Initiation of NALT Organogenesis Is Independent of the IL-7R, LTβR, and NIK Signaling Pathways but Requires the Id2 Gene and CD3−CD4+CD45+ Cells

AbstractInitiation of nasopharyngeal-associated lymphoid tissue (NALT) development is independent of the programmed cytokine cascade necessary for the formation of Peyer's patches (PP) and peripheral lymph nodes (PLN), a cytokine cascade which consists of IL-7R, LTα1β2/LTβR, and NIK. However, the subsequent organization of NALT seems to be controlled by these cytokine signaling cascades since the maturation of NALT structure is generally incomplete in those cytokine cascade-deficient mice. NALT as well as PP and PLN are completely absent in Id2−/− mice. NALT organogenesis is initiated following the adoptive transfer of CD3−CD4+CD45+ cells into Id2−/− mice, constituting direct evidence that CD3−CD4+CD45+ inducer cells can provide an IL-7R-, LTα1β2/LTβR-, and NIK-independent tissue organogenesis pathway for secondary lymphoid tissue development

Outstanding in vivo mechanical integrity of additively manufactured spinal cages with a novel “honeycomb tree structure” design via guiding bone matrix orientation

BACKGROUND CONTEXT: Therapeutic devices for spinal disorders, such as spinal fusion cages, must be able to facilitate the maintenance and rapid recovery of spinal function. Therefore, it would be advantageous that future spinal fusion cages facilitate rapid recovery of spinal function without secondary surgery to harvest autologous bone. PURPOSE: This study investigated a novel spinal cage configuration that achieves in vivo mechanical integrity as a devise/bone complex by inducing bone that mimicked the sound trabecular bone, hierarchically and anisotropically structured trabeculae strengthened with a preferentially oriented extracellular matrix. STUDY DESIGN/SETTINGS: In vivo animal study. METHODS: A cage possessing an anisotropic through-pore with a grooved substrate, that we termed “honeycomb tree structure,” was designed for guiding bone matrix orientation; it was manufactured using a laser beam powder bed fusion method through an additive manufacturing processes. The newly designed cages were implanted into sheep vertebral bodies for 8 and 16 weeks. An autologous bone was not installed in the newly designed cage. A pull-out test was performed to evaluate the mechanical integrity of the cage/bone interface. Additionally, the preferential orientation of bone matrix consisting of collagen and apatite was determined. RESULTS: The cage/host bone interface strength assessed by the maximum pull-out load for the novel cage without an autologous bone graft (3360±411 N) was significantly higher than that for the conventional cage using autologous bone (903±188 N) after only 8 weeks post-implantation. CONCLUSIONS: These results highlight the potential of this novel cage to achieve functional fusion between the cage and host bone. Our study provides insight into the design of highly functional spinal devices based on the anisotropic nature of bone. CLINICAL SIGNIFICANCE: The sheep spine is similar to the human spine in its stress condition and trabecular bone architecture and is widely recognized as a useful model for the human spine. The present design may be useful as a new spinal device for humans.Ishimoto T., Kobayashi Y., Takahata M., et al. Outstanding in vivo mechanical integrity of additively manufactured spinal cages with a novel “honeycomb tree structure” design via guiding bone matrix orientation. Spine Journal, 22, 10, 1742. https://doi.org/10.1016/j.spinee.2022.05.006

Giant Pulsations Excited by a Steep Earthward Gradient of Proton Phase Space Density: Arase Observation

AbstractWe present observational evidence of drift resonance between westward propagating odd mode standing ultralow frequency waves and energetic protons. Compressional ∼13 mHz (Pc4 band) waves and proton flux oscillations at >50 keV were detected at ∼03 hr magnetic local time by the Arase satellite on 15 April 2017. The azimuthal wave number (m number) is estimated to be ∼−50 from ground observations, while the theory of drift resonance gives m ∼− 49 for odd mode waves and ∼110‐keV protons, providing evidence that the drift resonance indeed took place in this event. We also found a steep earthward gradient of proton phase space density, which can quantitatively explain the wave excitation. The observed waves show typical features of giant pulsations (Pgs), regarding local time, m number, and flux oscillations. This study, therefore, has great implications to the field line mode structure and excitation mechanism of Pgs

Innovative design of bone quality-targeted intervertebral spacer: accelerated functional fusion guiding oriented collagen and apatite microstructure without autologous bone graft

