The Role of the Pre-B Cell Receptor in B Cell Development, Repertoire Selection, and Tolerance

Around four decades ago, it had been observed that there were cell lines as well as cells in the fetal liver that expressed antibody μ heavy (μH) chains in the apparent absence of bona fide light chains. It was thus possible that these cells expressed another molecule(s), that assembled with μH chains. The ensuing studies led to the discovery of the pre-B cell receptor (pre-BCR), which is assembled from Ig μH and surrogate light (SL) chains, together with the signaling molecules Igα and β. It is expressed on a fraction of pro-B (pre-BI) cells and most large pre-B(II) cells, and has been implicated in IgH chain allelic exclusion and down-regulation of the recombination machinery, assessment of the expressed μH chains and shaping the IgH repertoire, transition from the pro-B to pre-B stage, pre-B cell expansion, and cessation

Injectable local anaesthetic agents for dental anaesthesia

Background: Pain during dental treatment, which is a common fear of patients, can be controlled successfully by local anaesthetic. Several different local anaesthetic formulations and techniques are available to dentists. / Objectives: Our primary objectives were to compare the success of anaesthesia, the speed of onset and duration of anaesthesia, and systemic and local adverse effects amongst different local anaesthetic formulations for dental anaesthesia. We define success of anaesthesia as absence of pain during a dental procedure, or a negative response to electric pulp testing or other simulated scenario tests. We define dental anaesthesia as anaesthesia given at the time of any dental intervention. Our secondary objective was to report on patients' experience of the procedures carried out. / Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2018, Issue 1), MEDLINE (OVID SP), Embase, CINAHL PLUS, WEB OF SCIENCE, and other resources up to 31 January 2018. Other resources included trial registries, handsearched journals, conference proceedings, bibliographies/reference lists, and unpublished research. / Selection criteria: We included randomized controlled trials (RCTs) testing different formulations of local anaesthetic used for clinical procedures or simulated scenarios. Studies could apply a parallel or cross‐over design. / Data collection and analysis: We used standard Cochrane methodological approaches for data collection and analysis. / Main results: We included 123 studies (19,223 participants) in the review. We pooled data from 68 studies (6615 participants) for meta‐analysis, yielding 23 comparisons of local anaesthetic and 57 outcomes with 14 different formulations. Only 10 outcomes from eight comparisons involved clinical testing. We assessed the included studies as having low risk of bias in most domains. Seventy‐three studies had at least one domain with unclear risk of bias. Fifteen studies had at least one domain with high risk of bias due to inadequate sequence generation, allocation concealment, masking of local anaesthetic cartridges for administrators or outcome assessors, or participant dropout or exclusion. We reported results for the eight most important comparisons. / Success of anaesthesia: When the success of anaesthesia in posterior teeth with irreversible pulpitis requiring root canal treatment is tested, 4% articaine, 1:100,000 epinephrine, may be superior to 2% lidocaine, 1:100,000 epinephrine (31% with 2% lidocaine vs 49% with 4% articaine; risk ratio (RR) 1.60, 95% confidence interval (CI) 1.10 to 2.32; 4 parallel studies; 203 participants; low‐quality evidence). When the success of anaesthesia for teeth/dental tissues requiring surgical procedures and surgical procedures/periodontal treatment, respectively, was tested, 3% prilocaine, 0.03 IU felypressin (66% with 3% prilocaine vs 76% with 2% lidocaine; RR 0.86, 95% CI 0.79 to 0.95; 2 parallel studies; 907 participants; moderate‐quality evidence), and 4% prilocaine plain (71% with 4% prilocaine vs 83% with 2% lidocaine; RR 0.86, 95% CI 0.75 to 0.99; 2 parallel studies; 228 participants; low‐quality evidence) were inferior to 2% lidocaine, 1:100,000 epinephrine. Comparative effects of 4% articaine, 1:100,000 epinephrine and 4% articaine, 1:200,000 epinephrine on success of anaesthesia for teeth/dental tissues requiring surgical procedures are uncertain (RR 0.85, 95% CI 0.71 to 1.02; 3 parallel studies; 930 participants; very low‐quality evidence). Comparative effects of 0.5% bupivacaine, 1:200,000 epinephrine and both 4% articaine, 1:200,000 epinephrine (odds ratio (OR) 0.87, 95% CI 0.27 to 2.83; 2 cross‐over studies; 37 participants; low‐quality evidence) and 2% lidocaine, 1:100,000 epinephrine (OR 0.58, 95% CI 0.07 to 5.12; 2 cross‐over studies; 31 participants; low‐quality evidence) on success of anaesthesia for teeth requiring extraction are uncertain. Comparative effects of 2% mepivacaine, 1:100,000 epinephrine and both 4% articaine, 1:100,000 epinephrine (OR 3.82, 95% CI 0.61 to 23.82; 1 parallel and 1 cross‐over study; 110 participants; low‐quality evidence) and 2% lidocaine, 1:100,000 epinephrine (RR 1.16, 95% CI 0.25 to 5.45; 2 parallel studies; 68 participants; low‐quality evidence) on success of anaesthesia for teeth requiring extraction and teeth with irreversible pulpitis requiring endodontic access and instrumentation, respectively, are uncertain. For remaining outcomes, assessing success of dental local anaesthesia via meta‐analyses was not possible. / Onset and duration of anaesthesia: For comparisons assessing onset and duration, no clinical studies met our outcome definitions. Adverse effects (continuous pain measured on 170‐mm Heft‐Parker visual analogue scale (VAS)) Differences in post‐injection pain between 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine are small, as measured on a VAS (mean difference (MD) 4.74 mm, 95% CI ‐1.98 to 11.46 mm; 3 cross‐over studies; 314 interventions; moderate‐quality evidence). Lidocaine probably resulted in slightly less post‐injection pain than articaine (MD 6.41 mm, 95% CI 1.01 to 11.80 mm; 3 cross‐over studies; 309 interventions; moderate‐quality evidence) on the same VAS. For remaining comparisons assessing local and systemic adverse effects, meta‐analyses were not possible. Other adverse effects were rare and minor. / Patients' experience: Patients' experience of procedures was not assessed owing to lack of data. / Authors' conclusions: For success (absence of pain), low‐quality evidence suggests that 4% articaine, 1:100,000 epinephrine was superior to 2% lidocaine, 1:100,000 epinephrine for root treating of posterior teeth with irreversible pulpitis, and 2% lidocaine, 1:100,000 epinephrine was superior to 4% prilocaine plain when surgical procedures/periodontal treatment was provided. Moderate‐quality evidence shows that 2% lidocaine, 1:100,000 epinephrine was superior to 3% prilocaine, 0.03 IU felypressin when surgical procedures were performed. Adverse events were rare. Moderate‐quality evidence shows no difference in pain on injection when 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine were compared, although lidocaine resulted in slightly less pain following injection. Many outcomes tested our primary objectives in simulated scenarios, although clinical alternatives may not be possible. Further studies are needed to increase the strength of the evidence. These studies should be clearly reported, have low risk of bias with adequate sample size, and provide data in a format that will allow meta‐analysis. Once assessed, results of the 34 ‘Studies awaiting classification (full text unavailable)’ may alter the conclusions of the review

