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The sperm of infertile men have higher rates of chromosomal abnormalities than those of fertile men. Miscarriage rate is also higher following testicular sperm extraction combined with intracytoplasmic sperm injection (TESE-ICSI). Sperm chromosomal abnormalities are assumed to be the cause of miscarriages. Previous testicular sperm karyotyping studies have only examined a few selected chromosomes using fluorescence in situ hybridization. The aim of this study was to provide a more detailed analysis of sperm karyotyping by analyzing all chromosomes using next-generation sequencing (NGS) in clinically usable testicular sperm. Sperm discarded after clinical use was collected for NGS. Additionally, sperm were individually collected by micromanipulation from patients with obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) who underwent TESE-ICSI. For comparison, ejaculated sperm from control and balanced translocation (BT) carriers were examined. Karyotyping was performed on individual sperm cells using NGS. The number of normal and aberrant sperm was compared. Seventeen patients participated in this study: control (n = 4), BT (n = 3), OA (n = 5), and NOA (n = 5). Ten sperm samples per patient were analyzed. The total acquisition rate for single sperm karyotyping was 85% (145/170). Karyotyping of sperm from the BT group revealed sperm with unbalanced chromosomes derived from carrier translocations. Among the NOA group, 7/41 (17%) sperm samples exhibited aberrant karyotypes, whereas no aberrant sperm were identified in the control and OA groups. Individual differences were observed in the frequency of sperm chromosomal abnormalities among patients with NOA. In conclusion, sperm chromosomal abnormalities are frequently observed in patients with NOA even after sperm selection for clinical use. As the frequency of chromosomal abnormalities varies among patients with NOA, single sperm sequencing may help identify patients with NOA most likely to benefit from PGT-A.

Automatic algorithms are a proposed alternative to manual assessment of polysomnography data for analyzing sleep structure; however, none are acceptably accurate for clinical use. We investigated the feasibility of an automated sleep stage scoring system called Sleep Scope, which is intended for use with portable 1-channel electroencephalograph, and compared it with the traditional polysomnography scoring method. Twenty-six outpatients and fourteen healthy volunteers underwent Sleep Scope and polysomnography assessments simultaneously. Polysomnography records were manually scored by three sleep experts. Sleep Scope records were scored using a dedicated auto-staging algorithm. Sleep parameters, including total sleep time, sleep latency, wake after sleep onset, and sleep efficiency, were calculated. The epoch-by-epoch pairwise concordance based on the classification of sleep into five stages (i.e., wake, rapid eye movement, N1, N2, and N3) was also evaluated after validating homogeneity and bias between Sleep Scope and polysomnography. Compared with polysomnography, Sleep Scope seemed to overestimate sleep latency by approximately 3 min, but there was no consistent tendency in bias in other sleep parameters. The Κ values ranged from 0.66 to 0.75 for experts’ inter-rater polysomnography scores and from 0.62 to 0.67 for Sleep Scope versus polysomnography scores, which indicated sufficient agreement in the determination of sleep stages based on the Landis and Koch criteria. We observed sufficient concordance between Sleep Scope and polysomnography despite lower concordance in sleep disorder patients. Thus, this auto-staging system might serve as a novel clinical tool for reducing the time and expenses required of medical staff and patients.

