Charge-Sign Dependent Cosmic-Ray Modulation Observed with the Calorimetric Electron Telescope on the International Space Station.

We present the observation of a charge-sign dependent solar modulation of galactic cosmic rays (GCRs) with the Calorimetric Electron Telescope onboard the International Space Station over 6 yr, corresponding to the positive polarity of the solar magnetic field. The observed variation of proton count rate is consistent with the neutron monitor count rate, validating our methods for determining the proton count rate. It is observed by the Calorimetric Electron Telescope that both GCR electron and proton count rates at the same average rigidity vary in anticorrelation with the tilt angle of the heliospheric current sheet, while the amplitude of the variation is significantly larger in the electron count rate than in the proton count rate. We show that this observed charge-sign dependence is reproduced by a numerical "drift model" of the GCR transport in the heliosphere. This is a clear signature of the drift effect on the long-term solar modulation observed with a single detector.

Direct Measurement of the Cosmic-Ray Helium Spectrum from 40 GeV to 250 TeV with the Calorimetric Electron Telescope on the International Space Station.

We present the results of a direct measurement of the cosmic-ray helium spectrum with the CALET instrument in operation on the International Space Station since 2015. The observation period covered by this analysis spans from October 13, 2015, to April 30, 2022 (2392 days). The very wide dynamic range of CALET allowed for the collection of helium data over a large energy interval, from ∼40 GeV to ∼250 TeV, for the first time with a single instrument in low Earth orbit. The measured spectrum shows evidence of a deviation of the flux from a single power law by more than 8σ with a progressive spectral hardening from a few hundred GeV to a few tens of TeV. This result is consistent with the data reported by space instruments including PAMELA, AMS-02, and DAMPE and balloon instruments including CREAM. At higher energy we report the onset of a softening of the helium spectrum around 30 TeV (total kinetic energy). Though affected by large uncertainties in the highest energy bins, the observation of a flux reduction turns out to be consistent with the most recent results of DAMPE. A double broken power law is found to fit simultaneously both spectral features: the hardening (at lower energy) and the softening (at higher energy). A measurement of the proton to helium flux ratio in the energy range from 60 GeV/n to about 60 TeV/n is also presented, using the CALET proton flux recently updated with higher statistics.

Erratum: Charge-Sign Dependent Cosmic-Ray Modulation Observed with the Calorimetric Electron Telescope on the International Space Station [Phys. Rev. Lett. 130, 211001 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.211001.

Direct Measurement of the Spectral Structure of Cosmic-Ray Electrons+Positrons in the TeV Region with CALET on the International Space Station.

Detailed measurements of the spectral structure of cosmic-ray electrons and positrons from 10.6 GeV to 7.5 TeV are presented from over 7 years of observations with the CALorimetric Electron Telescope (CALET) on the International Space Station. The instrument, consisting of a charge detector, an imaging calorimeter, and a total absorption calorimeter with a total depth of 30 radiation lengths at normal incidence and a fine shower imaging capability, is optimized to measure the all-electron spectrum well into the TeV region. Because of the excellent energy resolution (a few percent above 10 GeV) and the outstanding e/p separation (10^{5}), CALET provides optimal performance for a detailed search of structures in the energy spectrum. The analysis uses data up to the end of 2022, and the statistics of observed electron candidates has increased more than 3 times since the last publication in 2018. By adopting an updated boosted decision tree analysis, a sufficient proton rejection power up to 7.5 TeV is achieved, with a residual proton contamination less than 10%. The observed energy spectrum becomes gradually harder in the lower energy region from around 30 GeV, consistently with AMS-02, but from 300 to 600 GeV it is considerably softer than the spectra measured by DAMPE and Fermi-LAT. At high energies, the spectrum presents a sharp break around 1 TeV, with a spectral index change from -3.15 to -3.91, and a broken power law fitting the data in the energy range from 30 GeV to 4.8 TeV better than a single power law with 6.9 sigma significance, which is compatible with the DAMPE results. The break is consistent with the expected effects of radiation loss during the propagation from distant sources (except the highest energy bin). We have fitted the spectrum with a model consistent with the positron flux measured by AMS-02 below 1 TeV and interpreted the electron+positron spectrum with possible contributions from pulsars and nearby sources. Above 4.8 TeV, a possible contribution from known nearby supernova remnants, including Vela, is addressed by an event-by-event analysis providing a higher proton-rejection power than a purely statistical analysis.

