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Peptides with suitable aggregation behavior and electrical properties are potential siRNA delivery vectors. However, identifying suitable peptides with ideal delivery and safety features is difficult owing to the variations in amino acid sequences. Here, a holistic program based on computer modeling and single‐cell RNA sequencing (scRNA‐seq) is used to identify ideal siRNA delivery peptides. Stage one of this program consists of a sequential screening process for candidates with ideal assembly and delivery ability; stage two is a cell subtype‐level analysis program that screens for high in vivo tissue safety. The leading candidate peptide selected from a library containing 12 amino acids showed strong lung‐targeted siRNA delivery capacity after hydrophobic modification. Systemic administration of these compounds caused the least damage to liver and lung tissues and has little impact on macrophage and neutrophil numbers. By loading STAT3 siRNA, strong anticancer effects are achieved in multiple models, including patient‐derived xenografts (PDX). This screening procedure may facilitate the development of peptide‐based RNA interference (RNAi) therapeutics. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Primary stage IV breast cancer is associated with a poor prognosis. At present, the value of local surgical treatment for patients with stage IV breast cancer remains uncertain; therefore, treatment principles remain controversial. Because of the high heterogeneity of these patients, it is often difficult to evaluate their prognoses. As a result, this study aimed to establish a prognostic nomogram to evaluate the prognosis of patients with breast cancer experiencing primary bone metastasis.The clinical characteristics and follow‐up data of patients with primary breast cancer and bone metastasis from 2010 to 2018 were collected from the Surveillance, Epidemiology, and End Results database and from 2013 to 2021 at the Peking Union Medical College Hospital. Patients were divided into training and validation groups. Multivariate Cox regression analysis was used to identify the independent prognostic variables for predicting cancer‐specific survival (CSS). On the basis of these independent risk factors, a nomogram was developed and used calibration curves to evaluate its accuracy. Patients were divided into three risk groups according to their scores and surgery‐related survival curves plotted using the log‐rank test.Overall, 6372 patients were included, with 6319 from the Surveillance, Epidemiology, and End Results database and 53 from the Peking Union Medical College Hospital Breast Surgery Department. Multivariate analysis showed that age, race, marital status, grade, tumor stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and burden of other metastatic lesions were all associated with CSS. Based on these results, a nomogram that predicted the 1‐, 3‐, and 5‐year CSS rates in patients with primary breast cancer and bone metastasis (concordance index > 0.69) was developed. After dividing patients into low‐risk, high‐risk, or super‐high‐risk groups based on nomogram scoring criteria, survival analysis revealed that patients in the low‐ and high‐risk groups had significant survival benefits from primary focal surgery.Independent risk factors for primary breast cancer in patients with bone metastasis were analyzed and a nomogram established to predict CSS. The prognostic tool derived in this study can assist clinicians in predicting the survival and surgical benefits of these patients through scoring, thereby providing further guidance for treatment strategies. [ABSTRACT FROM AUTHOR]

Oocyte maturation arrest, fertilization failure, and early embryonic arrest are important causes of female infertility, whereas the genetic events that contribute to these processes are largely unknown. Loss‐of‐function of PABPC1L in mice has been suggested to cause female infertility involved in the absence of mature oocytes or embryos in vivo or in vitro. However, the role of PABPC1L in human female reproduction remains largely elusive. In this study, we identified a homozygous missense mutation (c.536G>A, p.R179Q) and a compound heterozygous mutation (c.793C>T, p.R265W; c.1201C>T, p.Q401*) in PABPC1L in two unrelated infertile females characterized by recurrent oocyte maturation abnormalities and early embryonic arrest. These variants resulted in nonfunctional PABPC1L protein and were associated with impaired chromatin configuration and transcriptional silencing in GV oocytes. Moreover, the binding capacity of mutant PABPC1L to mRNAs related to oocyte maturation and early embryonic development was decreased significantly. Our findings revealed novel PABPC1L mutations causing oocyte maturation abnormalities and early embryonic arrest, confirming the essential role of PABPC1L in human female fertility. [ABSTRACT FROM AUTHOR]