Sleep and Biological Rhythms https://doi.org/10.1007/s41105-022-00421-5 In the original publication of this article, in Table 2, the lengths of each sleep stage (N1, N2, N3, REM) were incorrectly listed as the same for all participants, the patient group, and the healthy group. The correct data (Table 2) is given in this correction. Sleep outcome measures for the patient and healthy groups based on the Sleep Scope system and polysomnography findings Outcome measure Sleep Scope Polysomnography (expert) 1 2 3 All participants (N = 40) Total sleep time (min) 408 (69) 425 (69) 414 (72) 400 (74) Sleep onset latency (min) 24 (18) 21 (16) 21 (17) 21 (16) WASO (min) 70 (58) 55 (58) 67 (61) 81 (63) SE (%) 81 (12) 85 (12) 82 (13) 80 (13) Number of awakenings, ≤ 2 min 131 (115) 188 (69) 119 (77) 111 (57) Sleep stage N1 (min) 56 (50) 83 (49) 85 (60) 80 (54) N2 (min) 222 (64) 205 (57) 193 (72) 223 (86) N3 (min) 36 (34) 62 (40) 47 (33) 24 (23) REM (min) 93 (38) 74 (27) 88 (31) 73 (29) Undeterminable (% of total epochs of all participants) 0.214 1.11 0.546 0.0224 Patient group (N = 26) Total sleep time (min) 385 (71) 403 (72) 391 (76) 374 (75) Sleep onset latency (min) 21 (12) 18 (11) 18 (11) 19 (11) WASO (min) 88 (63) 72 (65) 86 (68) 101 (69) SE (%) 78 (14) 82 (14) 79 (15) 76 (15) Number of awakenings, ≤ 2 min 165 (126) 197 (58) 135 (83) 123 (61) Sleep stage N1 (min) 67 (58) 95 (55) 100 (67) 94 (60) N2 (min) 205 (69) 187 (60) 170 (76) 194 (90) N3 (min) 29 (36) 53 (41) 39 (36) 18 (21) REM (min) 84 (37) 69 (29) 82 (35) 67 (31) Undeterminable (% of total epochs of all participants) 0.327 1.19 0.642 0.00389 Healthy group (N = 14) Total sleep time (min) 450 (41) 466 (38) 456 (35) 448 (40) Sleep onset latency (min) 30 (24) 26 (22) 27 (22) 26 (22) WASO (min) 36 (19) 24 (17) 33 (18) 43 (20) SE (%) 87 (5) 90 (5) 88 (5) 87 (5) Number of awakenings, ≤ 2 min 69 (39) 169 (81) 89 (48) 90 (38) Sleep stage N1 (min) 37 (11) 62 (21) 59 (25) 53 (19) N2 (min) 254 (30) 238 (26) 237 (29) 276 (34) N3 (min) 49 (22) 80 (29) 62 (17) 35 (20) REM (min) 110 (33) 85 (17) 98 (18) 84 (19) Undeterminable (% of total epochs of all participants) 0.0138 0.976 0.374 0.0554 All participants (N = 40) All data are presented as the mean value and standard deviation [mean (SD)] N1 sleep stage N1, N2 sleep stage N2, N3 sleep stage N3, REM rapid eye movement, WASO wake after sleep onset, SE sleep efficiency Note (for all tables): Sleep Scope is manufactured by SleepWell Co., Ltd. (Osaka, Japan; https://sleepwell.co.jp/sleepscope) The original article has been corrected.

Programmed death ligand 1 (PD-L1) expression on the surface of cancer cells affects the efficacy of anti-PD-1/PD-L1 immune checkpoint therapy. However, the mechanism underlying PD-L1 expression in cancer cells is not fully understood, particularly after ionizing radiation (IR). Here, we examined the impact of high linear energy transfer (LET) carbon-ion irradiation on the expression of PD-L1 in human osteosarcoma U2OS cells. We found that the upregulation of PD-L1 expression after high LET carbon-ion irradiation was greater than that induced by X-rays at the same physical and relative biological effectiveness (RBE) dose, and that the upregulation of PD-L1 induced by high LET carbon-ion irradiation was predominantly dependent on ataxia telangiectasia and Rad3-related (ATR) kinase activity. Moreover, we showed that the downstream signaling, e.g. STAT1 phosphorylation and IRF1 expression, was upregulated to a greater extent after high LET carbon-ion irradiation than X-rays, and that IRF1 upregulation was also ATR dependent. Finally, to visualize PD-L1 molecules on the cell surface in 3D, we applied immunofluorescence-based super-resolution imaging. The three-dimensional structured illumination microscopy (3D-SIM) analyses revealed substantial increases in the number of presented PD-L1 molecules on the cell surface after high LET carbon-ion irradiation compared with X-ray irradiation.

Little is known about the molecular mechanisms underlying drug-induced taste disorders, which can cause malnutrition and reduce quality of life. One of taste disorders is known adverse effects of bisphosphonates, which are administered as anti-osteoporotic drugs. Therefore, the present study evaluated the effects of risedronate (a bisphosphonate) on taste bud cells. Expression analyses revealed that farnesyl diphosphate synthase (FDPS, a key enzyme in the mevalonate pathway) was present in a subset of mouse taste bud and tongue epithelial cells, especially type III sour-sensitive taste cells. Other mevalonate pathway-associated molecules were also detected in mouse taste buds. Behavioral analyses revealed that mice administered risedronate exhibited a significantly enhanced aversion to HCl but not for other basic taste solutions, whereas the taste nerve responses were not affected by risedronate. Additionally, the taste buds of mice administered risedronate exhibited significantly lower mRNA expression of desmoglein-2 , an integral component of desmosomes. Taken together, these findings suggest that risedronate may interact directly with FDPS to inhibit the mevalonate pathway in taste bud and tongue epithelial cells, thereby affecting the expression of desmoglein-2 related with epithelial barrier function, which may lead to alterations in behavioral responses to HCl via somatosensory nerves.