Direct Measurement of the Nickel Spectrum in Cosmic Rays in the Energy Range from 8.8 GeV/n to 240 GeV/n with CALET on the International Space Station.

The relative abundance of cosmic ray nickel nuclei with respect to iron is by far larger than for all other transiron elements; therefore it provides a favorable opportunity for a low background measurement of its spectrum. Since nickel, as well as iron, is one of the most stable nuclei, the nickel energy spectrum and its relative abundance with respect to iron provide important information to estimate the abundances at the cosmic ray source and to model the Galactic propagation of heavy nuclei. However, only a few direct measurements of cosmic-ray nickel at energy larger than ∼3 GeV/n are available at present in the literature, and they are affected by strong limitations in both energy reach and statistics. In this Letter, we present a measurement of the differential energy spectrum of nickel in the energy range from 8.8 to 240 GeV/n, carried out with unprecedented precision by the Calorimetric Electron Telescope (CALET) in operation on the International Space Station since 2015. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The particle's energy is measured by a homogeneous calorimeter (1.2 proton interaction lengths, 27 radiation lengths) preceded by a thin imaging section (3 radiation lengths) providing tracking and energy sampling. This Letter follows our previous measurement of the iron spectrum [1O. Adriani et al. (CALET Collaboration), Phys. Rev. Lett. 126, 241101 (2021).PRLTAO0031-900710.1103/PhysRevLett.126.241101], and it extends our investigation on the energy dependence of the spectral index of heavy elements. It reports the analysis of nickel data collected from November 2015 to May 2021 and a detailed assessment of the systematic uncertainties. In the region from 20 to 240 GeV/n our present data are compatible within the errors with a single power law with spectral index -2.51±0.07.

Observation of Spectral Structures in the Flux of Cosmic-Ray Protons from 50 GeV to 60 TeV with the Calorimetric Electron Telescope on the International Space Station.

A precise measurement of the cosmic-ray proton spectrum with the Calorimetric Electron Telescope (CALET) is presented in the energy interval from 50 GeV to 60 TeV, and the observation of a softening of the spectrum above 10 TeV is reported. The analysis is based on the data collected during ∼6.2 years of smooth operations aboard the International Space Station and covers a broader energy range with respect to the previous proton flux measurement by CALET, with an increase of the available statistics by a factor of ∼2.2. Above a few hundred GeV we confirm our previous observation of a progressive spectral hardening with a higher significance (more than 20 sigma). In the multi-TeV region we observe a second spectral feature with a softening around 10 TeV and a spectral index change from -2.6 to -2.9 consistently, within the errors, with the shape of the spectrum reported by DAMPE. We apply a simultaneous fit of the proton differential spectrum which well reproduces the gradual change of the spectral index encompassing the lower energy power-law regime and the two spectral features observed at higher energies.

Cosmic-Ray Boron Flux Measured from 8.4 GeV/n to 3.8 TeV/n with the Calorimetric Electron Telescope on the International Space Station.

We present the measurement of the energy dependence of the boron flux in cosmic rays and its ratio to the carbon flux in an energy interval from 8.4 GeV/n to 3.8 TeV/n based on the data collected by the Calorimetric Electron Telescope (CALET) during ∼6.4 yr of operation on the International Space Station. An update of the energy spectrum of carbon is also presented with an increase in statistics over our previous measurement. The observed boron flux shows a spectral hardening at the same transition energy E_{0}∼200 GeV/n of the C spectrum, though B and C fluxes have different energy dependences. The spectral index of the B spectrum is found to be γ=-3.047±0.024 in the interval 25

Measurement of the Iron Spectrum in Cosmic Rays from 10 GeV/n to 2.0 TeV/n with the Calorimetric Electron Telescope on the International Space Station.