BACKGROUND CONTEXT: Although autologous bone grafting is widely considered as an ideal source for interbody fusion, it still carries a risk of nonunion. The influence of the intervertebral device should not be overlooked. Requirements for artificial spinal devices are to join the vertebrae together and recover the original function of the spine rapidly. Ordered mineralization of apatite crystals on collagen accelerates bone functionalization during the healing process. Particularly, the stable spinal function requires the ingrowth of an ordered collagen and apatite matrix which mimics the intact intervertebral microstructure. This collagen and apatite ordering is imperative for functional bone regeneration, which has not been achieved using classical autologous grafting. PURPOSE: We developed an intervertebral body device to achieve high stability between the host bone and synthesized bone by controlling the ordered collagen and apatite microstructure. STUDY DESIGN: This was an in vivo animal study. METHODS: Intervertebral spacers with a through-pore grooved surface structure, referred to as a honeycomb tree structure, were produced using metal 3D printing. These spacers were implanted into normal sheep at the L2–L3 or L4–L5 disc levels. As a control group, grafting autologous bone was embedded. The mechanical integrity of the spacer/bone interface was evaluated through push-out tests. RESULTS: The spacer with honeycomb tree structure induced anisotropic trabecular bone growth with textured collagen and apatite orientation in the through-pore and groove directions. The push-out load of the spacer was significantly higher than that of the conventional autologous graft spacer. Moreover, the load was significantly correlated with the anisotropic texture of the newly formed bone matrix. CONCLUSIONS: The developed intervertebral spacer guided the regenerated bone matrix orientation of collagen and apatite, resulting in greater strength at the spacer/host bone interface than that obtained using a conventional gold-standard autologous bone graft. CLINICAL SIGNIFICANCE: Our results provide a foundation for designing future spacers for interbody fusion in human.Matsugaki A., Ito M., Kobayashi Y., et al. Innovative design of bone quality-targeted intervertebral spacer: accelerated functional fusion guiding oriented collagen and apatite microstructure without autologous bone graft. Spine Journal 23, 609 (2023); https://doi.org/10.1016/j.spinee.2022.12.011

Heliocentric Distance Dependence of Zodiacal Light Observed by Hayabusa2#

Zodiacal light (ZL) is sunlight scattered by interplanetary dust particles (IDPs) at optical wavelengths. The spatial distribution of IDPs in the Solar System may hold an important key to understanding the evolution of the Solar System and material transportation within it. The number density of IDPs can be expressed as $n(r) \sim r^{-\alpha}$, and the exponent $\alpha \sim 1.3$ was obtained by previous observations from interplanetary space by Helios 1/2 and Pioneer 10/11 in the 1970s and 1980s. However, no direct measurements of $\alpha$ based on ZL observations from interplanetary space outside Earth's orbit have been performed since then. Here, we introduce initial results for the radial profile of the ZL at optical wavelengths observed over the range 0.76-1.06 au by ONC-T aboard the Hayabusa2# mission in 2021-2022. The ZL brightness we obtained is well reproduced by a model brightness, although there is a small excess of the observed ZL brightness over the model brightness at around 0.9 au. The radial power-law index we obtained is $\alpha = 1.30 \pm 0.08$, which is consistent with previous results based on ZL observations. The dominant source of uncertainty arises from the uncertainty in estimating the diffuse Galactic light (DGL).Comment: 22 pages, 19 figures, 4 tables, accepted for publication by Earth, Planets and Spac

Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041)

PurposeThis phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma.MethodsPembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review.ResultsForty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3–5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3–5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3–43.5) for cutaneous melanoma and 25.0% (95% CI 3.2–65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma.ConclusionThe safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma

Adenovirus vector-mediated assay system for hepatitis C virus replication

The efficient delivery of the hepatitis C virus (HCV) RNA subgenomic replicon into cells is useful for basic and pharmaceutical studies. The adenovirus (Ad) vector is a convenient and efficient tool for the transduction of foreign genes into cells in vitro and in vivo. However, an Ad vector expressing the HCV replicon has never been developed. In the present study, we developed Ad vector containing an RNA polymerase (pol) I-dependent expression cassette and a tetracycline-controllable RNA pol I-dependent expression system. We prepared a hybrid promoter from the tetracycline-responsive element and the RNA pol I promoter. Ad vector particles coding the hybrid promoter-driven HCV replicon could be amplified, and interferon, an inhibitor of HCV replication, reduced HCV replication in cells transduced with the Ad vector coding HCV replicon. This is the first report of the development of an Ad vector-mediated HCV replicon system

Early-phase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients

Background: The features of early-phase acute respiratory distress syndrome (ARDS) are leakage of fluid into the extravascular space and impairment of its reabsorption, resulting in extravascular lung water (EVLW) accumulation. The current study aimed to identify how the initial EVLW values and their change were associated with mortality. Methods: This was a post hoc analysis of the PiCCO Pulmonary Edema Study, a multicenter prospective cohort study that included 23 institutions. Single-indicator transpulmonary thermodilution-derived EVLW index (EVLWi) and conventional prognostic factors were prospectively collected over 48 h after enrollment. Associations between 28-day mortality and each variable including initial (on day 0), mean, maximum, and Δ (subtracting day 2 from day 0) EVLWi were evaluated. Results: We evaluated 192 ARDS patients (median age, 69 years (quartile, 24 years); Sequential Organ Failure Assessment (SOFA) score on admission, 10 (5); all-cause 28-day mortality, 31%). Although no significant differences were found in initial, mean, or maximum EVLWi, Δ-EVLWi was significantly higher (i.e., more reduction in EVLWi) in survivors than in non-survivors (3.0 vs. ?0.3 mL/kg, p = 0.006). Age, maximum, and Δ-SOFA scores and Δ-EVLW were the independent predictors for survival according to the Cox proportional hazard model. Patients with Δ-EVLWi > 2.8 had a significantly higher incidence of survival than those with Δ-EVLWi ? 2.8 (log-rank test, χ2 = 7.08, p = 0.008). Conclusions: Decrease in EVLWi during the first 48 h of ARDS may be associated with 28-day survival. Serial EVLWi measurements may be useful for understanding the pathophysiologic conditions in ARDS patients. A large multination confirmative trial is required

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation