Artificial intelligence enables precision diagnosis of cervical cytology grades and cervical cancer.

Cervical cancer is a significant global health issue, its prevalence and prognosis highlighting the importance of early screening for effective prevention. This research aimed to create and validate an artificial intelligence cervical cancer screening (AICCS) system for grading cervical cytology. The AICCS system was trained and validated using various datasets, including retrospective, prospective, and randomized observational trial data, involving a total of 16,056 participants. It utilized two artificial intelligence (AI) models: one for detecting cells at the patch-level and another for classifying whole-slide image (WSIs). The AICCS consistently showed high accuracy in predicting cytology grades across different datasets. In the prospective assessment, it achieved an area under curve (AUC) of 0.947, a sensitivity of 0.946, a specificity of 0.890, and an accuracy of 0.892. Remarkably, the randomized observational trial revealed that the AICCS-assisted cytopathologists had a significantly higher AUC, specificity, and accuracy than cytopathologists alone, with a notable 13.3% enhancement in sensitivity. Thus, AICCS holds promise as an additional tool for accurate and efficient cervical cancer screening.

Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia.

OBJECTIVE: Idiopathic infantile hypercalcemia (IIH) is a rare disorder of PTH-independent hypercalcemia. CYP24A1 and SLC34A1 gene mutations cause two forms of hereditary IIH. In this study, the clinical manifestations and molecular aspects of six new Chinese patients were investigated. METHODS: The clinical manifestations and laboratory study of six patients with idiopathic infantile hypercalcemia were analyzed retrospectively. RESULTS: Five of the patients were diagnosed with hypercalcemia, hypercalciuria, and bilateral medullary nephrocalcinosis. Their clinical symptoms and biochemical abnormalities improved after treatment. One patient presented at age 11 years old with arterial hypertension, hypercalciuria and nephrocalcinosis, but normal serum calcium. Gene analysis showed that two patients had compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant, and three patients had a monoallelic SLC34A1 variant. Four novel CYP24A1 variants (c.116G > C, c.287T > A, c.476G > A and c.1349T > C) and three novel SLC34A1 variants (c.1322 A > G, c.1697_1698insT and c.1726T > C) were found in these patients. CONCLUSIONS: A monoallelic variant of CYP24A1 or SLC34A1 gene contributes to symptomatic hypercalcemia, hypercalciuria and nephrocalcinosis. Manifestations of IIH vary with onset age. Hypercalcemia may not necessarily present after infancy and IIH should be considered in patients with nephrolithiasis either in older children or adults.

Exposure to haloacetic acid disinfection by-products and male steroid hormones: An epidemiological and in vitro study.

Haloacetic acids (HAAs) are ubiquitous in drinking water and have been associated with impaired male reproductive health. However, epidemiological evidence exploring the associations between HAA exposure and reproductive hormones among males is scarce. In the current study, the urinary concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the internal exposure markers of HAAs, as well as sex hormones (testosterone [T], progesterone [P], and estradiol [E2]) were measured among 449 Chinese men. Moreover, in vitro experiments, designed to simulate the real-world scenarios of human exposure, were conducted to assess testosterone synthesis in the Leydig cell line MLTC-1 and testosterone metabolism in the hepatic cell line HepG2 in response to low-dose HAA exposure. The DCAA and TCAA urinary concentrations were found to be positively associated with urinary T, P, and E2 levels (all p < 0.001), but negatively associated with the ratio of urinary T to E2 (p < 0.05). Combined with in vitro experiments, the results suggest that environmentally-relevant doses of HAA stimulate sex hormone synthesis and steroidogenesis pathway gene expression in MLTC-1 cells. In addition, the inhibition of the key gene CYP3A4 involved in the testosterone phase Ⅰ catabolism, and induction of the gene UGT2B15 involved in testosterone phase Ⅱ glucuronide conjugation metabolism along with the ATP-binding cassette (ABC) transport genes (ABCC4 and ABCG2) in HepG2 cells could play a role in elevation of urinary hormone excretion upon low-dose exposure to HAAs. Our novel findings highlight that exposure to HAAs at environmentally-relevant concentrations is associated with increased synthesis and excretion of sex hormones in males, which potentially provides an alternative approach involving urinary hormones for the noninvasive evaluation of male reproductive health following exposure to DBPs.