The Calorimetric Electron Telescope (CALET), in operation on the International Space Station since 2015, collected a large sample of cosmic-ray iron over a wide energy interval. In this Letter a measurement of the iron spectrum is presented in the range of kinetic energy per nucleon from 10 GeV/n to 2.0 TeV/n allowing the inclusion of iron in the list of elements studied with unprecedented precision by space-borne instruments. The measurement is based on observations carried out from January 2016 to May 2020. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The energy is measured by a homogeneous calorimeter with a total equivalent thickness of 1.2 proton interaction lengths preceded by a thin (3 radiation lengths) imaging section providing tracking and energy sampling. The analysis of the data and the detailed assessment of systematic uncertainties are described and results are compared with the findings of previous experiments. The observed differential spectrum is consistent within the errors with previous experiments. In the region from 50 GeV/n to 2 TeV/n our present data are compatible with a single power law with spectral index -2.60±0.03.

Direct Measurement of the Cosmic-Ray Carbon and Oxygen Spectra from 10 GeV/n to 2.2 TeV/n with the Calorimetric Electron Telescope on the International Space Station.

In this paper, we present the measurement of the energy spectra of carbon and oxygen in cosmic rays based on observations with the Calorimetric Electron Telescope on the International Space Station from October 2015 to October 2019. Analysis, including the detailed assessment of systematic uncertainties, and results are reported. The energy spectra are measured in kinetic energy per nucleon from 10 GeV/n to 2.2 TeV/n with an all-calorimetric instrument with a total thickness corresponding to 1.3 nuclear interaction length. The observed carbon and oxygen fluxes show a spectral index change of ∼0.15 around 200 GeV/n established with a significance >3σ. They have the same energy dependence with a constant C/O flux ratio 0.911±0.006 above 25 GeV/n. The spectral hardening is consistent with that measured by AMS-02, but the absolute normalization of the flux is about 27% lower, though in agreement with observations from previous experiments including the PAMELA spectrometer and the calorimetric balloon-borne experiment CREAM.

Direct Measurement of the Cosmic-Ray Proton Spectrum from 50 GeV to 10 TeV with the Calorimetric Electron Telescope on the International Space Station.

In this paper, we present the analysis and results of a direct measurement of the cosmic-ray proton spectrum with the CALET instrument onboard the International Space Station, including the detailed assessment of systematic uncertainties. The observation period used in this analysis is from October 13, 2015 to August 31, 2018 (1054 days). We have achieved the very wide energy range necessary to carry out measurements of the spectrum from 50 GeV to 10 TeV covering, for the first time in space, with a single instrument the whole energy interval previously investigated in most cases in separate subranges by magnetic spectrometers (BESS-TeV, PAMELA, and AMS-02) and calorimetric instruments (ATIC, CREAM, and NUCLEON). The observed spectrum is consistent with AMS-02 but extends to nearly an order of magnitude higher energy, showing a very smooth transition of the power-law spectral index from -2.81±0.03 (50-500 GeV) neglecting solar modulation effects (or -2.87±0.06 including solar modulation effects in the lower energy region) to -2.56±0.04 (1-10 TeV), thereby confirming the existence of spectral hardening and providing evidence of a deviation from a single power law by more than 3σ.

Autoantibody to transcriptional intermediary factor-1ß as a myositis-specific antibody: clinical correlation with clinically amyopathic dermatomyositis or dermatomyositis with mild myopathy.

BACKGROUND: Myositis-specific autoantibodies (MSAs) are associated with unique clinical subsets in polymyositis/dermatomyositis (PM/DM). Autoantibodies against transcriptional intermediary factor (TIF)-1γ and TIF-1α are known to be MSAs. Previously, we reported that TIF-1ß is also targeted in patients with DM with or without concomitant anti-TIF-1α/γ antibodies. OBJECTIVES: To evaluate the clinical features of seven cases with anti-TIF-1ß antibodies alone. METHODS: Serum autoantibody profiles were determined, and protein and RNA immunoprecipitation studies were conducted. Western blotting was performed to confirm autoantibody reactivity against TIF-1ß. RESULTS: Anti-TIF-1ß antibody was identified by immunoprecipitation assay in 24 cases. Among them, seven patients were positive for anti-TIF-1ß antibody alone. Six of the seven patients were classified as having DM. Among the six cases of DM, two patients had no muscle weakness and normal creatine kinase (CK) levels, and were classified as having clinically amyopathic DM. Four patients had muscle weakness, but three of them had normal serum CK levels that responded well to systemic steroids. Characteristic features of DM included skin rashes, such as Gottron sign, periungual erythema, punctate haemorrhage on the perionychium and facial erythema including heliotrope, which were observed in 86%, 57%, 86% and 71% of our cases, respectively. One of the seven patients had appendiceal cancer. None of the patients had interstitial lung disease. CONCLUSIONS: Seven patients were confirmed to have anti-TIF-1ß antibody without any other MSAs, including TIF-1α/γ antibodies, and six of them were diagnosed with DM. We suggest that anti-TIF-1ß antibody is an MSA, and that it is associated with clinically amyopathic DM or DM with mild myopathy.

