A transcriptional rheostat couples past activity to future sensory responses.

Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here, we show that each of the ∼1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.

A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction.

Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the "necklace" subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.

Author Correction: Structure and flexibility in cortical representations of odour space.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structure and flexibility in cortical representations of odour space.

The cortex organizes sensory information to enable discrimination and generalization1-4. As systematic representations of chemical odour space have not yet been described in the olfactory cortex, it remains unclear how odour relationships are encoded to place chemically distinct but similar odours, such as lemon and orange, into perceptual categories, such as citrus5-7. Here, by combining chemoinformatics and multiphoton imaging in the mouse, we show that both the piriform cortex and its sensory inputs from the olfactory bulb represent chemical odour relationships through correlated patterns of activity. However, cortical odour codes differ from those in the bulb: cortex more strongly clusters together representations for related odours, selectively rewrites pairwise odour relationships, and better matches odour perception. The bulb-to-cortex transformation depends on the associative network originating within the piriform cortex, and can be reshaped by passive odour experience. Thus, cortex actively builds a structured representation of chemical odour space that highlights odour relationships; this representation is similar across individuals but remains plastic, suggesting a means through which the olfactory system can assign related odour cues to common and yet personalized percepts.

Tympanostomy Tubes or Medical Management for Recurrent Acute Otitis Media.

BACKGROUND: Official recommendations differ regarding tympanostomy-tube placement for children with recurrent acute otitis media. METHODS: We randomly assigned children 6 to 35 months of age who had had at least three episodes of acute otitis media within 6 months, or at least four episodes within 12 months with at least one episode within the preceding 6 months, to either undergo tympanostomy-tube placement or receive medical management involving episodic antimicrobial treatment. The primary outcome was the mean number of episodes of acute otitis media per child-year (rate) during a 2-year period. RESULTS: In our main, intention-to-treat analysis, the rate (±SE) of episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P = 0.66). Because 10% of the children in the tympanostomy-tube group did not undergo tympanostomy-tube placement and 16% of the children in the medical-management group underwent tympanostomy-tube placement at parental request, we conducted a per-protocol analysis, which gave corresponding episode rates of 1.47±0.08 and 1.72±0.11, respectively. Among secondary outcomes in the main analysis, results were mixed. Favoring tympanostomy-tube placement were the time to a first episode of acute otitis media, various episode-related clinical findings, and the percentage of children meeting specified criteria for treatment failure. Favoring medical management was children's cumulative number of days with otorrhea. Outcomes that did not show substantial differences included the frequency distribution of episodes of acute otitis media, the percentage of episodes considered to be severe, and antimicrobial resistance among respiratory isolates. Trial-related adverse events were limited to those included among the secondary outcomes of the trial. CONCLUSIONS: Among children 6 to 35 months of age with recurrent acute otitis media, the rate of episodes of acute otitis media during a 2-year period was not significantly lower with tympanostomy-tube placement than with medical management. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02567825.).

Allometry: revealing evolution's engineering principles.

An animal's body size impacts many aspects of its structure and function (Y); insights that only become apparent when viewed over several orders of magnitude of body mass (M) and expressed allometrically in the form of power law equations (Y=aMb). The resulting relationships are apparent clusters of similar exponents (b) revealing emergent 'patterns of design' that shed light on the universal principles of structure and function. Basic physical principles of surface area, volume and heat exchange apply to all objects, including animals, and many consequences must be attributed to these fundamental properties. Starting with Galileo's description of the shapes of bones in the 16th century and extending to 19th century explanations of heat production and loss by Sarrus and Rameaux, allometric patterns have provided numerous biological insights. Here, we examine several of these insights and explore how the selective pressures and scaling may differ when comparing animals in a vegetative (basal) state and those utilizing their maximum metabolic capacities. It seems that the selective pressures under those two conditions differ. We caution that allometric patterns invite explanations that lack supporting data or may be dismissed because there is hesitation among biologists to make comparisons lacking phylogenetic support. We argue that emergent allometric patterns have inherent value and continue to be the fodder for many fruitful hypotheses.

Identifying Children Likely to Benefit From Antibiotics for Acute Sinusitis: A Randomized Clinical Trial.