A Habitable Fluvio-Lacustrine Environment at Yellowknife Bay, Gale Crater, Mars

The Curiosity rover discovered fine-grained sedimentary rocks, inferred to represent an ancient lake, preserve evidence of an environment that would have been suited to support a Martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. C, H, O, S, N, and P were measured directly as key biogenic elements, and by inference N and P are assumed to have been available. The environment likely had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars

Biological Data Questions the Support of the Self Inhibition Required for Pattern Generation in the Half Center Model

Locomotion control in mammals has been hypothesized to be governed by a central pattern generator (CPG) located in the circuitry of the spinal cord. The most common model of the CPG is the half center model, where two pools of neurons generate alternating, oscillatory activity. In this model, the pools reciprocally inhibit each other ensuring alternating activity. There is experimental support for reciprocal inhibition. However another crucial part of the half center model is a self inhibitory mechanism which prevents the neurons of each individual pool from infinite firing. Self-inhibition is hence necessary to obtain alternating activity. But critical parts of the experimental bases for the proposed mechanisms for self-inhibition were obtained in vitro, in preparations of juvenile animals. The commonly used adaptation of spike firing does not appear to be present in adult animals in vivo. We therefore modeled several possible self inhibitory mechanisms for locomotor control. Based on currently published data, previously proposed hypotheses of the self inhibitory mechanism, necessary to support the CPG hypothesis, seems to be put into question by functional evaluation tests or by in vivo data. This opens for alternative explanations of how locomotion activity patterns in the adult mammal could be generated

Diversified physiological sensory input connectivity questions the existence of distinct classes of spinal interneurons

The spinal cord is engaged in all forms of motor performance but its functions are far from understood. Because network connectivity defines function, we explored the connectivity of muscular, tendon, and tactile sensory inputs among a wide population of spinal interneurons in the lower cervical segments. Using low noise intracellular whole cell recordings in the decerebrated, non-anesthetized cat in vivo, we could define mono-, di-, and trisynaptic inputs as well as the weights of each input. Whereas each neuron had a highly specific input, and each indirect input could moreover be explained by inputs in other recorded neurons, we unexpectedly also found the input connectivity of the spinal interneuron population to form a continuum. Our data hence contrasts with the currently widespread notion of distinct classes of interneurons. We argue that this suggested diversified physiological connectivity, which likely requires a major component of circuitry learning, implies a more flexible functionality