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STUDY QUESTION Does a homozygous nonsense mutation in ACR lead to total fertilization failure (TFF) resulting in male infertility in humans? SUMMARY ANSWER A novel homozygous nonsense mutation of ACR (c.167G>A, p.Trp56X) was identified in two infertile brothers and shown to cause human TFF. WHAT IS KNOWN ALREADY ACROSIN, encoded by ACR , is a major acrosomal enzyme expressed only in the acrosome of the sperm head. Inhibition of acrosin prevents sperm penetration of the zona pellucida (ZP) in several species, including humans. Acr -knockout in hamsters causes male infertility with completely blocked fertilization. Of note, there are no reports of ACR mutations associated with TFF in humans. STUDY DESIGN, SIZE, DURATION Whole-exome sequencing (WES) was used for the identification of pathogenic genes for male factor TFF in eight involved couples. PARTICIPANTS/MATERIALS, SETTING, METHODS Data from eight infertile couples who had experienced TFF during their IVF or ICSI attempts were collected. Functional assays were used to verify the pathogenicity of the potential genetic factors identified by WES. Subzonal insemination (SUZI) and IVF assays were performed to determine the exact pathogenesis of TFF caused by deficiencies in ACROSIN. MAIN RESULTS AND THE ROLE OF CHANCE A novel homozygous nonsense mutation in ACR , c.167G>A, p.Trp56X, was identified in two additional primary infertile brothers whose parents were first cousins. This rare mutation caused ACROSIN deficiency and acrosomal ultrastructural defects in the affected sperm. Spermatozoa lacking ACROSIN were unable to penetrate the ZP, rather than hampering sperm binding, disrupting gamete fusion, or preventing oocyte activation. These findings were supported by the fertilization success of SUZI and ICSI attempts, as well as the normal expression of ACTL7A and PLCζ in the mutant sperm, suggesting that ICSI without remedial assisted oocyte activation is an optimal treatment for ARCOSIN-deficient TFF. LIMITATIONS, REASONS FOR CAUTION The absence of another independent pedigree to support our argument is a limitation of this study. WIDER IMPLICATIONS OF THE FINDINGS The findings expand our understanding of the genes involved in human TFF, providing information for appropriate genetic counseling and fertility guidance for these patients. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Natural Science Foundation of China (grant no. 82201803, 81901541, 82271639, and 32000584), University Synergy Innovation Program of Anhui Province (GXXT-2019-044), and the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (grant no. 2019PT310002). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Study Question: What is the potential of applying non-invasive preimplantation genetic testing (niPGT) for chromosome abnormalities in blastocysts reported with a mosaic trophectoderm (TE) biopsy?Summary Answer: niPGT of cell-free DNA in blastocyst culture medium exhibited a good diagnostic performance in putative mosaic blastocysts.What Is Known Already: Advances in niPGT have demonstrated the potential reliability of cell-free DNA as a resource for genetic assessment, but information on mosaic embryos is scarce because the mosaicism may interfere with niPGT. In addition, the high incidence of mosaicism reported in the context of PGT and the viability of mosaic blastocysts raise questions about whether mosaicism really exists.Study Design, Size, Duration: The study was performed between May 2020 and July 2020. First, clinical data collected by a single-center over a 6-year period on PGT for chromosome aneuploidies (PGT-A) or chromosomal structural rearrangements (PGT-SR) were analyzed. After confirming the reliability of niPGT, 41 blastocysts classified as mosaics by trophectoderm (TE) biopsy were re-cultured. The chromosomal copy number of the blastocyst embryo (BE, the gold standard), TE re-biopsy, and corresponding cell-free DNA in the culture medium was assessed.Participants/materials, Setting, Methods: Data on patients enrolled for PGT at a single center from 2014 to 2019 were collected and the cycles with available putative mosaic blastocysts were evaluated. To verify the diagnostic validity of niPGT, eight aneuploid blastocysts were thawed and re-cultured for 14-18 h. The concordance of the niPGT diagnosis results and the whole blastocyst testing results was analyzed. Forty-one blastocysts reported as mosaics from 22 patients were included and re-cultured for 14-18 h. The genetic material of the BE, TE re-biopsy, and corresponding cell-free DNA in the culture medium was amplified using multiple annealing and looping-based amplification cycles. The karyotype data from niPGT and TE re-biopsy were compared with that from the whole blastocyst, and the efficiency of niPGT was assessed.Main Results and the Role Of Chance: Data on 3738 blastocysts from 785 PGT-A or PGT-SR cycles of 677 patients were collected. According to the TE biopsy report, of the 3662 (98%) successfully amplified samples, 24 (0.6%) yielded no results, 849 (23.2%) were euploid, 2245 (61.3%) were aneuploid, and 544 (14.9%) were mosaic. Sixty patients without euploid blastocysts opted for a single mosaic blastocyst transfer, and 30 (50%) of them obtained a clinical pregnancy. With the BE chromosome copy number as the gold standard, niPGT and TE re-biopsy showed reliable detection ability and diagnostic efficiency in eight putative aneuploid blastocysts. Of the 41 putative mosaic blastocysts re-cultured and re-tested, 35 (85.4%) showed euploid BE results. All but two of the blastocysts previously diagnosed with segmental chromosomal mosaic were actually euploid. In addition, all blastocysts previously classified as low degree (20-50%) mosaics were identified as euploid by BE PGT, whereas four of the six putative high degree (50-80%) mosaic blastocysts showed chromosomal abnormalities. The raw concordance rates of spent culture medium (SCM) and TE re-biopsies compared with BE were 74.4% and 82%, respectively, in terms of overall ploidy and 96.2% and 97.6%, respectively, per single chromosome when considering all degree mosaic results as true positives. However, when we set a mosaicism identification threshold of 50%, the concordance rates of SCM and TE re-biopsies compared with BE were 87.2% and 85% at the overall ploidy level and 98.8% and 98.3% at the chromosomal level, respectively. At the full ploidy level, the sensitivity and false negative rates for niPGT were 100% and 0, respectively. After adjustment of the threshold for mosaicism, the specificity of niPGT increased from 69.7% to 84.8% in terms of overall ploidy and from 96.1% to 98.9% at the chromosomal level.Limitations, Reasons For Caution: The primary limitation of this study is the small sample size, which decreases the strength of our conclusions. If possible, identifying the clinical outcome of niPGT on reassessed mosaic blastocysts would be further progress in this field.Wider Implications Of the Findings: This study is the first to explore the practicability of niPGT in diagnostic reassessment of putative mosaicism. The present study provides a novel opportunity for patients with only mosaic blastocysts and no euploid blastocysts, regardless of the technical or biological basis of mosaicism. Employing niPGT after 14-18 h of re-culturing might be a superior option for the best use of blastocysts because of its minimally invasive nature.Study Funding/competing Interest(s): This work was supported by grants from National Key Technology Research and Development Program of China (No. 2017YFC1002004), the Central Guiding the Science and Technology Development of the Local (2018080802D0081) and College Natural Science Project of Anhui Province (KJ2019A0287). There are no competing interests to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Remote sensing technologies are frequently employed in monitoring and evaluating agricultural meteorological disasters because they can provide high throughput and cost-effective accesses to obtain a variety of real-time spatial data related to crop growth information. Accurately and timely estimating the drought dynamics using remote sensing is valuable for improving crop management level and promoting agricultural sustainable development. In this study, the responses of winter wheat during the critical growth stages to different drought levels from 2010 to 2020 in the Huang-Huai-Hai (HHH) region of China were evaluated based on Google Earth Engine. Four critical developmental stages of winter wheat were highlighted: greening－jointing, jointing－heading, heading－milking maturity, and milking maturity－maturity stages. The temperature vegetation dryness index (TVDI) was constructed for evaluating the drought of winter wheat. Our results indicated that the winter wheat in the HHH region during 2010－2020 was clearly impacted by drought disasters, mainly mild