Synergism of Feeding and Digestion Regulated by the Neuropeptide F System in Ostrinia furnacalis Larvae.

Feeding is crucial for the growth and survival of animals, including humans, but relatively little is known about how it is regulated. Here, we show that larval feeding in Ostrinia furnacalis is regulated by neuropeptide F (NPF, the homologous peptide of mammalian NPY) via the insulin signalling pathway in the midgut. Furthermore, the genes pi3k and mtor in the insulin pathway positively regulate α-amylase and lipase of the midgut by recruiting the transcription factors c-Myc and PPARγ for binding to the promotors of these two enzymes. Importantly, we find that the feeding behaviour and the digestive system of midgut in O. furnacalis larvae are closely related and interactive in that knocking down α-amylase or lipase induces a reduction in larval feeding, while food-deprived larvae lead to fewer expressions of α-amylase and lipase. Importantly, it is the gut NPF that regulates the α-amylase and lipase, while variations of α-amylase and lipase may feed back to the brain NPF. This current study reveals a molecular feedback mechanism between feeding behaviour and the digestive system that is regulated by the conserved NPF via insulin signalling systems in the midgut of O. furnacalis larvae.

Incidence of Childhood Type 1 Diabetes in Beijing During 2011-2020 and Predicted Incidence for 2025-2035: A Multicenter, Hospitalization-Based Study.

INTRODUCTION: China has a low incidence of type 1 diabetes mellitus (T1DM); however, based on the large population, the absolute numbers are high. Our aim was to assess the incidence of childhood T1DM in Beijing during 2011-2020, predicted incidence for 2025-2035, and to determine the incidence of diabetic ketosis or diabetic ketoacidosis (DK/DKA) in this population. METHODS: Data on patients aged less than 15 years of age with newly diagnosed T1DM between January 1, 2011 and December 31, 2020 was obtained from five tertiary hospitals in Beijing and retrospectively analyzed. RESULTS: In all, 636 children aged less than 15 years were diagnosed with T1DM during 2011-2020. The incidence of T1DM was 3.11-5.46 per 100,000 per year, with an average increase of 5.10% per year. The age-specific incidence for ages 0-4 years, 5-9 years, and 10-14 years was 2.97, 4.69, and 4.68 per 100,000 per year, respectively. The highest average annual increase (7.07%) in incidence was for the youngest age group. DK or DKA was present at the time of diagnosis of T1DM in 84.6% of patients. The age-specific incidence of T1DM among children aged less than 15 years was predicted to be 7.32, 11.4, and 11.52 per 100,000 in 2035 for ages 0-4 years, 5-9 years, and 10-14 years, respectively. CONCLUSIONS: The was a gentle increase in the incidence of childhood T1DM during 2011-2020 in Beijing. This increase is expected to continue for the next 15 years.

Cytosolic and mitochondrial ribosomal proteins mediate the locust phase transition via divergence of translational profiles.

The phase transition from solitary to gregarious locusts is crucial in outbreaks of locust plague, which threaten agricultural yield and food security. Research on the regulatory mechanisms of phase transition in locusts has focused primarily on the transcriptional or posttranslational level. However, the translational regulation of phase transition is unexplored. Here, we show a phase-dependent pattern at the translation level, which exhibits different polysome profiles between gregarious and solitary locusts. The gregarious locusts exhibit significant increases in 60S and polyribosomes, while solitary locusts possess higher peaks of the monoribosome and a specific "halfmer." The polysome profiles, a molecular phenotype, respond to changes in population density. In gregarious locusts, ten genes involved in the cytosolic ribosome pathway exhibited increased translational efficiency (TE). In solitary locusts, five genes from the mitochondrial ribosome pathway displayed increased TE. The high expression of large ribosomal protein 7 at the translational level promotes accumulation of the free 60S ribosomal subunit in gregarious locusts, while solitary locusts employ mitochondrial small ribosomal protein 18c to induce the assembly of mitochondrial ribosomes, causing divergence of the translational profiles and behavioral transition. This study reveals the translational regulatory mechanism of locust phase transition, in which the locusts employ divergent ribosome pathways to cope with changes in population density.

The efficacy of PD-1 inhibitors in the maintenance treatment of diffuse large B-cell lymphoma: A single-center retrospective analysis.

