year-old children's motor competence: A pooled cross-sectional analysis of 6241 children.

There is some, albeit inconsistent, evidence supporting sex differences in preschoolers' motor competence (MC), with these observations not uniform when analyzed by age, and cultural groups. Thus, this study examined sex differences across ages in 3- to 5-year-old children's MC. A cross-country pooled sample of 6241 children aged 3-5 years (49.6% girls) was assessed for MC using the Test of Gross Motor Development-2nd/3rd edition, and children were categorized into groups of age in months. Multiple linear regression models and predictive margins were calculated to explore how sex and age in months affect scores of MC (i.e., locomotor and ball skills), with adjustments for country and BMI. The Chow's Test was used to test for the presence of a structural break in the data. Significant differences in favor of girls were seen at 57-59 and 66-68 months of age for locomotor skills; boys performed better in ball skills in all age periods, except for 42-44 and 45-47 months of age. The higher marginal effects were observed for the period between 45-47 and 48-50 months for locomotor skills (F = 30.21; and F = 25.90 for girls and boys, respectively), and ball skills (F = 19.01; and F = 42.11 for girls and boys, respectively). A significantly positive break point was seen at 45-47 months, highlighting the age interval where children's MC drastically improved. The identification of this breakpoint provides an evidence-based metric for when we might expect MC to rapidly increase, and an indicator of early delay when change does not occur at that age.

Tunable Intervalence Charge Transfer in Ruthenium Prussian Blue Analog Enables Stable and Efficient Biocompatible Artificial Synapses.

Emerging concepts for neuromorphic computing, bioelectronics, and brain-computer interfacing inspire new research avenues aimed at understanding the relationship between oxidation state and conductivity in unexplored materials. This report expands the materials playground for neuromorphic devices to include a mixed valence inorganic 3D coordination framework, a ruthenium Prussian blue analog (RuPBA), for flexible and biocompatible artificial synapses that reversibly switch conductance by more than four orders of magnitude based on electrochemically tunable oxidation state. The electrochemically tunable degree of mixed valency and electronic coupling between N-coordinated Ru sites controls the carrier concentration and mobility, as supported by density functional theory computations and application of electron transfer theory to in situ spectroscopy of intervalence charge transfer. Retention of programmed states is improved by nearly two orders of magnitude compared to extensively studied organic polymers, thus reducing the frequency, complexity, and energy costs associated with error correction schemes. This report demonstrates dopamine-mediated plasticity of RuPBA synapses and biocompatibility of RuPBA with neuronal cells, evoking prospective application for brain-computer interfacing.

Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials.

OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.

Modulating the Influenza A Virus-Target Membrane Fusion Interface With Synthetic DNA-Lipid Receptors.

Influenza A virus (IAV) binds to sialylated glycans on the cell membrane before endocytosis and fusion. Cell-surface glycans are highly heterogeneous in length and glycosylation density, which leads to variations in the distance and rigidity with which IAV is held away from the cell membrane. To gain mechanistic insight into how receptor length and rigidity impact the mechanism of IAV entry, we employed synthetic DNA-lipids as highly tunable surrogate receptors. We tethered IAV to target membranes with a panel of DNA-lipids to investigate the effects of the distance and tether flexibility between virions and target membranes on the kinetics of IAV binding and fusion. Tether length and the presence of a flexible linker led to higher rates of IAV binding, while the efficiencies of lipid and content mixing were typically lower for longer and more rigid DNA tethers. For all DNA tether modifications, we found that the rates of IAV lipid and content mixing were unchanged. These results suggest that variations in the interface between IAV and a target membrane do not significantly impact the rate-limiting step of fusion or the low-pH-triggered engagement of viral fusion peptides with the target membrane. However, our results imply that the flexibility of the viral receptor is important for ensuring that hemifusion events are able to successfully proceed to pore formation.

The combination of three movement behaviours is associated with object control skills, but not locomotor skills, in preschoolers.

