bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Levels of Inhibin‐A and Immunoreactive Inhibin in Aged Male Wistar Rats With Testicular Leydig Cell Tumor
Authors: HERATH CHANDANA B. , WATANABE GEN , WANZHU JIN , NOGUCHI JUNKO , AKIYAMA KYOICHI , KURAMOTO KAZUNAO , GROOME NIGEL P. , TAYA KAZUYOSHI
Published: November 2023

ABSTRACT: This study was undertaken to investigate the endocrine changes that occur in male Tig: Wistar rats with Leydig cell tumors, with special reference to immunoreactive inhibin (ir‐inhibin) and its dimeric forms. Adult male rats from 2 to 28 months of age were used. Blood samples were taken to measure plasma concentrations of ir‐inhibin, inhibin‐A, inhibin‐B, 17β‐estradiol (E2), testosterone, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH). Inhibin bioactivity in both peripheral plasma and testicular extracts was also measured. Rats aged 18 months and older had testicular Leydig cell tumor. Testicular tissue sections from 27‐month‐old rats examined immunohistochemically showed strong positive staining for all 3 inhibin subunits, in particular inhibin α and βA subunits, in the tumor cells. Plasma concentrations of ir‐inhibin began to rise significantly (P < .05) at 18 months of age. High bioactivity of inhibin was detected not only in testicular extracts but also in peripheral plasma of aged rats. Thus, plasma concentrations of bioactive inhibin‐A, but not inhibin‐B, were significantly elevated with increasing age. The concentrations were significantly higher than those in normal male (P < .01) or normal female (P < .05) rats. Plasma concentrations of E2 were significantly (P < .05) elevated only at 23–24 months of age. A marked reduction (P < .05 to .001) in plasma LH and FSH concentrations was observed at 18 months of age and older. Plasma concentrations of testosterone were highest at 2 months of age and then decreased gradually and significantly (P < .05 to .001) afterward. Significant (P < .05 to .001) positive (testosterone vs LH) and negative (ir‐inhibin vs FSH, ir‐inhibin vs LH, and E2 vs FSH) correlations were observed. It is suggested that plasma inhibin‐A levels are elevated in male Tig: Wistar rats with Leydig cell tumor, and thus inhibin‐A may be used as a specific marker of testicular Leydig cell tumors. The present results also suggest that the age‐related decline in plasma gonadotropins and thus testosterone levels in Tig: Wistar rats may be due to the development of tumors of the Leydig cells rather than to aging per se.
The Inter‐Sertoli Tight Junction Permeability Barrier Is Regulated by the Interplay of Protein Phosphatases and Kinases: An In Vitro Study
Authors: LI JONATHAN C.H. , MRUK DOLORES , CHENG C. YAN
Published: November 2023

ABSTRACT: The timely opening and closing of inter‐Sertoli cell tight junctions in the rat testis are essential cellular events in the completion of spermatogenesis. They permit the passage of preleptotene and leptotene spermatocytes to cross the blood‐testis barrier from the basal compartment to the adluminal compartment of the seminiferous epithelium so that these cells can continue their further development into spermatids. However, the mechanism by which these events is regulated remains a mystery in male reproductive physiology. As part of our long‐term goal of understanding the biology of this event and its regulation, transepithelial electrical resistance (TER) across the Sertoli cell epithelia when inter‐Sertoli tight junctions were being assembled in vitro was quantified to assess the effects of different inhibitors of phosphatases and kinases on the inter‐Sertoli tight junction permeability barrier. It was shown that inhibitors of protein tyrosine phosphatases (PTPi) and inhibitors of protein Ser/Thr phosphatases (PPi) could perturb the assembly and maintenance of the inter‐Sertoli tight junction permeability barrier. Moreover, the inhibitory effects of PTPi were abolished by pretreating Sertoli cells with protein tyrosine kinase inhibitor (PTKi), which illustrates the specificity of the PTPi treatment. A cyclic adenosine monophosphate‐dependent protein kinase A (PKA) activator and inhibitors of calcium‐diacylglycerol‐dependent protein kinase C (PKC) can also perturb the inter‐Sertoli tight junction permeability barrier, which suggests that opening and closing of the inter‐Sertoli tight junctions during spermatogenesis is likely regulated, at least in part, by the PKA/PKC pathways. Needless to say, these results illustrate that the interplay of protein kinases and phosphatases, which regulate the intracellular phosphoprotein content of Sertoli cells possibly via PKA and PKC signal transduction pathways, plays a crucial role in modulating the assembly and maintenance of inter‐Sertoli tight junctions in the testis.
Efficacy of Vardenafil and Sildenafil in Facilitating Penile Erection in an Animal Model
Authors: CHOI SEONG , O'CONNELL LUKE , MIN KWEONSIK , KIM NOEL N. , MUNARRIZ RICARDO , GOLDSTEIN IRWIN , BISCHOFF ERWIN , TRAISH ABDULMAGED M.
Published: November 2023