Purpose: To explore the impact of PD-1 maintenance therapy on the relapse-free survival (RFS) of patients with diffuse large B-cell lymphoma (DLBCL). Methods: We retrospectively analyzed patients with DLBCL admitted to our center between January 2018 and July 2019 who achieved complete remission (CR) after induction chemotherapy. Forty-five patients who received PD-1 inhibitor maintenance therapy were considered the treatment group. Forty-five patients who did not undergo maintenance treatment during the same period were selected as the control group. The base levels of the two groups of patients were similar. The 2-year RFS rate of the two groups was compared. The correlation between the adverse prognosis factors of the patients and the RFS rate was performed subgroup analysis. Results: The 2-year RFS rates of the treatment and control groups were 86.7% VS 75.6% (P = 0.178), respectively, until July 2021. A single factor analysis showed that patients with International Prognostic Index (IPI) score ≥ 3, non-GCB DLBCL receiving PD-1 inhibitor maintenance treatment, can improve their 2-year RFS (72.2% VS 30.8%, P = 0.022; 88.5% VS 62.5%, P = 0.032). For non-GCB patients, the 2-year RFS of the treatment group can reach 88.5%, while the 2-year RFS of the control group is 62.5%, which is statistically significant (P = 0.032). In all patients treated with PD-1 inhibitors, the adverse reactions were all grade I-II, and there were no grade III-IV adverse reactions. There were no clear adverse events in the follow-up patients in the control group. Conclusion: Maintenance treatment with PD-1 inhibitors can improve the 2-year RFS rate of patients with IPI score of ≥3 and non-GCB DLBCL. This prompts the potential advantage of PD-1 inhibitors in DLBCL maintenance treatment. However, longer follow-ups remain needed to obtain more definite data.

DNA Hypermethylation and a Specific Methylation Spectrum on the X Chromosome in Turner Syndrome as Determined by Nanopore Sequencing.

The molecular genetic mechanism of Turner syndrome (TS) still leaves much to be discovered. Methods: TS (45X0) patients and age-matched controls (46XX and 46XY) were selected. The nanopore sequencing combined with trio-whole exome sequencing (trio-WES) were used for the first time to investigate TS. Results: Thirteen TS (45X0) patients and eight controls were enrolled. Trio-WES analysis did not find any pathogenetic or likely pathogenic variants except X chromosome (chrX) deletion. The average methylation levels and patterns of chrX in 45X0 and 46XY were similar, and significantly higher than in 46XX (p = 2.22 × 10-16). Both hyper-methylation and hypo-methylation were detected in the CpG island (CGI), CGI_shore, promoter, genebody, and PAR1-region, while in the transposon element inactivation regions of the chrX and hypermethylation were predominant. A total of 125 differentially methylated genes were identified in 45X0 compared to 46XX, including 8 and 117 hypermethylated and hypomethylated genes, respectively, with the enrichment terms of mitophagy, regulation of DNA-binding transcription factor activity, etc. Conclusions: The results suggest that the methylation profile in patients with TS might be determined by the number of X chromosomes; the patterns of methylation in TS were precisely associated with the maintenance of genomic stability and improvement of gene expression. Differentially methylated genes/pathways might reveal the potential epigenetic modulation and lead to better understanding of TS.

First Clinical Study on Long-Acting Growth Hormone Therapy in Children with Turner Sydrome.

Study on long-acting growth hormone (LAGH) therapy in Turner syndrome (TS) is a 2-year retrospective study including patients diagnosed with TS from 2018-2021. Patients were divided into four groups: Group 1 to 4 were low dose (0.1 mg/kg/ w), high-dose (0.2 mg/kg/w) LAGH, daily GH (0.38 mg/kg/w), and untreated control. The efficacy and safety data were analyzed. Seventy-five TS cases with the age 7.9±2.9 years and the bone age 6.8±2.8 years were recruited. In year 1: The change of height standard deviation score (ΔHtSDS) and height velocity (HV) in Group 2 were comparable to Group 3, both two groups were higher than Group 1. ΔHtSDS and HV in all GH treatment group were higher than untreated group. IGF1 increased in all treatment groups, only 4 cases had IGF1>3 SD. In year 2: ΔHtSDS and HV in Group 2 and 3 were comparable. Five cases had IGF1>3 SD. Correlation analysis for LAGH efficacy at year 1 indicated that baseline variables correlated with ΔHtSDS include: GH dose, CA (chronological age), and bone age (BA). The HV was positively correlated with baseline GH dose, HtSDS, IGF-1SDS and negatively correlated with baseline CA, BA, and BMI. No GH-related serious adverse effects were observed. The high-dose LAGH treatment in TS patients is effective and safe as daily GH for 2 years. The favorable prognosis factors include sufficient GH dose and early treatment. IGF1 monitoring and weight control are important.