The objective of this study is to analyze the association between combinations of adherence to movement behaviour recommendations and fundamental movement skills (FMS) in preschoolers. This is a cross-sectional study. Participants of the study were 212 preschool children (M = 3.97 years old; 51.4% male), who provided objectively assessed physical activity (PA) data (Actigraph wGT3X), and completed FMS assessments (TGMD-2). Sleep time and screen time were parent-reported through face-to-face interview. Associations between the combination of two or three movement behaviours and FMS were analyzed using structural equation modeling (Mplus; 8.0; p < 0.05). Positive and significant associations were found between adherence to screen + sleep recommendations and locomotor skills (ß = 0.23; p = 0.027); and between adherence to PA + screen + sleep recommendations with object control skills (ß = 0.28; p = 0.014). Negative and significant associations were found between screen + sleep with object control skills (ß = - 0.28; p = 0.007). The adherence to the 24-h movement behaviour recommendations explained locomotor and object control skills variability by 5% and 7%, respectively.Conclusion: The adherence to the combined movement behaviour recommendations may be a more important influence on FMS in preschoolers compared to any single movement behaviour in isolation. What is Known: • The association between the isolated adherence to movement behaviour (physical activity, screen time and sleep time) recommendations and fundamental movement skills (FMS) in preschoolers, and the role of the 24-h movement behaviours on FMS, has been previously reported. What is New: • This study adds important information to the current literature, when highlighting that the combined adherence to physical activity, screen time and sleep time recommendations is positively associated with object control skills (such as throwing and kicking), and the combination of screen time and sleep is positively associated with locomotor skills (such as running and hopping).

Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach.

Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABAA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10-15% transient GABAA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo n = 26; padsevonil n = 24). Their median age was 36 years (range 18-60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14; P = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted P = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.

Membrane-tethered mucin-like polypeptides sterically inhibit binding and slow fusion kinetics of influenza A virus.

The mechanism(s) by which cell-tethered mucins modulate infection by influenza A viruses (IAVs) remain an open question. Mucins form both a protective barrier that can block virus binding and recruit IAVs to bind cells via the sialic acids of cell-tethered mucins. To elucidate the molecular role of mucins in flu pathogenesis, we constructed a synthetic glycocalyx to investigate membrane-tethered mucins in the context of IAV binding and fusion. We designed and synthesized lipid-tethered glycopolypeptide mimics of mucins and added them to lipid bilayers, allowing chemical control of length, glycosylation, and surface density of a model glycocalyx. We observed that the mucin mimics undergo a conformational change at high surface densities from a compact to an extended architecture. At high surface densities, asialo mucin mimics inhibited IAV binding to underlying glycolipid receptors, and this density correlated to the mucin mimic's conformational transition. Using a single virus fusion assay, we observed that while fusion of virions bound to vesicles coated with sialylated mucin mimics was possible, the kinetics of fusion was slowed in a mucin density-dependent manner. These data provide a molecular model for a protective mechanism by mucins in IAV infection, and therefore this synthetic glycocalyx provides a useful reductionist model for studying the complex interface of host-pathogen interactions.

Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis.

Clostridioides (formerly Clostridium) difficile is a leading cause of healthcare-associated infections. Although considerable progress has been made in the understanding of its genome, the epigenome of C. difficile and its functional impact has not been systematically explored. Here, we perform a comprehensive DNA methylome analysis of C. difficile using 36 human isolates and observe a high level of epigenomic diversity. We discovered an orphan DNA methyltransferase with a well-defined specificity, the corresponding gene of which is highly conserved across our dataset and in all of the approximately 300 global C. difficile genomes examined. Inactivation of the methyltransferase gene negatively impacts sporulation, a key step in C. difficile disease transmission, and these results are consistently supported by multiomics data, genetic experiments and a mouse colonization model. Further experimental and transcriptomic analyses suggest that epigenetic regulation is associated with cell length, biofilm formation and host colonization. These findings provide a unique epigenetic dimension to characterize medically relevant biological processes in this important pathogen. This study also provides a set of methods for comparative epigenomics and integrative analysis, which we expect to be broadly applicable to bacterial epigenomic studies.

A Complete Genome Screening Program of Clinical Methicillin-Resistant Staphylococcus aureus Isolates Identifies the Origin and Progression of a Neonatal Intensive Care Unit Outbreak.