Tuning the Pairing Interaction in a d-Wave Superconductor by Paramagnons Injected through Interfaces.

Unconventional superconductivity and magnetism are intertwined on a microscopic level in a wide class of materials. A new approach to this most fundamental and hotly debated issue focuses on the role of interactions between superconducting electrons and bosonic fluctuations at the interface between adjacent layers in heterostructures. Here we fabricate hybrid superlattices consisting of alternating atomic layers of the heavy-fermion superconductor CeCoIn_{5} and antiferromagnetic (AFM) metal CeRhIn_{5}, in which the AFM order can be suppressed by applying pressure. We find that the superconducting and AFM states coexist in spatially separated layers, but their mutual coupling via the interface significantly modifies the superconducting properties. An analysis of upper critical fields reveals that, upon suppressing the AFM order by applied pressure, the force binding superconducting electron pairs acquires an extreme strong-coupling nature. This demonstrates that superconducting pairing can be tuned nontrivially by magnetic fluctuations (paramagnons) injected through the interface.

Extended Measurement of the Cosmic-Ray Electron and Positron Spectrum from 11 GeV to 4.8 TeV with the Calorimetric Electron Telescope on the International Space Station.

Extended results on the cosmic-ray electron + positron spectrum from 11 GeV to 4.8 TeV are presented based on observations with the Calorimetric Electron Telescope (CALET) on the International Space Station utilizing the data up to November 2017. The analysis uses the full detector acceptance at high energies, approximately doubling the statistics compared to the previous result. CALET is an all-calorimetric instrument with a total thickness of 30 X_{0} at normal incidence and fine imaging capability, designed to achieve large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum in the region below 1 TeV shows good agreement with Alpha Magnetic Spectrometer (AMS-02) data. In the energy region below ∼300 GeV, CALET's spectral index is found to be consistent with the AMS-02, Fermi Large Area Telescope (Fermi-LAT), and Dark Matter Particle Explorer (DAMPE), while from 300 to 600 GeV the spectrum is significantly softer than the spectra from the latter two experiments. The absolute flux of CALET is consistent with other experiments at around a few tens of GeV. However, it is lower than those of DAMPE and Fermi-LAT with the difference increasing up to several hundred GeV. The observed energy spectrum above ∼1 TeV suggests a flux suppression consistent within the errors with the results of DAMPE, while CALET does not observe any significant evidence for a narrow spectral feature in the energy region around 1.4 TeV. Our measured all-electron flux, including statistical errors and a detailed breakdown of the systematic errors, is tabulated in the Supplemental Material in order to allow more refined spectral analyses based on our data.

Energy Spectrum of Cosmic-Ray Electron and Positron from 10 GeV to 3 TeV Observed with the Calorimetric Electron Telescope on the International Space Station.

First results of a cosmic-ray electron and positron spectrum from 10 GeV to 3 TeV is presented based upon observations with the CALET instrument on the International Space Station starting in October, 2015. Nearly a half million electron and positron events are included in the analysis. CALET is an all-calorimetric instrument with total vertical thickness of 30 X_{0} and a fine imaging capability designed to achieve a large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum over 30 GeV can be fit with a single power law with a spectral index of -3.152±0.016 (stat+syst). Possible structure observed above 100 GeV requires further investigation with increased statistics and refined data analysis.

Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.