Vardenafil and sildenafil are potent and specific phosphodiesterase type 5 (PDE 5) inhibitors. In human penile cavernosal smooth muscle cells, we have previously shown that vardenafil has a lower biochemical inhibition constant (Ki) than sildenafil. In this study, we compared the efficacy of vardenafil and sildenafil in facilitating penile erection in a rabbit model. Penile erections were elicited by submaximal (2.5 or 6 Hz) pelvic nerve stimulation (PNS) repeated every 5 minutes for 30 minutes with or without intravenous (IV) administration of vardenafil (1–30 μg/kg) or sildenafil (10–30 μg/kg). Erectile response was assessed by continuously recording intracavernosal pressure (ICP) and systemic arterial pressure (SAP). All data were expressed as a ratio of ICP:SAP. IV administration of either PDE 5 inhibitor facilitated PNS‐induced erection and increased ICP:SAP in a dose‐dependent manner, reaching peak response at approximately 5 minutes. However, the threshold dose at which facilitation of erection occurred was lower for vardenafil (3 μg/kg) than for sildenafil (10 μg/kg). At the 10‐μg/kg dose (IV), the response duration was significantly greater with vardenafil (169 ± 23 seconds) than with sildenafil (137 ± 31 seconds). Direct intracavernosal (IC) injection of 1–30 μg/kg vardenafil or sildenafil also caused dose‐dependent increases in ICP: SAP in the absence of PNS. Response durations increased in a dose‐dependent manner and lasted more than 5 times that of IV drug administration coupled with PNS. Irrespective of the route of administration (IC or IV), at equivalent doses, vardenafil was significantly more efficacious than sildenafil in facilitating pelvic nerve‐mediated penile erection and in eliciting erection in the absence of PNS. The increases in ICPs occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. On the basis of the biochemical data and physiological responses from this study, further clinical evaluation of vardenafil as treatment for erectile dysfunction is warranted.
Effect of Carboplatin on the Functional Integrity of the Human Sperm Membrane In Vitro
Authors: REITER WERNER J. , TOMEK SANDRA , ZIELINSKI CHRISTOPH C. , MARBERGER MICHAEL
Published: November 2023

Although it is well known that carboplatin is a drug that binds directly to DNA, causing DNA‐DNA and DNA‐protein crosslinks, which is the presumptive method for killing cells, the whole mechanism of action of carboplatin on spermatozoa is unclear. There are no published data in peer‐reviewed journals focused on the interaction between carboplatin and cell membranes. Therefore, the purpose of this study was to investigate the minimal concentration of carboplatin that would affect the functional integrity of the human sperm membrane in an in vitro model. Human‐ejaculated spermatozoa were obtained from 20 healthy normozoospermic donors. Solutions (SOL) of 0.5 mL of the semen samples and 0.5 mL NaCl (0.9%) containing increasing concentrations (7.5, 15, 30, and 60 ng) of carboplatin per 1 mL of SOL were prepared. Then, the hypoosmotic‐swelling (HOS) test and the eosin test were performed on these samples and compared with the control (no carboplatin) group. Significant damage to the plasma membrane in the head region (eosin test positive) and in the tail region of spermatozoa, as assessed by the HOS test, was observed in concentrations of 30 and 60 ng carboplatin per 1 mL of SOL in comparison to the values evaluated in the control group. The results demonstrate that a minimal carboplatin concentration of 30 ng/mL causes significant damage to membrane integrity of spermatozoa in healthy volunteers.
Capacitation and Induction of the Acrosome Reaction in Bull Spermatozoa With Norepinephrine
Authors: WAY AMY L. , KILLIAN GARY J.
Published: November 2023