Whole-genome sequencing (WGS) of Staphylococcus aureus is increasingly used as part of infection prevention practices. In this study, we established a long-read technology-based WGS screening program of all first-episode methicillin-resistant Staphylococcus aureus (MRSA) blood infections at a major urban hospital. A survey of 132 MRSA genomes assembled from long reads enabled detailed characterization of an outbreak lasting several months of a CC5/ST105/USA100 clone among 18 infants in a neonatal intensive care unit (NICU). Available hospital-wide genome surveillance data traced the origins of the outbreak to three patients admitted to adult wards during a 4-month period preceding the NICU outbreak. The pattern of changes among complete outbreak genomes provided full spatiotemporal resolution of its progression, which was characterized by multiple subtransmissions and likely precipitated by equipment sharing between adults and infants. Compared to other hospital strains, the outbreak strain carried distinct mutations and accessory genetic elements that impacted genes with roles in metabolism, resistance, and persistence. This included a DNA recognition domain recombination in the hsdS gene of a type I restriction modification system that altered DNA methylation. Transcriptome sequencing (RNA-Seq) profiling showed that the (epi)genetic changes in the outbreak clone attenuated agr gene expression and upregulated genes involved in stress response and biofilm formation. Overall, our findings demonstrate the utility of long-read sequencing for hospital surveillance and for characterizing accessory genomic elements that may impact MRSA virulence and persistence.

Sociodemographic Differences in Young Children Meeting 24-Hour Movement Guidelines.

BACKGROUND: Little is known about variation in meeting the 24-Hour Movement Guidelines (including physical activity [PA], sleep, and screen time [ST]) in early childhood. The aim was to evaluate sociodemographic differences in meeting the 24-Hour Movement Guidelines. METHODS: Parents of 3-4 year old children reported sociodemographic information and ST. Sleep and PA were measured using accelerometry, and height and weight were objectively measured. The 24-Hour Movement Guidelines include daily PA (total PA: ≥3 h; including ≥1 h of moderate to vigorous), sleep (10-13 h), and ST (≤1 h). Meeting guidelines by age, sex, race, poverty level, and weight status were assessed using chi-square and linear regression models. RESULTS: Of 107 children, 57% were white and 26% lived in households at or below the poverty level. Most children met the PA (91.5%) and sleep (86.9%) guidelines, but few met ST (14.0%) or all 3 (11.3%) guidelines. African American children and children who lived at or below the poverty level were less likely to meet the sleep, ST, and all 3 guidelines compared with others (P < .01 for all). There were no other differences. CONCLUSION: These results suggest future interventions should focus on reducing differences in movement, namely in sleep and ST.

pH Dependence of Zika Membrane Fusion Kinetics Reveals an Off-Pathway State.

The recent spread of Zika virus stimulated extensive research on its structure, pathogenesis, and immunology, but mechanistic study of entry has lagged behind, in part due to the lack of a defined reconstituted system. Here, we report Zika membrane fusion measured using a platform that bypasses these barriers, enabling observation of single-virus fusion kinetics without receptor reconstitution. Surprisingly, target membrane binding and low pH are sufficient to trigger viral hemifusion to liposomes containing only neutral lipids. Second, although the extent of hemifusion strongly depends on pH, hemifusion rates are relatively insensitive to pH. Kinetic analysis shows that an off-pathway state is required to capture this pH-dependence and suggests this may be related to viral inactivation. Our surrogate-receptor approach thus yields new understanding of flaviviral entry mechanisms and should be applicable to many emerging viruses.

Screen-Time Policies and Practices in Early Care and Education Centers in Relationship to Child Physical Activity.