Importance: The large overlap between symptoms of acute sinusitis and viral upper respiratory tract infection suggests that certain subgroups of children being diagnosed with acute sinusitis, and subsequently treated with antibiotics, derive little benefit from antibiotic use. Objective: To assess if antibiotic therapy could be appropriately withheld in prespecified subgroups. Design, Setting, and Participants: Randomized clinical trial including 515 children aged 2 to 11 years diagnosed with acute sinusitis based on clinical criteria. The trial was conducted between February 2016 and April 2022 at primary care offices affiliated with 6 US institutions and was designed to evaluate whether symptom burden differed in subgroups defined by nasopharyngeal Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis on bacterial culture and by the presence of colored nasal discharge. Interventions: Oral amoxicillin (90 mg/kg/d) and clavulanate (6.4 mg/kg/d) (n = 254) or placebo (n = 256) for 10 days. Main Outcomes and Measures: The primary outcome was symptom burden based on daily symptom scores on a validated scale (range, 0-40) during the 10 days after diagnosis. Secondary outcomes included treatment failure, adverse events including clinically significant diarrhea, and resource use by families. Results: Most of the 510 included children were aged 2 to 5 years (64%), male (54%), White (52%), and not Hispanic (89%). The mean symptom scores were significantly lower in children in the amoxicillin and clavulanate group (9.04 [95% CI, 8.71 to 9.37]) compared with those in the placebo group (10.60 [95% CI, 10.27 to 10.93]) (between-group difference, -1.69 [95% CI, -2.07 to -1.31]). The length of time to symptom resolution was significantly lower for children in the antibiotic group (7.0 days) than in the placebo group (9.0 days) (P = .003). Children without nasopharyngeal pathogens detected did not benefit from antibiotic treatment as much as those with pathogens detected; the between-group difference in mean symptom scores was -0.88 (95% CI, -1.63 to -0.12) in those without pathogens detected compared with -1.95 (95% CI, -2.40 to -1.51) in those with pathogens detected. Efficacy did not differ significantly according to whether colored nasal discharge was present (the between-group difference was -1.62 [95% CI, -2.09 to -1.16] for colored nasal discharge vs -1.70 [95% CI, -2.38 to -1.03] for clear nasal discharge; P = .52 for the interaction between treatment group and the presence of colored nasal discharge). Conclusions: In children with acute sinusitis, antibiotic treatment had minimal benefit for those without nasopharyngeal bacterial pathogens on presentation, and its effects did not depend on the color of nasal discharge. Testing for specific bacteria on presentation may represent a strategy to reduce antibiotic use in this condition. Trial Registration: ClinicalTrials.gov Identifier: NCT02554383.

Shape Coexistence at Zero Spin in

The low-spin structure of the semimagic ^{64}Ni nucleus has been considerably expanded: combining four experiments, several 0^{+} and 2^{+} excited states were identified below 4.5 MeV, and their properties established. The Monte Carlo shell model accounts for the results and unveils an unexpectedly complex landscape of coexisting shapes: a prolate 0^{+} excitation is located at a surprisingly high energy (3463 keV), with a collective 2^{+} state 286 keV above it, the first such observation in Ni isotopes. The evolution in excitation energy of the prolate minimum across the neutron N=40 subshell gap highlights the impact of the monopole interaction and its variation in strength with N.

N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle.

Since its belated discovery, our understanding of the giant protein titin has grown exponentially from its humble beginning as a sarcomeric scaffold to recent recognition of its critical mechanical and signaling functions in active muscle. One uniquely useful model to unravel titin's functions, muscular dystrophy with myositis (mdm), arose spontaneously in mice as a transposon-like LINE repeat insertion that results in a small deletion in the N2A region of titin. This small deletion profoundly affects hypertrophic signaling and muscle mechanics, thereby providing insights into the function of this specific region and the consequences of its dysfunction. The impact of this mutation is profound, affecting diverse aspects of the phenotype including muscle mechanics, developmental hypertrophy, and thermoregulation. In this review, we explore accumulating evidence that points to the N2A region of titin as a dynamic "switch" that is critical for both mechanical and signaling functions in skeletal muscle. Calcium-dependent binding of N2A titin to actin filaments triggers a cascade of changes in titin that affect mechanical properties such as elastic energy storage and return, as well as hypertrophic signaling. The mdm phenotype also points to the existence of as yet unidentified signaling pathways for muscle hypertrophy and thermoregulation, likely involving titin's PEVK region as well as the N2A signalosome.

Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children.

