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Gravity wave characteristics in the middle- to high-latitude Southern Hemisphere are analyzed using simulation data over 3 yr from a high-resolution middle-atmosphere general circulation model without using any gravity wave parameterizations. Gravity waves have large amplitudes in winter and are mainly distributed in the region surrounding the polar vortex in the middle and upper stratosphere, while the gravity wave energy is generally weak in summer. The wave energy distribution in winter is not zonally uniform, but it is large leeward of the southern Andes and Antarctic Peninsula. Linear theory in the three-dimensional framework indicates that orographic gravity waves are advected leeward significantly by the mean wind component perpendicular to the wavenumber vector. Results of ray-tracing and cross-correlation analyses are consistent with this theoretical expectation. The leeward energy propagation extends to several thousand kilometers, which explains part of the gravity wave distribution around the polar vortex in winter. This result indicates that orographic gravity waves can affect the mean winds at horizontal locations that are far distant from the source mountains. Another interesting feature is a significant downward energy flux in winter, which is observed in the lower stratosphere to the south of the southern Andes. The frequency of the downward energy flux is positively correlated with the gravity wave energy over the southern Andes. Partial reflection from a rapid increase in static stability around 10 hPa and/or gravity wave generation through nonlinear processes are possible mechanisms to explain the downward energy flux.

Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4 CRBN . To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4 CRBN complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 ( KPNB1 ) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.

The relative abundance of light elements in the Earth’s core has long been controversial. Recently, the presence of carbon in the core has been emphasized, because the density and sound velocities of the inner core may be consistent with solid Fe 7 C 3 . Here we report the longitudinal wave velocity of liquid Fe 84 C 16 up to 70 GPa based on inelastic X-ray scattering measurements. We find the velocity to be substantially slower than that of solid iron and Fe 3 C and to be faster than that of liquid iron. The thermodynamic equation of state for liquid Fe 84 C 16 is also obtained from the velocity data combined with previous density measurements at 1 bar. The longitudinal velocity of the outer core, about 4% faster than that of liquid iron, is consistent with the presence of 4–5 at.% carbon. However, that amount of carbon is too small to account for the outer core density deficit, suggesting that carbon cannot be a predominant light element in the core. The composition of the Earth's core, particularly the light elements present, is not well constrained. Here, the authors report sound velocities of liquid iron-carbon alloy as measured at very high pressures using inelastic X-ray scattering and suggest that carbon cannot be predominant in the outer core.

PurposeThe aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan.MethodsThis study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30–83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom.ResultsThe original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30–39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70–79 age group.ConclusionsThis study provided a large-scale quantitative database of [123I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database.

Acute graft‐versus‐host disease (aGvHD) remains a major threat to a successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Although antibody‐based targeting of the CD40/CD40 ligand costimulatory pathway can prevent aGvHD, side effects hampered their clinical application, prompting a need for other ways to interfere with this important dendritic T‐cell costimulatory pathway. Here, we used small interfering RNA (siRNA) complexed with β‐glucan allowing the binding and uptake of the siRNA/β‐glucan complex (siCD40/schizophyllan [SPG]; chemical modifications called NJA‐312, NJA‐302, and NJA‐515) into Dectin1+ cells, which recognize this pathogen‐associated molecular pattern receptor. aGvHD was induced by the transplantation of splenocytes and bone marrow cells from C57BL/6J into CBF1 mice. Splenic dendritic cells retained Dectin1 expression after HSCT but showed lower expression after irradiation. The administration of siCD40/SPG, NJA‐312, and NJA‐302 ameliorated aGvHD‐mediated lethality and tissue damage of spleen and liver, but not skin. Multiple NJA‐312high injections prevented aGvHD but resulted in early weight loss in allogeneic HSCT mice. In addition, NJA‐312 treatment caused delayed initial donor T and B‐cell recovery but resulted in stable chimerism in surviving mice. Mechanistically, NJA‐312 reduced organ damage by suppressing CCR2+, F4/80+, and IL17A‐expressing cell accumulation in spleen, liver, and thymus but not the skin of mice with aGvHD. Our work demonstrates that siRNA targeting of CD40 delivered via the PAMP‐recognizing lectin Dectin1 changes the immunological niche, suppresses organ‐specific murine aGvHD, and induces immune tolerance after organ transplantation. Our work charts future directions for therapeutic interventions to modulate tissue‐specific immune reactions using Pathogen‐associated molecular pattern (PAMP) molecules like 1,3‐β‐glucan for cell delivery of siRNA.

Autonomic urinary dysfunction affects patients with progressive supranuclear palsy (PSP); however, the severity and prevalence of urinary dysfunctions in these patients compared with those observed in patients with Parkinson's disease (PD) and multiple system atrophy (MSA) are unknown. We compared urinary dysfunction characteristics in patients with PSP, PD, and MSA. Forty-seven patients who satisfied the probable or possible criteria of the National Institute for Neurological Diseases and Stroke and Society for PSP were assessed using the urinary symptoms questionnaire and the urodynamic study at Chiba and Toho Universities (n = 26 and 21, respectively). The results were compared with those of patients with PD and MSA (n = 218 and 193, respectively). The mean disease duration of PSP and the mean age were 2.97 ± 0.26 and 71.4 ± 0.88 years, respectively. The mini-mental state examination and frontal assessment battery scores were 22.6 ± 0.70 and 10.7 ± 0.49, respectively. Urinary storage and voiding symptoms were observed in 57% and 56% of patients with PSP, respectively. Detrusor overactivity in the urodynamic study was detected in 81% of patients with PSP, which was slightly more than that found in patients with PD (69%) and MSA (67%); however, this was not statistically significant. Postvoid residual volume in patients with PSP was significantly more than that in patients with PD (P < 0.01), but was equivalent to that in patients with MSA. The present study demonstrated that patients with PSP experienced various urinary dysfunctions. Urinary storage dysfunction in patients with PSP was not different from that in patients with PD or MSA, whereas urinary voiding dysfunction in patients with PSP was milder than that in patients with MSA and more severe than that in patients with PD. These features should be taken into account for the differentiation of PSP from PD and MSA.