The Multiband Ultraviolet Spectrum Imager (MUSI) is an optical remote sensing instrument scheduled to launch on the Fengyun‐4C meteorological satellite in 2024. MUSI is designed to measure the airglow emissions between ∼120 and 160 nm above the East Asia and Pacific region from a geostationary orbit to infer ionospheric parameters. Here we develop a lookup‐table algorithm for retrieving the peak electron density (nmF2) and the Total Electron Content (TEC) from nighttime observations of the OI 135.6 nm emission. The algorithm takes into account the north‐south asymmetry of the equatorial ionization anomaly and the atmospheric variations with solar activity and local time. Analysis of synthetic observations shows that the assumptions made in the algorithm only lead to ∼2%–4% uncertainties in the retrievals under the modeled ionospheric conditions. The algorithm is verified by retrieving nmF2 and TEC from the Global‐Scale Observations of the Limb and Disk (GOLD) mission and comparing with coincided radio measurements. The comparison indicates almost negligible systematic differences (typically less than ∼3%) between the GOLD and the ionosonde nmF2, which are within the error limit of the GOLD retrievals. The accuracy of the GOLD TEC retrievals is shown to be comparable to (or in some sense even better than) that of the measurements from the Global Navigation Satellite System. Several simplified yet robust retrieval methods are also developed, which can be readily implemented for both existing and upcoming missions. Our results promote far ultraviolet (FUV) remote sensing to be a key technology for accurate determination of the ionospheric state. Key Points: We develop a lookup‐table algorithm for ionosphere retrieval with the FUV spectral imager on the Fengyun‐4C geostationary satelliteAssumptions made in the algorithm lead to only ∼2%–4% uncertainties in the nmF2 and Total Electron Content (TEC) retrievals under the modeled ionospheric conditionsThe algorithm is verified by retrieving nmF2 and TEC from the Global‐Scale Observations of the Limb and Disk observations and comparing with external radio measurements [ABSTRACT FROM AUTHOR]

In situ vaccination is a desirable strategy for cancer immunotherapy due to its convenience and capacity to target tumor antigens. Here, an in situ nanovaccine based on a cationic peptide with cholesterol‐modified, DP7‐C, for cancer immunotherapy is rationally designed, and developed a cancer nanovaccine that is easy to preparate. The nanovaccine includes cocktail small interfering RNAs (siRNAs) and immunologic adjuvant CpG ODNs, has synergistic effect in the cancer treatment. This nanovaccine can induce tumor cell death, promote antigen presentation and relieve immune suppression in the tumor microenvironment (TME). Moreover, this nanovaccine is administered to CT26 (hot) and B16F10 (cold) tumor model mice, in which it targeted the primary tumors and induced systemic antitumor immunity to inhibit metastasis. It is validated that the nanovaccine can convert cold tumors into hot tumors. Furthermore, the nanovaccine increased the immune response to anti‐PD‐1 therapy by modulating the TME in both CT26‐ and B16F10‐tumor‐bearing mice. The siRNA cocktail/CpG ODN/self‐assembling peptide nanovaccine is a simple and universal tool that can effectively generate specific tumor cell antigens and can be combined with immuno‐oncology agents to enhance antitumor immune activity. The versatile methodology provides an alternative approach for developing cancer nanovaccines. [ABSTRACT FROM AUTHOR]

Background: Multiple morphological abnormalities of the sperm flagella (MMAF), which is characterized as asthenoteratospermia involving absent, short, bent, coiled, and/or irregular‐caliber flagella, is a rare recessive inherited disorder associated with male infertility. To date, genetic causes of MMAF cases are not fully explored. Methods: Whole‐exome sequencing was conducted to identify pathogenic variants in a patient with MMAF. The functional effect of the identified mutations was investigated by immunofluorescence staining and western blotting. Intracytoplasmic sperm injection was used to assist fertilization for the patient with MMAF. Results: We identified novel biallelic mutations, a splicing variant NC_000004.12:g.146937593C>T (c.254+1G>A), and a nonsense mutation NM_001300761.4:c.1185C>G (NP_001287690.1:p.Tyr395*), in TTC29 from an infertile patient. In addition to the typical MMAF phenotype, the patient also presented aberrant morphology of sperm heads. Further functional experiments confirmed the absence of TTC29 expression in the spermatozoa. We also explored the specific expression pattern of TTC29 in human and mouse spermatogenesis. The outcome of intracytoplasmic sperm injection in the patient was unsuccessful, while additional female risk factors should not be excluded. Conclusions: Our study revealed the novel biallelic mutations in TTC29 in a MMAF patient, which findings expand the mutational spectrum of TTC29 and further contribute to the diagnosis, genetic counseling, and prognosis of male infertility. [ABSTRACT FROM AUTHOR]

Background: Ultrasound is more widely used than mammography for early diagnosis of breast cancer in China as most Chinese women have small and dense mammary glands. This study compared the diagnostic performance of ultrasound and mammography for breast cancer among Chinese women with suspected breast lesions. Methods: From November 2019 to November 2021, we compared the results of ultrasound and mammography for breast lesion diagnosis in 2737 consecutive participants with suspected breast lesions; all patients underwent biopsies. We measured the sensitivity, specificity, and diagnostic accuracy separately. Results: Among the 2737 participants, 2844 breast lesions were detected, including 1935 (68.0%) breast cancers and 909 (32.0%) benign lesions. Of the breast cancers, ultrasound detected 1851 (95.7%), whereas mammography detected 1527 (78.9%). The sensitivity of ultrasound for breast cancer diagnosis was significantly higher than that of mammography (95.7% vs. 78.9%, p < 0.001), whereas the specificity was significantly lower than that of mammography (42.9% vs. 62.3%, p < 0.001). The receiver operating characteristic curves revealed that ultrasound was more accurate in detecting breast cancer than mammography (76.8% vs. 71.3%, p < 0.001). Age, body mass index, and breast density did not influence ultrasound sensitivity and accuracy. Conclusions: Ultrasound is more sensitive and accurate than mammography and detects more breast cancers with a lower specificity. [ABSTRACT FROM AUTHOR]

