Strains missing several genes required for chemotaxis toward amino acids, peptides, and certain sugars were tethered and their rotational behavior was analyzed. Null strains (called gutted) were deleted for genes that code for the transducers Tsr, Tar, Tap, and Trg and for the cytoplasmic proteins CheA, CheW, CheR, CheB, CheY, and CheZ. Motor switch components were wild type, flaAII(cheC), orflaBll(cheV). Gutted cells with wild-type motors spun exclusively counterclockwise, while those with mutant motors changed their directions of rotation. CheY reduced the bias (the fraction of time that cells spun counterclockwise) in either case. CheZ offset the effect of CheY to an extent that varied with switch allele but did not change the bias when tested alone. Transducers also increased the bias in the presence of CheY but not when tested alone. However, cells containing transducers and CheY failed to respond to attractants or repellents normally detected in the periplasm. This sensitivity was restored by addition of CheA and CheW. Thus, CheY both enhances clockwise rotation and couples the transducers to the flagella. CheZ acts, at the level of the motor, as a CheY antagonist. CheA or CheW or both are required to complete the signal pathway. A model is presented that explains these results and is consistent with other data found in the literature.Sensory transduction in bacterial chemotaxis involves receipt of information about the external environment, passage of this information across the cytoplasmic membrane, generation of signals that converge on the flagellar motors, and activation of mechanisms that permit adaptation. The concentrations of certain chemicals are sensed by transmembrane receptors, also called transducers or methylaccepting chemotaxis proteins (1, 11,39; for a review, see reference 10). Four transducers are known, one sensitive to aspartate, maltose, and certain repellents (Tar), a second sensitive to serine and certain other repellents (Tsr), a third sensitive to galactose and ribose (Trg), and a fourth sensitive to dipeptides (Tap [17]). Changes in receptor occupancy, through a series of intermediate events that we hope to understand, alter the probability that the flagella spin clockwise (CW) or counterclockwise (CCW). If they spin CW, the cells move erratically with little net displacement (they tumble); if they spin CCW, the cells swim smoothly (they run) (15,16). If a run happens to carry the cell up a spatial gradient of an attractant (e.g., of aspartate), the probability of CW rotation decreases and the probability of CCW rotation increases (4, 5), extending the run. This enables the cell to move toward a more favorable environment (3).How is sensory information transferred from the receptors to the flagella? From measurements of signal propagation in filamentous cells, Segall et al. (31) showed that there is an internal signal but that its range is short, only a few micrometers. To explain this limited range, they suggested that the signal is a small protein or ligand that is inactivated ...

CONTEXT: Research reveals racial, ethnic, and socioeconomic disparities in autism diagnosis; there is limited information on potential disparities related to other dimensions of services.OBJECTIVE: We reviewed evidence related to disparities in service use, intervention effectiveness, and quality of care provided to children with autism by race, ethnicity, and/or socioeconomic status.

BACKGROUND: Current guidelines from the American Academy of Pediatrics recommend screening children for developmental problems by using a standardized screening tool and referring at-risk patients to early intervention (EI) or subspecialists. Adoption of guidelines has been gradual, with research showing many children still not being screened and referred. METHODS: We analyzed American Academy of Pediatrics Periodic Survey data from 2002 (response rate = 58%; N = 562), 2009 (response rate = 57%; N = 532), and 2016 (response rate = 47%, N = 469). Surveys included items on pediatricians' knowledge, attitudes, and practices regarding screening and referring children for developmental problems. We used descriptive statistics and a multivariable logistic regression model to examine trends in screening and referral practices and attitudes. RESULTS: Pediatricians' reported use of developmental screening tools increased from 21% in 2002 to 63% in 2016 (P , .001). In 2016, on average pediatricians reported referring 59% of their at-risk patients to EI, up from 41% in 2002 (P , .001), and pediatricians in 2016 were more likely than in 2002 to report being "very likely" to refer a patient with global developmental delay, milestone loss, language delay, sensory impairment, motor delays, and family concern to EI. CONCLUSIONS: Pediatricians' reported use of a standardized developmental screening tool has tripled from 2002 to 2016, and more pediatricians are self-reporting making referrals for children with concerns in developmental screening. To sustain this progress, additional efforts are needed to enhance referral systems, improve EI programs, and provide better tracking of child outcomes.

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OBJECTIVE: Pediatric primary care providers (PCPs) caring for patients with autism spectrum disorder (ASD) often encounter irritability (vocal or motoric outbursts expressive of anger, frustration, or distress) and problem behavior (directed acts of aggression toward other people, self, or property). The Autism Intervention Research Network on Physical Health and Autism Speaks Autism Treatment Network charged a multidisciplinary workgroup with developing a practice pathway to assist PCPs in the evaluation and treatment of irritability and problem behavior (I/PB). METHODS:The workgroup reviewed the literature on the evaluation and treatment of contributory factors for I/PB in ASD. The workgroup then achieved consensus on the content and sequence of each step in the pathway. RESULTS:The practice pathway is designed to help the PCP generate individualized treatment plans based on contributing factors identified in each patient. These factors may include medical conditions, which the PCP is in a key position to address; functional communication challenges that can be addressed at school or at home; psychosocial stressors that may be ameliorated; inadvertent reinforcement of I/PB; and co-occurring psychiatric conditions that can be treated. The pathway provides guidance on psychotropic medication use, when indicated, within an individualized treatment plan. In addition to guidance on assessment, referral, and initial treatment, the pathway includes monitoring of treatment response and periodic reassessment. CONCLUSIONS:The pediatric PCP caring for the patient with ASD is in a unique position to help generate an individualized treatment plan that targets factors contributing to I/PB and to implement this plan in collaboration with parents, schools, and other providers. Dr McGuire contributed to the design of the practice pathway, played a leading role in drafting the initial manuscript, and revised the manuscript; Drs Fung, Hagopian, Vasa, Mahajan, Bernal, and Coury and Ms Silberman and Ms Wolfe contributed to the design of the practice pathway and reviewed and revised the manuscript; Drs Hardan and Veenstra-VanderWeele contributed to the conceptualization and design of the practice pathway and reviewed and revised the manuscript; Dr Whitaker played a leading role in conceptualizing and designing the practice pathway, drafted portions of the initial manuscript, and reviewed and revised the manuscript; and all authors approved the fi nal manuscript as submitted.