BACKGROUND: Completion of multiple dose vaccine schedules is crucial to ensure a protective immune response, and maximise vaccine cost-effectiveness. While barriers and facilitators to vaccine uptake have recently been reviewed, there is no comprehensive review of factors influencing subsequent adherence or completion, which is key to achieving vaccine effectiveness. This study identifies and summarises the literature on factors affecting completion of multi-dose vaccine schedules by adolescents. METHODS: Ten online databases and four websites were searched (February 2014). Studies with analysis of factors predicting completion of multi-dose vaccines were included. Study participants within 9-19 years of age were included in the review. The defined outcome was completion of the vaccine series within 1 year among those who received the first dose. RESULTS: Overall, 6159 abstracts were screened, and 502 full texts were reviewed. Sixty one studies were eligible for this review. All except two were set in high-income countries. Included studies evaluated human papillomavirus vaccine, hepatitis A, hepatitis B, and varicella vaccines. Reported vaccine completion rates, among those who initiated vaccination, ranged from 27% to over 90%. Minority racial or ethnic groups and inadequate health insurance coverage were risk factors for low completion, irrespective of initiation rates. Parental healthcare seeking behaviour was positively associated with completion. Vaccine delivery in schools was associated with higher completion than delivery in the community or health facilities. Gender, prior healthcare use and socio-economic status rarely remained significant risks or protective factors in multivariate analysis. CONCLUSIONS: Almost all studies investigating factors affecting completion have been carried out in developed countries and investigate a limited range of variables. Increased understanding of barriers to completion in adolescents will be invaluable to future new vaccine introductions and the further development of an adolescent health platform. PROSPERO reg# CRD42014006765.

Survival outcomes of 220 consecutive patients with three-staged thoracoscopic esophagectomy.

Patients with thoracic esophageal cancer are often treated by minimally invasive esophagectomy. However, the long-term survival benefits of minimally invasive esophagectomy remain unclear. Two approaches are available for thoracoscopic surgery: one with the patient in the left lateral decubitus position (LLDP), and the other with the patient in the prone position (PP). We investigated the survival benefit of thoracoscopic esophagectomy according to the tumor stage and patient position during the thoracoscopic procedure. We reviewed the records of 220 consecutive patients with esophageal cancer treated from 1998 to 2012. In total, 146 and 74 patients were treated with thoracoscopic esophagectomy in the LLDP and PP, respectively. No patients were initially proposed to be candidates for esophagectomy by thoracotomy during the study period. Data collection was performed with a focus on survival and recurrent disease. Among all the 220 patients, the overall 5-year survival rates were 83.7%, 74.1%, 45.5%, 78.6%, 44.2%, 29.4% and 24.3% in the patients with pStage IA, IB, IIA, IIB, IIIA, IIIB and IIIC disease, respectively. Despite the greater number of dissected mediastinal lymph nodes in the PP procedure, there were no significant differences in the survival curves between the LLDP and PP procedures. The long-term results of thoracoscopic esophagectomy are comparable and acceptable. The PP procedure was not confirmed to offer a superior survival benefit to the LLDP procedure in this retrospective study.

Polyhydroxyalkanoate (PHA) accumulation potential and PHA-accumulating microbial communities in various activated sludge processes of municipal wastewater treatment plants.

AIMS: To clarify the polyhydroxyalkanoate (PHA) accumulation potential and the PHA-accumulating microbial community structure in activated sludge in municipal wastewater treatment plants (WWTPs) and to identify their influential factors. METHODS AND RESULTS: Nine activated sludge samples were collected from municipal WWTPs employing various biological treatment processes. In acetate-fed 24-h batch experiments under aerobic and nitrogen- and phosphorus-limited conditions, polyhydroxybutyrate (PHB) content of activated sludge increased from 0-1·3 wt% to 7·9-24 wt%, with PHB yields of 0·22-0·50 C-mol 3-hydroxybutyrate (C-mol acetate)(-1). Microbial community analyses found that activated sludge samples that accumulated >20 wt% of PHB after 24-h PHA accumulation experiments had >5·0 × 10(8) copies g(-1)-mixed liquor-suspended solid of phaC genes. CONCLUSIONS: Results indicated that (i) activated sludge in municipal WWTPs can accumulate up to approx. 20 wt% of PHA without enrichment processes, (ii) PHA accumulation potential of activated sludge varied depending on the operational conditions (treatment processes) of WWTPs, and (iii) phaC gene number can provide a simple indication of PHA accumulation potential. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to compare the PHA accumulation potential and PHA-accumulating microbial communities in activated sludge of various treatment processes. Our findings may be useful for enhancing the resource recovery potential of wastewater treatment systems.