Background T-cell based immunotherapy for lung cancer (LC) could be a promising and novel therapeutic approach. Six-transmembrane epithelial antigen of the prostate (STEAP) and the polycomb group protein enhancer of zeste homolog 2 (EZH2) are highly expressed in LC and since the expression of molecules in normal tissue is significantly lower as compared to tumor cells, these proteins are considered as potential tumor-associated antigens (TAAs) for developing T-cell based immunotherapy. Methods We assessed the capacity of predicted CD4 T-cell epitopes from STEAP and EZH2 to induce anti-tumor immune responses to LC cell lines. Results Out of several predicted epitopes, two synthetic peptides, STEAP 281-296 and EZH2 95-109 , were effective in inducing CD4 T-cell responses that were restricted by HLA-DR1, DR15, or DR53 molecules, indicating that the peptides function as promiscuous T-cell epitopes. Moreover, STEAP 281-296 and EZH2 95-109 -reactive T-cells could directly recognize STEAP or EZH2 expressing LC cells in an HLA-DR restricted manner. In addition, some STEAP-reactive T-cells responded to STEAP+ tumor cell lysates presented by autologous dendric cells. Most significantly, both of these peptides were capable of stimulating in vitro T-cell responses in patients with LC. Conclusions Peptides STEAP 281-296 and EZH2 95-109 function as strong CD4 T-cell epitopes that can elicit effective anti-tumor T-cell responses against STEAP or EZH2 expressing LC. These observations may facilitate the translation of T-cell based immunotherapy into the clinic for the treatment of LC.

Preeclampsia is a pregnancy-induced disorder that is characterized by hypertension and is a leading cause of perinatal and maternal–fetal morbidity and mortality. HLA-G is thought to play important roles in maternal–fetal immune tolerance, and the associations between HLA-G gene polymorphisms and the onset of pregnancy-related diseases have been explored extensively. Because contiguous genomic sequencing is difficult, the association between the HLA-G genotype and preeclampsia onset is controversial. In this study, genomic sequences of the HLA-G region (5.2 kb) from 31 pairs of mother–offspring genomic DNA samples (18 pairs from normal pregnancies/births and 13 from preeclampsia births) were obtained by single-molecule real-time sequencing using the PacBio RS II platform. The HLA-G alleles identified in our cohort matched seven known HLA-G alleles, but we also identified two new HLA-G alleles at the fourth-field resolution and compared them with nucleotide sequences from a public database that consisted of coding sequences that cover the 3.1-kb HLA-G gene span. Intriguingly, a potential association between preeclampsia onset and the poly T stretch within the downstream region of the HLA-G*01:01:01:01 allele was found. Our study suggests that long-read sequencing of HLA-G will provide clues for characterizing HLA-G variants that are involved in the pathophysiology of preeclampsia.

The role of sprouting in regeneration was compared betweenfour co‐occurring Castanopsis species in an evergreen broad‐leavedforest in southern China. We considered the largest stem of an individualto be the main stem, while all of the other stems were consideredto be sprouts. To evaluate the degree of dependence on sproutingin the regeneration of each species, we measured the ratio of thenumber of all sprouts to the number of main stems in a population.The ratio was 4.3 in Castanopsis fordii and > 1in Castanopsis fabri and Castanopsis carlesii, althoughit was < 1 in Castanopsis fargesii. The ratioof the number of all sprouts to the number of main stems in a populationwas represented by the product of two factors of sprouting ability:the proportion of sprouting individuals among all individuals andthe number of sprouts per sprouting individual. The proportion ofsprouting individuals among all individuals differed significantlyamong the four species, while the number of sprouts per sproutingindividual did not. Specific variations in sprouting traits werein agreement with the population structure of each species. Specieswith fewer small individuals in the size distribution had a higherratio than species with L‐shaped distribution. Furthermore, specieswith a clumped distribution had a larger ratio than species thatwere randomly distributed. These results suggested that specieswhose recruitment by seedlings was temporally and spatially restrictedwere relatively more dependent on sprouting in the regeneration.The specific gradient of sprouting ability and the relative dependencyon sprouts to maintain a population can enhance the coexistenceof these four congeneric species.

Small intestinal anisakiasis is a rare disease that is very difficult to diagnose, and its initial diagnosis is often surgical. However, it is typically a benign disease that resolves with conservative treatment, and unnecessary surgery can be avoided if it is appropriately diagnosed. This case report is an example of small intestinal obstruction caused by anisakiasis that resolved with conservative treatment. A 63-year-old man admitted to our department with acute abdominal pain. A history of raw fish (sushi) ingestion was recorded. Abdominal CT demonstrated small intestinal dilatation with wall thickening and contrast enhancement. Ascitic fluid was found on the liver surface and in the Douglas pouch. His IgE (RIST) was elevated, and he tested positive for the anti-Anisakis antibodies IgG and IgA. Small intestinal obstruction by anisakiasis was highly suspected and conservative treatment was performed, ileus tube, fasting, and fluid replacement. Symptoms quickly resolved, and he was discharged on the seventh day of admission. Small intestinal anisakiasis is a relatively uncommon disease, the diagnosis of which may be difficult. Because it is a self-limiting disease that usually resolves in 1-2 weeks, a conservative approach is advisable to avoid unnecessary surgery.