Noninvasive examination of the cardiac properties of insect embryos enabled by optical coherence tomography.

Understanding the cardiac properties of insect embryos at different development stages is important, however, few works have been conducted probably due to the lack of effective tools. Using locust embryos as an example, here we show, for the first time, that optical coherence tomography (OCT) is capable of obtaining detailed information of embryos' heart activities and irregularities, such as the heart rate, cardiac cycle, diastolic and systolic diameters, hemolymph pumping rate and ejection fraction at different stages of embryonic development and at different temperatures. We develop algorithms and mathematical methods for extracting and analyzing cardiac behavior information of locust embryos. We discover that locust embryos experienced suspended development (quiescence) caused by cold storage have a heart rate 20% more than that of embryos without experiencing quiescence and that the hemolymph pumping rate of the two types of embryos behaves differently as the embryos grow. In addition, using OCT as an accurate cardiac activity examination tool, we show that the heart rates of locust embryos are effectively reduced due to nitric oxide synthase gene silencing by RNA interference, indicating potential application of using locust embryos as a good model organism to study cardiovascular diseases, including the congenital heart disease and arrhythmia. Finally, the capabilities offered by OCT in the studies of locust embryonic development may also prove helpful to promote locust reproduction for nutritions or restrain locust reproduction for pest control.

A novel non-invasive identification of genome editing mutants from insect exuviae.

With the wide application of genome editing in insects, a simple and efficient identification method is urgently needed to meet the increasing demand for mutation detection. Here, taking migratory locusts as a model system, we developed a non-invasive method to accurately identify genome-edited mutants by using DNA from insect exuviae. We compared the quantity and quality of genomic DNA from exuviae in five instar hoppers and found that the 1st instar exuviae had the highest DNA yield and content, while the 3rd instar exuviae had the best quality. Consensus genotypes were identified from genomic DNA of hoppers at different developmental stages in the same individuals. Moreover, we demonstrated that the amplification products from DNA extracted from locust exuviae are the consensus sequences with those from the hemolymph and foreleg pre-tarsus. Therefore, non-invasive samples provide the same genotyping results as minimally invasive and invasive samples of the same individuals. Furthermore, this identification method that uses genomic DNA from exuviae can be used for early screening of positive genome-edited individuals in each generation for adult crossing. In our study, the non-invasive identification method was not only simpler and provided results earlier than existing methods, but also had a better reproducibility and accuracy. This non-invasive identification approach using genomic DNA from exuviae can be adapted to meet the growing demand for genetic analysis and will find wide application in insect genome editing research.

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients.

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis. Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis. Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients. Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

Interactive effect of photoperiod and temperature on the induction and termination of embryonic diapause in the migratory locust.

BACKGROUND: Diapause plays a vital role in the survival and population reproduction of the migratory locust in temperate regions. Although some studies have suggested that photoperiod and temperature are two important environmental factors involved in the induction and termination of embryonic diapause in locusts, the independent or synergetic roles of these two factors are still unclear. RESULTS: We designed crossover experiments to investigate the effects of photoperiod, temperature and treatment time on the induction and termination of embryonic diapause in locusts by optical coherence tomography (OCT), which can track the entire embryonic developmental process via noninvasive 3D real-time imaging. Diapause induction experiments showed that a short photoperiod (in adults) and a low egg treatment temperature are the most important prerequisites for inducing egg diapause. The diapause rate reached 90.7% when the adults were reared under a short photoperiod (8 L:16 D) and the eggs were treated at 22 °C. However, the adult rearing temperature had no significant effect on diapause induction. Analysis of variance also confirmed that there was a significant interactive effect between parental photoperiod and egg treatment temperature. Moreover, diapause termination experiments showed that 13 °C (near the developmental threshold temperature of 15 °C) for 20 days is the most effective condition for terminating diapause. CONCLUSION: Our study provides accurate photoperiod and temperature thresholds for inducing and terminating diapause in the migratory locust, suggesting potential applications in the prediction and control of locust plagues. © 2021 Society of Chemical Industry.