BACKGROUND: Limiting the duration of antimicrobial treatment constitutes a potential strategy to reduce the risk of antimicrobial resistance among children with acute otitis media. METHODS: We assigned 520 children, 6 to 23 months of age, with acute otitis media to receive amoxicillin-clavulanate either for a standard duration of 10 days or for a reduced duration of 5 days followed by placebo for 5 days. We measured rates of clinical response (in a systematic fashion, on the basis of signs and symptomatic response), recurrence, and nasopharyngeal colonization, and we analyzed episode outcomes using a noninferiority approach. Symptom scores ranged from 0 to 14, with higher numbers indicating more severe symptoms. RESULTS: Children who were treated with amoxicillin-clavulanate for 5 days were more likely than those who were treated for 10 days to have clinical failure (77 of 229 children [34%] vs. 39 of 238 [16%]; difference, 17 percentage points [based on unrounded data]; 95% confidence interval, 9 to 25). The mean symptom scores over the period from day 6 to day 14 were 1.61 in the 5-day group and 1.34 in the 10-day group (P=0.07); the mean scores at the day-12-to-14 assessment were 1.89 versus 1.20 (P=0.001). The percentage of children whose symptom scores decreased more than 50% (indicating less severe symptoms) from baseline to the end of treatment was lower in the 5-day group than in the 10-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P=0.003). We found no significant between-group differences in rates of recurrence, adverse events, or nasopharyngeal colonization with penicillin-nonsusceptible pathogens. Clinical-failure rates were greater among children who had been exposed to three or more children for 10 or more hours per week than among those with less exposure (P=0.02) and were also greater among children with infection in both ears than among those with infection in one ear (P<0.001). CONCLUSIONS: Among children 6 to 23 months of age with acute otitis media, reduced-duration antimicrobial treatment resulted in less favorable outcomes than standard-duration treatment; in addition, neither the rate of adverse events nor the rate of emergence of antimicrobial resistance was lower with the shorter regimen. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources; ClinicalTrials.gov number, NCT01511107 .).

Multifaceted Quadruplet of Low-Lying Spin-Zero States in

A search for shape isomers in the ^{66}Ni nucleus was performed, following old suggestions of various mean-field models and recent ones, based on state-of-the-art Monte Carlo shell model (MCSM), all considering ^{66}Ni as the lightest nuclear system with shape isomerism. By employing the two-neutron transfer reaction induced by an ^{18}O beam on a ^{64}Ni target, at the sub-Coulomb barrier energy of 39 MeV, all three lowest-excited 0^{+} states in ^{66}Ni were populated and their γ decay was observed by γ-coincidence technique. The 0^{+} states lifetimes were assessed with the plunger method, yielding for the 0_{2}^{+}, 0_{3}^{+}, and 0_{4}^{+} decay to the 2_{1}^{+} state the B(E2) values of 4.3, 0.1, and 0.2 Weisskopf units (W.u.), respectively. MCSM calculations correctly predict the existence of all three excited 0^{+} states, pointing to the oblate, spherical, and prolate nature of the consecutive excitations. In addition, they account for the hindrance of the E2 decay from the prolate 0_{4}^{+} to the spherical 2_{1}^{+} state, although overestimating its value. This result makes ^{66}Ni a unique nuclear system, apart from ^{236,238}U, in which a retarded γ transition from a 0^{+} deformed state to a spherical configuration is observed, resembling a shape-isomerlike behavior.

Chronic eccentric arm cycling improves maximum upper-body strength and power.

INTRODUCTION: Eccentric leg cycling (cycle ergometry adapted to impose muscle lengthening contractions) offers an effective exercise for restoring lower-body muscular function, maintaining health, and improving performance in clinical and athletic populations. PURPOSE: We extended this model to the upper body and evaluated the effectiveness of a 7-week eccentric arm cycling (ECCarm) intervention to improve upper-body muscular function. We also explored whether ECCarm would alter arterial function. METHODS: Participants performed ECCarm (n = 9) or concentric arm cycling (CONarm; n = 8) 3×/week while training intensity increased (5-20 min, 60-70% upper-body peak heart rate). Maximum elbow extensor strength, upper-body concentric power, and peripheral and central arterial stiffness were assessed before and after training. RESULTS: During training, heart rates and perceived exertion did not differ between groups (~68% upper-body peak heart rate, ~12 Borg units, both P > 0.05), whereas power during ECCarm was ~2× that for CONarm (122 ± 43 vs. 59 ± 20 W, P < 0.01). Muscle soreness for ECCarm was greater than CONarm (P = 0.02), however, soreness was minimal for both groups (<0.50 cm). Following training, ECCarm exhibited greater changes in elbow extensor strength (16 ± 10 vs. 1 ± 9%, P = 0.01) and upper-body power (6 ± 8 vs. -3 ± 7%, P < 0.01) compared to CONarm. Peripheral and central arterial stiffness did not change for either group (both P > 0.05). CONCLUSION: Upper-body eccentric exercise improved dynamic muscular function while training at low exertion levels. Results occurred with minimal soreness and without compromising arterial function. ECCarm findings parallel eccentric leg cycling findings and indicate that eccentric cycle ergometry offers a robust model for enhancing upper-body muscular function. ECCarm could have applications in rehabilitation and sport training.

Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience.

Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.