Salvage chemoradiotherapy for locally advanced esophageal carcinomas.

'Salvage chemoradiotherapy (CRT)' was introduced in 2005 to treat thoracic esophageal carcinomas deemed unresectable based on the intraoperative findings. The therapeutic concept is as follows: the surgical plan is changed to an operation that aims to achieve curability by the subsequent definitive CRT. For this purpose, the invading tumor is resected as much as possible, and systematic lymph node dissection is performed except for in the area around the bilateral recurrent nerves. The definitive CRT should be started as soon as possible and should be performed as planned. We hypothesized that this treatment would be feasible and provide good clinical effects. We herein verified this hypothesis. Twenty-seven patients who received salvage CRT were enrolled in the study, and their clinical course, therapeutic response, and prognosis were evaluated. The patients who had poor oral intake because of esophageal stenosis were able to eat solid food soon after the operation. The radiation field could be narrowed after surgery, and this might have contributed to the high rate of finishing the definitive CRT as planned. As a result, the overall response rate was 74.1%, and 48.1% of the patients had a complete response. No patient experienced fistula formation. The 1-, 3-, and 5-year overall survival rates were 66.5%, 35.2%, and 35.2%, respectively. Salvage CRT had clinical benefits, such as the fact that patients became able to have oral intake, that fistula formation could be prevented, that the adverse events associated with the definitive CRT could be reduced, and that prognosis of the patients was satisfactory. Although the rate of recurrent nerve paralysis was relatively high even after the suspension of aggressive bilateral recurrent nerve lymph node dissection, and the rate of the progressive disease after the definitive CRT was high, salvage CRT appears to provide some advantages for the patients who would otherwise not have other treatment options following a non-curative and residual operation.

Beta 1 integrin-mediated interaction with extracellular matrix proteins regulates cytokine gene expression in synovial fluid cells of rheumatoid arthritis patients.

Inflammatory cytokines have been implicated in the pathogenesis of rheumatoid arthritis (RA), whereas the mechanisms for constitutive production of inflammatory cytokines in affected joints are largely unknown. Recently, integrin-mediated interaction with extracellular matrix (ECM) proteins has been demonstrated to play a role in regulating cytokine production in T cells and monocytes. In this study, we investigated the contribution of the beta 1 integrin-mediated interaction with ECM proteins to the persistent cytokine gene expression in RA synovial fluid mononuclear cells (SFMNC). We examined mRNA expression of 14 cytokines in the SFMNC of three RA patients, which were either fresh or cultured overnight in serum-free medium on ECM-coated plates, by polymerase chain reaction with a panel of oligonucleotide primers specific for each cytokine. The persistent expression of various cytokine mRNA found in fresh SFMNC was maintained after overnight culture in serum-free medium on ECM proteins, especially on laminin (LM), but not on serum albumin. This effect of LM was inhibited by an anti-integrin beta 1 chain (CD29) mAb, as well as by an anti-CD3 mAb, indicating an important role of the beta 1 integrin-mediated interaction with ECM proteins in regulating persistent cytokine gene expression in RA SFMNC, and a key role of T cells in regulating inflammatory monokine production.

Selective use of the VHQ52 family in functional VH to DJH rearrangements in a B precursor cell line.

AT11-2, an Abelson virus-transformed cell line has DJH complexes on both chromosomes and is able to form functional variable region genes by the joins of VH genes to the DJH complexes during culture. Therefore we examined which VH gene family was used in functional VH to DJH recombinations in AT11-2. Surprisingly, of 32 independent functional VH to DJH recombinational events in AT11-2, 31 events used the VH segments of the VHQ52 family, and the remaining one used the VH segment of the VH7183 family. Thus, we describe here the first B precursor cell line that almost selectively uses the VHQ52 family in functional VH to DJH rearrangements. The selective use of the VHQ52 family in this B precursor cell line strongly indicates nonrandom use of VH gene families, and the existence of a stage at which the VHQ52 family is preferentially used during the normal development of early pre-B cells and has important implications for understanding the ontogeny of VH repertoire development. Furthermore, this cell line should prove extremely valuable in further studies of this kind.