to moderate droughts. In particular, the TVDI index during the critical development stages of winter wheat from 2010 to 2020 wavered in the scope of 0.48 and 0.61, and the soil moisture content at a depth of 10 cm tended to obviously reducing with a rate of − 0.1615/a. For critical growth stages, the winter wheat in the HHH Region was the most prone to threatened by drought during the stage of jointing－heading, following the stage of milking maturity－maturity. The high probability incidence of drought in winter wheat gradually shifted from the nutritional growth to the reproductive growth stages, which increased the risk of drought affecting yield. Furthermore, the notable spatial variations of drought in winter wheat in the HHH region were found. The winter wheat was evidently threatened by moderate and severe droughts in certain areas such as southern Hebei province, northern Jiangsu province, Anhui province, etc. Our results provide new insights into the studies on monitoring and evaluating agricultural meteorological disasters based on remote sensing technology. [Display omitted] • We established temperature vegetation dryness index (TVDI) for winter wheat. • We explored the spatiotemporal dynamics in drought of winter wheat based on TVDI. • We revealed the responses of winter wheat during the critical stages to droughts. • Google Earth Engine technology and long-term field observations were used. [ABSTRACT FROM AUTHOR]

Idiopathic oligoastenoteratozoospermia (iOAT) affects 30% of infertile men of reproductive age. However, the associations between Cr, Fe, Cu, Se or Co levels and iOAT risk have not been determined. This research aimed to assess the associations between Cr, Fe, Cu, Se and Co levels as well as their mixtures in seminal plasma and the risk of iOAT and severe iOAT. Therefore, a case‒control study including 823 participants (416 iOAT patients and 407 controls) recruited from October 2021 to August 2022 at the reproductive medicine center of the First Affiliated Hospital of Anhui Medical University was conducted in Anhui, China. The concentrations of Cr, Fe, Cu, Se and Co in seminal plasma were detected via inductively coupled plasma‒mass spectrometry. Binary logistic regression models were used to assess the associations between the levels of Cr, Fe, Cu, Se and Co and the risk of iOAT and severe iOAT; additionally, Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regressions were performed to evaluate the joint effect of seminal plasma levels of Cr, Fe, Cu, Se and Co on the risk of iOAT and explore which elements contributed most to the relationship. We found significant associations between the concentrations of Fe, Cu and Se in seminal plasma and iOAT risk after adjusting for covariates (Fe, lowest tertile vs. second tertile: aOR = 1.86, 95% CI = 1.31, 2.64; Cu, lowest tertile vs. second tertile: aOR = 1.95, 95% CI = 1.37, 2.76; Se, lowest tertile vs. second tertile: aOR = 1.65, 95% CI = 1.17, 2.35). A lower Se concentration in seminal plasma (lowest tertile vs. second tertile: aOR = 1.84, 95% CI = 1.10, 3.10) was positively associated with the risk of severe iOAT. Additionally, we also observed an association between the concentration of Cr in seminal plasma and the risk of iOAT before adjusting for covariates (Cr, third tertile vs. lowest tertile: OR=1.44, 95% CI: 1.03, 2.02). According to the BKMR analyses, the risk of iOAT increased when the overall concentrations were less than the 25th percentile. The results from the WQS regression indicated that a negative WQS index was significantly associated with the iOAT risk, while a positive WQS index was not. Se and Fe had significant weights in the negative direction. In conclusion, lower Cu, Fe and Se levels in seminal plasma were positively associated with iOAT risk, while higher Cr levels in seminal plasma were positively associated with iOAT risk according to the single element model, and lower levels of Se were related to a greater risk of severe iOAT; when comprehensively considering all the results from BKMR and WQS regression, Fe, Se and Cr levels contributed most to this relationship. [Display omitted] • Lower Cr, Fe, Cu, Se and Co increased risk of iOAT. • Se and Fe plays a dominant role in modulating the risk of iOAT. • Lower Se was associated with risk of iOAT severity. • Lower Cu, Fe and Se were individually associated with increased iOAT risk. • Higher Cr was associated with increased iOAT risk. [ABSTRACT FROM AUTHOR]