We carried out studies with Escherichia coli to determine the site at which the methylation-independent pathways for taxis to oxygen and to sugars of the phosphoenolpyruvate:sugar phosphotransferase transport system converge with the methylation-dependent chemotaxis pathways. Using genetic reconstitution of the pathways in a null strain, we determined that all pathways examined required the products of the genes cheA, cheW, and cheY. Thus, we conclude that both the methylation-independent and methylation-dependent pathways converge at CheA, the histidine kinase product of cheA.In Escherichia coli and Salmonella typhimurium, taxis to either oxygen (aerotaxis) or substrates of the phosphoenolpyruvate phosphotransferase transport system (PTS) does not require chemoreceptor methylation and demethylation for adaptation (4,8,13). In contrast, chemotactic adaptation to certain amino acids, dipeptides, or non-PTS sugars requires methylation and demethylation. (For a review of chemotaxis see references 2, 7, and 14.) In E. coli, the tsr, tar, trg, and tap genes encode the methylation-dependent chemoreceptors (in S. typhimurium, tip substitutes for tap) while the genes cheR, cheB, cheA, cheW, cheY, and cheZ encode the cytoplasmic proteins that make up the methylation-dependent pathway. Of these cytoplasmic proteins, CheR and CheB catalyze chemoreceptor methylation and demethylation, respectively (12, 17). CheW, in association with the signaling domain located on the cytoplasmic surface of each chemoreceptor, modulates the rate of CheA autophosphorylation of the CheA residue His-48 (2). Phospho-CheA then serves as the phosphodonor for CheY autophosphorylation of the CheY residue Asp-57. PhosphoCheY binds to the flagellar motor switch, increasing the probability of clockwise (CW) rotation (5). Finally, the CheZ protein accelerates dephosphorylation of phospho-CheY, a process that restores counterclockwise (CCW) rotation (5). Whereas bacteria swim in gently curved paths when their motors rotate CCW, they abruptly change direction by tumbling chaotically when some of the motors rotate briefly in a CW direction (7).Aerotaxis in both E. coli and S. typhimurium requires an electron transport system (11). Chemotaxis to a PTS substrate requires both a functional PTS and the transport of that substrate (9, 16). The signal transduction pathways by which the electron transport system and the PTS communicate with the flagellar motors remain unknown, although evidence that the former involves the proton motive force exists (10). Since all chemotaxis pathways utilize the same motor and flagellar structures, the aerotaxis and phosphotransferase pathways must converge with the methylation-dependent pathway at, or before, the flagellar motor switch. We have investigated this point of convergence, determining which signal transduction components of the methylation-dependent pathways are also required for aerotaxis and PTS chemotaxis. Table 1 lists the strains, plasmids, and phages used in the present study. Cells were grown at 30ЊC in trypt...

Our interest has focused on the excitation pathway that involves CheA, CheW, CheY, and CheZ. In work described earlier (16), we constructed null (gutted) strains deleted for genes coding for all the known transducers (Tsr, Tar, Tap, and Trg) and all the known cytoplasmic chemotaxis proteins (CheA, CheW, CheY, CheZ, CheR, and CheB). If the flagellar motors of these cells were wild type, they spun exclusively CCW. When the cells were reconstituted with CheY, their motors spun alternately CW and CCW. CheZ behaved as a CheY antagonist. When the gutted cells were reconstituted with CheA and CheW, their motors continued to spin CCW. However, when they also contained the receptor for aspartate (Tar) and CheY, they spun CW and responded to aspartate. CheA and CheW were not tested separately. We now report that responses to aspartate require both CheA and CheW. Our earlier work also suggested that CheA or CheW or both act synergistically with CheY to increase the fraction of time that the flagella spin CW. We now report that this effect requires both CheA and CheW.For the work described here, three parental gutted strains were prepared with two deletions of the che gene region (Fig. 1). Strain HCB437 is A(tsr)7021 A(trg)100 zbd::Tn5 A(cheA-cheZ)2209, strain HCB440 is A(tsr)7021 A(cheAcheY)::XhoI(TnS), and strain HCB721 is A(tsr)7021 A(cheAcheY)::XhoI(TnS) trg::TnlO. The second and third strains differ only by the disruption of trg. Strain HCB437 was used for our earlier work (16). The deletion A(cheA-cheZ)2209

CONTEXT: Recommendations conflict regarding universal application of formal screening instruments in primary care (PC) and PC-like settings for autism spectrum disorder (ASD).OBJECTIVES: We systematically reviewed evidence for universal screening of children for ASD in PC.