The Short Physical Performance Battery (SPPB) is a well-established tool to assess the lower extremity physical performance status. The purpose of this study is to examine the impact of brain natriuretic peptide (BNP) levels and SPPB scores on short-term readmission in older patients with heart failure (HF). This prospective cohort study enrolled 325 patients with HF who were hospitalized for acute decompensated HF between November 2017 and December 2021. Variables were analyzed using the Cox proportional hazards model, receiver operating characteristic (ROC) curve, and Kaplan–Meier analysis. The 107 patients who met the inclusion criteria were divided into readmission (within 90 days of discharge; n  = 25) and non-readmission ( n  = 82) groups. Multivariate analysis revealed that BNP level and SPPB score were independent risk factors for readmission within 90 days after discharge. Patients were classified into three groups according to the BNP and SPPB cutoff values calculated using ROC curves. The risk of readmission was significantly higher in Group 3 (BNP ≥ 384 pg/mL and SPPB ≤ 7 points) than in Group 1 (BNP < 384 pg/mL and SPPB > 7 points; hazard ratio: 27.68, 95% confidence interval: 3.672 − 208.700, P  = 0.0012). Our study showed that HF patients with high BNP levels and low SPPB scores have a dramatically increased risk of readmission within 90 days of discharge.

Molluscan gastropods have long been used for studying the cellular and molecular mechanisms underlying learning and memory. One such gastropod, the pond snail , exhibits long-term memory (LTM) following both classical and operant conditioning. Using , we have successfully elucidated cellular mechanisms of learning and memory utilizing an aversive classical conditioning procedure, conditioned taste aversion (CTA). Here, we present the behavioral changes following CTA training and show that the memory score depends on the duration of food deprivation. Then, we describe the relationship between the memory scores and the monoamine contents of the central nervous system (CNS). A comparison of learning capability in two different strains of , as well as the filial 1 (F ) cross from the two strains, presents how the memory scores are correlated in these populations with monoamine contents. Overall, when the memory scores are better, the monoamine contents of the CNS are lower. We also found that as the insulin content of the CNS decreases so does the monoamine contents which are correlated with higher memory scores. The present review deepens the relationship between monoamine and insulin contents with the memory score.

Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans.

To gain a better understanding of the effects of biologics, we evaluated clinical outcomes in patients with moderate to severe exacerbations of ulcerative colitis (UC). This retrospective, multicenter study retrieved the entire clinical courses of UC patients who began treatments between 2004 and 2018. All exacerbations and clinical parameters, including treatment details for exacerbations and both remission and re-exacerbation dates, were identified during the observation period. Two different endpoints, the cumulative incidence rates of surgical resection and re-exacerbation, were evaluated separately in moderate to severe exacerbation events. Among 1401 patients, 1626 exacerbation events were determined according to a partial Mayo score (remission: < 2, mild: 2–4, moderate: 5–7, and severe: > 7). During the observation period, as administration rates of biologics increased, both surgical resection and hospitalization rates decreased, for 959 moderate to severe exacerbation events. We confirmed that biologics significantly reduced the cumulative re-exacerbation rate in moderate to severe exacerbation events during the study period compared with suboptimal therapies (a 0.507-fold decreased risk according to COX regression analysis, P  < 0.001). However, they had not enough impact in reducing the cumulative incidence rate of surgical resection in moderate to severe exacerbation events that were corticosteroid-refractory or dependent (a 0.878-fold decreased risk according to COX regression analysis, P  = 0.606). Biologics may improve remission duration, but these agents had no significant impact in reducing the risk of surgical resection in moderate to severe active UC.

Squamous cell carcinoma (SCC) is one of the most common skin cancers. Because its potential to recur and metastasize leads to a poor prognosis and significant mortality, it is necessary to develop new early diagnostic tools and new therapeutic approaches. In this study, we found protein levels of ERK1 and ERK2 were increased in SCC cell lines without changing mRNA levels and that ERK1/2 mediates abnormal cell proliferation in these cells. Then, mechanisms underlying the overexpression of ERK1/2 in SCC were investigated focusing on microRNA. We found that miR-214 is the regulator of ERK1, whereas ERK2 is regulated by miR-124 and miR-214. Expression of miR-124 and miR-214 was significantly down-regulated in SCC in vitro and in vivo. Treatment with 5-aza-deoxycytidine and trichostatin A synergistically recovered the miR-124/-214 down-regulation in SCC cell line. However, bisulphite sequencing revealed the methylation status of miR-124/-214 promoter was not increased in the SCC cell line and tumor tissue. Taken together, the down-regulation of miR-124/-214 in SCC is most likely caused, at least in part, by hypermethylation of other promoter regions rather than the miR-124/-214 promoter. Supplementation of these microRNAs in the SCC cell line reduced the abnormal cell proliferation by normalizing ERK1/2 levels. Additionally, serum concentration of miR-124 was correlated with miR-124 expression levels in the tumor tissues and inversely correlated with tumor progression. On the other hand, miR-214 was not detected in the serum. Investigation of the regulatory mechanisms of keratinocyte proliferation by microRNA may lead to develop new biomarkers and treatments using microRNA.