BACKGROUND: Few preschool children meet physical activity recommendations, whereas the majority exceeds screen-time recommendations. The purpose of this study was to examine the relationship of screen-time policies and practices with children's physical activity and sedentary time in early care and education (ECE) centers. METHODS: We conducted a cross-sectional study of 104 children (3.3 ± 0.5 years; 50% girls) attending 10 ECE centers in the United States. Physical activity was measured by accelerometry. Screen-time practices were measured by classroom observation and director report. Mixed linear models were used to examine the relationship of screen-time practices with children's total physical activity (TPA) and moderate-to-vigorous physical activity (MVPA) and sedentary time, adjusting for child's age, sex, and BMI z-score and taking into account the clustering of children within each center. Models were repeated to include director-reported active play time as a covariate. RESULTS: More limited/supervised screen-time (by observation) was related to higher TPA (p = 0.0003) and lower sedentary time (p = 0.0003). More limited/supervised screen-time (by director report) was related to higher TPA (p < 0.0001) and MVPA (p = 0.021) and lower sedentary time (p < 0.0001). Associations remained significant when active play time was included as a covariate. TPA was inversely related to computer access (p = 0.0015) and positively related to the use of educational screen-time compared with noneducational screen-time (p = 0.04). CONCLUSIONS: Limiting computer usage and ensuring screen-time is educational, and integrated within the curriculum may benefit children's physical activity levels and reduce time spent sedentary.

Pediatric diabetes training for healthcare professionals in Europe: Time for change.

BACKGROUND: Training for healthcare professionals (HCPs) in Europe who care for children and young people (CYP) with type 1 diabetes and their families is variable depending on the country. Building on the work of SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) and using the German Certified Diabetes Educators (CDEs) curriculum, a European collaboration of pediatric diabetes experts aimed to (1) establish current core elements that should be included in a pediatric diabetes education training course and (2) create a template for a European CDE's training curriculum. METHODS: A qualitative methodology incorporating a survey questionnaire, focus group discussions, individual semi-structured interviews and workshops was employed to explore participants' experiences and opinions. HCPs-pediatric consultants, diabetes nurses, dietitians and psychologists, national and local diabetes leads, academic and education leads and children, and young people with diabetes and families took part in the study. The total number of participants equaled 186. RESULTS: A template for a European Certified Diabetes Educator Curriculum (EU-CDEC) was developed based on the themes that emerged from the participants' expertise and experiences. This provides a model for HCPs' pediatric diabetes training provision. CONCLUSIONS: There is a severe shortage of high quality, standardized training for HCPs across the majority of European countries. Lack of trained HCPs for CYP with diabetes will result in the delivery of suboptimal care and impact on health, wellbeing and clinical and psychological outcomes. The EU-CDEC template can be used to increase access to high quality training provision for all HCPs across Europe and worldwide.

Genomic confirmation of vancomycin-resistant Enterococcus transmission from deceased donor to liver transplant recipient.

In a liver transplant recipient with vancomycin-resistant Enterococcus (VRE) surgical site and bloodstream infection, a combination of pulsed-field gel electrophoresis, multilocus sequence typing, and whole genome sequencing identified that donor and recipient VRE isolates were highly similar when compared to time-matched hospital isolates. Comparison of de novo assembled isolate genomes was highly suggestive of transplant transmission rather than hospital-acquired transmission and also identified subtle internal rearrangements between donor and recipient missed by other genomic approaches. Given the improved resolution, whole-genome assembly of pathogen genomes is likely to become an essential tool for investigation of potential organ transplant transmissions.

Randomized double-blind comparison of cognitive and EEG effects of lacosamide and carbamazepine.

Differential effectiveness of antiepileptic drugs (AEDs) is more commonly determined by tolerability than efficacy. Cognitive effects of AEDs can adversely affect tolerability and quality of life. This study evaluated cognitive and EEG effects of lacosamide (LCM) compared with carbamazepine immediate-release (CBZ-IR). A randomized, double-blind, double-dummy, two-period crossover, fixed-dose study in healthy subjects compared neuropsychological and EEG effects of LCM (150mg, b.i.d.) and CBZ-IR (200mg, t.i.d.). Testing was conducted at screening, predrug baseline, the end of each treatment period (3-week titration; 3-week maintenance), and the end of each washout period (4weeks after treatment). A composite Z-score was derived for the primary outcome variable (computerized cognitive tests and traditional neuropsychological measures) and separately for the EEG measures. Other variables included individual computer, neuropsychological, and EEG scores and adverse events (AEs). Subjects included 60 healthy adults (57% female; mean age: 34.4years [SD: 10.5]); 44 completed both treatments; 41 were per protocol subjects. Carbamazepine immediate-release had worse scores compared with LCM for the primary composite neuropsychological outcome (mean difference=0.33 [SD: 1.36], p=0.011) and for the composite EEG score (mean difference=0.92 [SD: 1.77], p=0.003). Secondary analyses across the individual variables revealed that CBZ-IR was statistically worse than LCM on 36% (4/11) of the neuropsychological tests (computerized and noncomputerized) and 0% of the four EEG measures; none favored CBZ-IR. Drug-related AEs occurred more with CBZ-IR (49%) than LCM (22%). Lacosamide had fewer untoward neuropsychological and EEG effects and fewer AEs and AE-related discontinuations than CBZ-IR in healthy subjects. Lacosamide exhibits a favorable cognitive profile.