Supramolecular peptide hydrogel has shown promising potential in vaccine development largely because of its ability to function both as antigen depot and immune adjuvant. Nap‐GdFdFdY, a tetrapeptide hydrogel that has been previously reported to exhibit adjuvant effect, is inadvertently found to contain conserved peptide sequence for insulin, proinsulin, and glutamic acid decarboxylase, 3 major autoantigens for the autoimmune type 1 diabetes (T1D). At present, despite being managed clinically with insulin replacement therapy, T1D remains a major health threat with rapidly increasing incidences, especially in children and young adults, and antigen‐specific immune tolerance induction has been proposed as a feasible approach to prevent or delay T1D progression at an early stage. Here, it is reported that innoculation of Nap‐GdFdFdY leads to complete protection of nonobese diabetic (NOD) mice from T1D development till the age of 36 weeks. Better maintenance of pancreatic islet morphology with minimal immune cell infiltration is also observed from mice exposed to Nap‐GdFdFdY. This beneficial impact is mainly due to its facilitative role on enhancing peripheral T regulatory cell (Treg) population, shown as increased splenic Treg percentage, and function, demonstrated by maintenance of circulating TGF‐β1 level. Serum cytokine microarray data further implicate a "buffering" role of Nap‐GdFdFdY on systemic inflammatory tone in NOD mice. Thus, with its versatility, applicability, and excellent potency, Nap‐GdFdFdY is posited as a novel therapeutic intervention for T1D. [ABSTRACT FROM AUTHOR]

Testis‐specific protein Y‐encoded 1 (TSPY1), a Y chromosome‐linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl‐histone H4 and trimethylated histone H3‐lysine 4, two post–translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1‐CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen‐AR axis‐regulated oncogene, suggesting a novel and potential target for PCa therapy. [ABSTRACT FROM AUTHOR]

Background: Brachydactyly (BD) is a rare autosomal dominant inherited disease characterized by shortness of the fingers and/or toes, which has been classified into the subtypes A–E. However, the exact cause and mechanism of BD remain to be illuminated. Here, we aim to reveal the clinical and genetic characteristics of a subtype of BD, brachydactyly‐anonychia. Methods: In this study, a large Chinese family with three members affected by brachydactyly‐anonychia was investigated. Both whole‐exome sequencing and microarray‐based comparative genomic hybridization (CGH) were performed on this family and the results of copy number variation (CNV) were verified by quantitative real‐time PCR (qPCR). Results: All the affected individuals showed short fingers and toes as well as missing nails; and the absence of middle phalanges in figure II‐V of the upper and lower extremities was observed by X‐ray examination. A duplication involving in the region of 17q24.3 was detected by CGH. The results of qPCR also represented this duplication in 17q24.3 in all the patients. Conclusion: In summary, our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly‐anonychia in this family, which support the prior report that brachydactyly‐anonychia is associated with 17q24.3 duplication, and further indicates the pathogenic correlation between BD and CNVs. [ABSTRACT FROM AUTHOR]

The testis‐specific protein, Y‐linked 1 (TSPY1), a newly recognized cancer/testis antigen, has been suggested to accelerate tumor progression. However, the mechanisms underlying TSPY1 cancer‐related function remain limited. By mining the RNA sequencing data of lung and liver tumors from The Cancer Genome Atlas, we found frequent ectopic expression of TSPY1 in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC), and the male‐specific protein was associated with higher mortality rate and worse overall survival in patients with LUAD and LIHC. Overexpression of TSPY1 promotes cell proliferation, invasiveness, and cycle transition and inhibits apoptosis, whereas TSPY1 knockdown has the opposite effects on these cancer cell phenotypes. Transcriptomic analysis revealed the involvement of TSPY1 in PI3K/AKT and RAS signaling pathways in both LUAD and LIHC cells, which was further confirmed by the increase in the levels of phosphorylated proteins in the PI3K‐AKT and RAS signaling pathways in TSPY1‐overexpressing cancer cells, and by the suppression on the activity of these two pathways in TSPY1‐knockdown cells. Further investigation identified that TSPY1 could directly bind to the promoter of insulin growth factor binding protein 3 (IGFBP3) to inhibit IGFBP3 expression and that downregulation of IGFBP3 increased the activity of PI3K/AKT/mTOR/BCL2 and RAS/RAF/MEK/ERK/JUN signaling in LUAD and LIHC cells. Taken together, the observations reveal a novel mechanism by which TSPY1 could contribute to the progression of LUAD and LIHC. Our finding is of importance for evaluating the potential of TSPY1 in immunotherapy of male tumor patients with TSPY1 expression. [ABSTRACT FROM AUTHOR]