Regulatory mechanism of daily sleep by miR-276a.

MiRNAs have attracted more attention in recent years as regulators of sleep and circadian rhythms after their roles in circadian rhythm and sleep were discovered. In this study, we explored the roles of the miR-276a on daily sleep in Drosophila melanogaster, and found a regulatory cycle for the miR-276a pathway, in which miR-276a, regulated by the core CLOCK/CYCLE (CLK/CYC) transcription factor upstream, regulates sleep via suppressing targets TIM and NPFR1. (a) Loss of miR-276a function makes the flies sleep more during both daytime and nighttime, while flies with gain of miR-276a function sleep less; (b) MiR-276a is widely expressed in the mushroom body (MB), the pars intercerebralis (PI) and some clock neurons lateral dorsal neurons (LNds), in which tim neurons is important for sleep regulation; (c) MiR-276a promoter is identified to locate in the 8th fragment (aFrag8) of the pre-miR-276a, and this fragment is directly activated and regulated by CLK/CYC; (4) MiR-276a is rhythmically oscillating in heads of the wild-type w1118 , but this oscillation disappears in the loss of function mutant clkjrk ; (5) The neuropeptide F receptor 1 (npfr1) was found to be a downstream target of miR-276a. These results clarify that the miR-276a is a very important factor for sleep regulation.

The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy.

BACKGROUND: Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. METHODS: In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. RESULTS: A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. CONCLUSIONS: Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.

AKH-FOXO pathway regulates starvation-induced sleep loss through remodeling of the small ventral lateral neuron dorsal projections.

Starvation caused by adverse feeding stresses or food shortages has been reported to result in sleep loss in animals. However, how the starvation signal interacts with the central nervous system is still unknown. Here, the adipokinetic hormone (AKH)-Fork head Box-O (FOXO) pathway is shown to respond to energy change and adjust the sleep of Drosophila through remodeling of the s-LNv (small ventral lateral neurons) dorsal projections. Our results show that starvation prevents flies from going to sleep after the first light-dark transition. The LNvs are required for starvation-induced sleep loss through extension of the pigment dispersing factor (PDF)-containing s-LNv dorsal projections. Further studies reveal that loss of AKH or AKHR (akh receptor) function blocks starvation-induced extension of s-LNv dorsal projections and rescues sleep suppression during food deprivation. FOXO, which has been reported to regulate synapse plasticity of neurons, acts as starvation response factor downstream of AKH, and down regulation of FOXO level considerably alleviates the influence of starvation on s-LNv dorsal projections and sleep. Taking together, our results outline the transduction pathways between starvation signal and sleep, and reveal a novel functional site for sleep regulation.

Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19.

Since December 2019, novel coronavirus infected pneumonia emerged in Wuhan city and rapidly spread throughout China. In severe novel coronavirus pneumonia cases, the number of platelets, their dynamic changes during the treatment, platelet-to-lymphocyte ratio (PLR) were a concern. We sought to describe the platelet feature of these cases. Single-center case series of the 30 hospitalized patients with confirmed coronavirus disease (COVID)-19 in Huizhou municipal central hospital from January 2020 to February 2020 were retrospectively analyzed. Demographic, clinical, blood routine results, other laboratory results, and treatment data were collected and analyzed. Outcomes of severe patients and nonsevere patients were compared. Univariate analysis showed that: age, platelet peaks, and PLR at peak platelet were the influencing factors in severe patients, multivariate analysis showed that the PLR value at peak platelet during treatment was an independent influencing factor in severe patients. The average hospitalization day of patients with platelet peaks during treatment was longer than those without platelet peaks (P < .05). The average age of patients with platelet peaks during treatment was older than those without platelet peaks (P < .05). The patients with significantly elevated platelets during treatment had longer average hospitalization days. And the higher PLR of patients during treatment had longer average hospitalization days. Single-center case series of the 30 hospitalized patients with confirmed COVID-19 in Huizhou Municipal Central Hospital, presumed that the number of platelets and their dynamic changes during the treatment may have a suggestion on the severity and prognosis of the disease. The patient with markedly elevated platelets and longer average hospitalization days may be related to the cytokine storm. The PLR of patients means the degree of cytokine storm, which might provide a new indicator in the monitoring in patients with COVID-19.