Low-Temperature Adsorption and Diffusion of Methanol in ZIF-8 Nanoparticle Films.

The adsorption of methanol by a zeolitic imidazolate framework-8 (ZIF-8) nanoparticle thin film was studied in situ using temperature-programmed desorption and X-ray photoelectron spectroscopy under low-temperature, low-pressure conditions. Partial pore penetration was observed at 90 K, but upon increasing the exposure temperature of the film to 130 K pore penetration was significantly enhanced. Although many studies exist involving bulk powders, this is the first work to our knowledge that demonstrates the ability to control and monitor the entry of a molecule into a metal organic framework (MOF) film in situ using temperature. In this case, nanoparticle films of ZIF-8 were prepared and studied in ultrahigh vacuum. The ability to control and monitor surface adsorption versus pore adsorption in situ is key to future fundamental study of MOFs, for example, in the identification of active sites in reaction mechanisms.

What makes a good children's doctor? Exploring the child perspective in the OSCE setting.

BACKGROUND: Patient feedback is increasingly important in clinical practice, and this should include children's views. 28 children aged 8-10 years participating in a large-scale OSCE underwent cranial nerve examination by student candidates. They scored each out of 10 for the question: 'If you had to see a doctor again, how happy would you be to see this one?' An age-adapted qualitative focus group methodology was used to explore why they scored some students more highly than others. RESULTS: Children's scores for the 256 medical students ranged from 2 to 10 (median 9; mean 8.46). 76% of scores were above 8. 'Good' doctor attributes included: 'friendly', 'funny', 'knowledgeable', 'confident'; 'bad' doctor attributes were: 'making mistakes', 'not paying attention', 'forgot everything', 'serious'. Children's reasons for specific scores are further explored. DISCUSSION AND CONCLUSION: Scores were positively skewed, in line with most patient/simulated patient feedback, and children discriminated between candidates. It should not be assumed that clinician examiners can accurately represent the views of child patients who may value different qualities in doctors. Children participating in our study had clear views of what they want from a doctor: a consultative approach with clear and kind explanation of the process of examination.

Emergency planning for people with disabilities and others with access and functional needs to ensure inclusiveness.

Recent investigations and litigation have prompted a shift in the way the field of emergency management plans for people with disabilities and others with access and functional needs. The purpose of this article is to aid readers in understanding some of the legal and practical requirements that may apply to jurisdictions' emergency preparedness programs to ensure the ability of plans, planning efforts, programs, and services to meet the needs of people with disabilities and others with access and functional needs. The cases of Communities Actively Living Independent and Free (CALIF) v. City of Los Angeles and Brooklyn Center for Independence of the Disabled v. Bloomberg will be used as case studies. Note that this is not intended nor should it be construed as legal advice.

Investigating the proteome reactivity and selectivity of aryl halides.

Protein-reactive electrophiles are critical to chemical proteomic applications including activity-based protein profiling, site-selective protein modification, and covalent inhibitor development. Here, we explore the protein reactivity of a panel of aryl halides that function through a nucleophilic aromatic substitution (S(N)Ar) mechanism. We show that the reactivity of these electrophiles can be finely tuned by varying the substituents on the aryl ring. We identify p-chloro- and fluoronitrobenzenes and dichlorotriazines as covalent protein modifiers at low micromolar concentrations. Interestingly, investigating the site of labeling of these electrophiles within complex proteomes identified p-chloronitrobenzene as highly cysteine selective, whereas the dichlorotriazine favored reactivity with lysines. These studies illustrate the diverse reactivity and amino-acid selectivity of aryl halides and enable the future application of this class of electrophiles in chemical proteomics.