Abstract: Observations of vertical ion drift velocities (Vz) at the topside of the ionosphere by Defense Meteorological Satellite Program (DMSP) satellites have been accumulated over decades and provide us a unique opportunity to study the vertical ion drifts through the ionosphere on different temporal and spatial scales. In this paper, Vz data of F13, which are of high quality, are taken as the reference to rescale the measurements of DMSP F11, F12, F14, F15, and F16 at high latitudes from 50°N/S to 90°N/S, which show significant differences from each other in magnitudes. Through rescaling, all Vz data of F11–F16 are in a similar order of magnitudes. Moreover, their spatial and temporal distributions resemble each other on average and are consistent with the excepted averaged behaviors reported in previous studies. Thus, the rescaling is basically effective, which provides an opportunity to construct a data set of Vz from 1995 to 2014 that covers nearly two solar cycles for further statistical analysis. Meanwhile, it should be noted that the rescaling results are qualitative/semiqualitative with some uncertainty, which needs more detailed discussion and analysis in future studies. [ABSTRACT FROM AUTHOR]

An incubation experiment is conducted at 20 °C for 30 days to explore the influence of biochar, nitrogen, and their interactions on CH4, CO2, and N2O emissions, as well as C and N variations in soils with milk vetch and rape residue amendment or in soils without plant residue. Both the biochar and nitrogen additions had negative effects on the cumulative CH4 and CO2 emissions in the presence of milk vetch and rape residues. Regardless of the biochar and nitrogen addition, the CH4 and CO2 emissions from soils amended with milk vetch residue are the highest, followed by those from soils amended with rape residue and those from soils with no plant residue. With the N application, N2O emissions from soils amended with rape residue are significantly higher than those from soils without plant residue, whereas the N2O emissions from soils amended with milk vetch residue are significantly lower than those from soil without plant residue. DOC is positively related with CO2 emissions. NH4+N, NO3−N, and TIN are also positively correlated with N2O emissions. In soils with the N fertilizer application, milk vetch residue, and biochar decreases the global warming potential, whereas rape residue increases the global warming potential. The results indicate that milk vetch residue in combination with biochar could benefit greenhouse gas mitigation and should be recommended for agricultural practices at high nitrogen level. In contrast, rape residue incorporated with biochar should be applied cautiously, especially in N abundant soils. [ABSTRACT FROM AUTHOR]

Aims The selective endothelin ( ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. Materials and methods Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians ( N = 77) and North Americans ( N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients. Results Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d ( P = .44) and −48.0% vs −28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (β = −1.09 per m2; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/ dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. Conclusion The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention. [ABSTRACT FROM AUTHOR]

Based on the measurements from Defense Meteorological Satellite Program (DMSP) F12, F13, and F15 satellites in 1995–2014, we report significant hemispheric asymmetries in vertical ion drift velocity (Vz) at dawn (0500–0700 solar local time) in geomagnetic and geographic coordinates. Vz is distributed in 0300–0900 magnetic local time sector in both the northern (NH) and southern (SH) hemispheres. The north‐south asymmetries are persistent no matter under what kind of seasonal, solar activity, and IMF conditions. In the polar cap, downward Vz is stronger in the SH. Such difference shows clear IMF BY dependence and is more significant in the local winter and/or under low solar activity conditions. In the geomagnetic coordinates, the auroral zone is dominated by upward Vz in the NH but by downward Vz in the SH statistically. In the geographic coordinates, the geographic longitudinal variation of Vz is more pronounced in the SH. The seasonal variations of high‐latitude Vz are different in the NH and SH. The average asymmetric feature of Vz largely depends on the occurrence and magnitude of ion upflow/outflow, which are modulated by the combined effects of the asymmetric magnetic field configuration between the two hemispheres, and the dynamic processes in the tightly coupled ionosphere‐thermosphere system, and their (probably nonlinear) interactions with each other. Key Points: There is obvious north-south asymmetry in the vertical ion drift in the topside ionosphere at dawn in geomagnetic and geographic coordinateThe hemispheric asymmetries depend on seasonal, solar activity, and IMF orientationThe asymmetries may be caused by magnetic field configuration and dynamic processes in the ionosphere/thermosphere, and their interactions [ABSTRACT FROM AUTHOR]