First Evidence of Shape Coexistence in the

The N=48 ^{80}Ge nucleus is studied by means of ß-delayed electron-conversion spectroscopy at ALTO. The radioactive ^{80}Ga beam is produced through the isotope separation on line photofission technique and collected on a movable tape for the measurement of γ and e^{-} emission following ß decay. An electric monopole E0 transition, which points to a 639(1) keV intruder 0_{2}^{+} state, is observed for the first time. This new state is lower than the 2_{1}^{+} level in ^{80}Ge, and provides evidence of shape coexistence close to one of the most neutron-rich doubly magic nuclei discovered so far, ^{78}Ni. This result is compared with theoretical estimates, helping to explain the role of monopole and quadrupole forces in the weakening of the N=50 gap at Z=32. The evolution of intruder 0_{2}^{+} states towards ^{78}Ni is discussed.

Skeletal muscle tissue in movement and health: positives and negatives.

The history of muscle physiology is a wonderful lesson in 'the scientific method'; our functional hypotheses have been limited by our ability to decipher (observe) muscle structure. The simplistic understanding of how muscles work made a large leap with the remarkable insights of A. V. Hill, who related muscle force and power to shortening velocity and energy use. However, Hill's perspective was largely limited to isometric and isotonic contractions founded on isolated muscle properties that do not always reflect how muscles function in vivo. Robert Josephson incorporated lengthening contractions into a work loop analysis that shifted the focus to dynamic muscle function, varying force, length and work done both by and on muscle during a single muscle work cycle. It became apparent that muscle is both a force generator and a spring. Titin, the missing filament in the sliding filament model, is a muscle spring, which functions very differently in cardiac versus skeletal muscle; its possible role in these two muscle types is discussed relative to their contrasting function. The good news for those of us who choose to work on skeletal muscle is that muscle has been reluctant to reveal all of its secrets.

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

Importance: Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. Objective: To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Design, Setting, and Participants: Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Interventions: Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. Main Outcomes and Measures: The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Results: Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Conclusions and Relevance: Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01984697.

Muscle force, work and cost: a novel technique to revisit the Fenn effect.

Muscle produces force by forming cross-bridges, using energy released from ATP. While the magnitude and duration of force production primarily determine the energy requirement, nearly a century ago Fenn observed that muscle shortening or lengthening influenced energetic cost of contraction. When work is done by the muscle, the energy cost is increased and when work is done on the muscle the energy cost is reduced. However, the magnitude of the 'Fenn effect' and its mirror ('negative Fenn effect') have not been quantitatively resolved. We describe a new technique coupling magnetic resonance spectroscopy with an in vivo force clamp that can directly quantify the Fenn effect [E=I+W, energy liberated (E) equals the energy cost of isometric force production (I) plus the work done (W)] and the negative Fenn effect (E=I-W) for one muscle, the first dorsal interosseous (FDI). ATP cost was measured during a series of contractions, each of which occurred at a constant force and for a constant duration, thus constant force-time integral (FTI). In all subjects, as the FTI increased with load, there was a proportional linear increase in energy cost. In addition, the cost of producing force greatly increased when the muscle shortened, and was slightly reduced during lengthening contraction. These results, though limited to a single muscle, contraction velocity and muscle length change, do quantitatively support the Fenn effect. We speculate that they also suggest that an elastic element within the FDI muscle functions to preserve the force generated within the cross-bridges.

The gut microbiome as novel cardio-metabolic target: the time has come!

Recent studies reveal a potential contribution of intestinal microbes in the expression of certain human cardio-metabolic diseases. The mechanisms through which intestinal microbiota and/or their metabolic products alter systemic homoeostasis and cardio-metabolic disease risks are just beginning to be dissected. Intervention studies in humans aiming to either selectively alter the composition of the intestinal microbiota or to pharmacologically manipulate the microbiota to influence production of their metabolites are crucial next steps. The intestinal microbiome represents a new potential therapeutic target for the treatment of cardio-metabolic diseases.

Ultrasound evaluation of urachal abscess in a young infant.

The urachus is a tubular structure extending from the dome of the bladder to the umbilicus. Normally, this allantoic and cloacal remnant obliterates into a fibrous band by late fetal development. Urachal abnormalities include a patent urachus, urachal cyst, umbilical urachal sinus, and a vesicourachal diverticulum. These abnormalities are most often asymptomatic and only come to clinical attention when associated with infection. A 2-month-old male infant presented to our tertiary pediatric hospital with several days of intermittent fevers and a focal region of swelling and erythema over the umbilicus. On physical examination, a tender mass was palpated in the umbilical region. Ultrasound revealed a long tubular structure coursing from the dome of the bladder anteriorly and superiorly to the subumbilical region. This tubular structure was fluid filled with internal echoes suggestive of infection with abscess formation. The urachal abscess was drained surgically, at which time a patent urachus was also excised. This case demonstrates the importance of having a thorough understanding of urachal anomalies when evaluating infants presenting with umbilical pathology.