Identification of norepinephrine (NE) within the microenvironment of the bovine oviduct suggests a potential role for catecholamines in the events surrounding fertilization. Previous studies have shown that the catecholamines capacitate and induce the acrosome reaction in spermatozoa from several species. The current project was undertaken to investigate the role of catecholamines in bovine sperm capacitation and the acrosome reaction. Freshly ejaculated bovine spermatozoa were incubated in NE (0–1000 ng/mL) and induced to acrosome‐react with lysophosphatidylcholine (LPC). Additionally, spermatozoa capacitated with heparin were incubated with NE (0–1000 ng/mL) to assess its ability to induce the acrosomereaction in capacitated spermatozoa. Concentrations of NE were chosen on the basis of physiological concentrations previously determined for bovine oviductal fluid. NE at concentrations of 10 and 20 ng/mL capacitated bovine spermatozoa after 2 hours of incubation. Additionally, spermatozoa incubated for 2 hours with heparin were induced to acrosome‐react with 10 and 20 ng/mL NE. Interestingly, higher concentrations of NE inhibited both capacitation and the acrosome reaction. Incubating spermatozoa with dopamine or epinephrine did not result in capacitation or the acrosome reaction, suggesting that the action of NE was specific to that catecholamine. The ability of NE to capacitate or induce the acrosome reaction appears to be dependent on the presence of another membrane‐destabilizing factor. Although adrenergic receptors have not been identified on spermatozoa from any species, the action of NE on spermatozoa may be a receptor‐mediated event. This study suggests a possible function for oviductal catecholamines in sperm preparation prior to fertilization.
Identification of Candidate Genes Involved in Gonocyte Development
Authors: VAN DEN HAM RENE , Van DISSEL‐EMILIANI FEDERICA M.F. , Van PELT ANS M.M.
Published: November 2023

Several germ cell tumors that occur in adult men likely originate from gonocytes that are impaired in their development. To select candidate genes that are involved in the normal development of the gonocytes, we constructed a complementary DNA (cDNA) library from rat gonocytes as well as from single, paired, and aligned A spermatogonia (As, Apr, and Aal spermatogonia, respectively), their direct descendants. Five hundred gonocyte clones were differentially screened using both libraries. Successive verification by dot blot assays yielded 7 clones that were consistently highly abundant only in the gonocyte cDNA library. Also, in situ hybridization of these clones confirmed their differential expression. They encoded for, respectively, succinate dehydrogenase, ribosomal protein S15a, and the 65‐kilodalton scaffolding subunit (α isoform) of protein phosphatase 2A. No clues regarding the nature of the remaining four clones could be found. Hence, using differential screening on both constructed cDNA libraries, we were able to select several genes that are interesting candidates for studying the molecular mechanisms of normal gonocyte development.
Exogenous Protein Kinases A and C, But Not Endogenous Prostasome‐Associated Protein Kinase, Phosphorylate Semenogelins I and II From Human Semen
Authors: EK PIA , MALM JOHAN , LILJA HANS , CARLSSON LENA , RONQUIST GUNNAR
Published: November 2023

ABSTRACT: Semenogelins I and II are the quantitatively dominating proteins in human semen. They comprise the major part of the spermentrapping gel formed at ejaculation, which subsequently liquefies due to proteolysis of the gel‐forming proteins by prostate‐specific antigen (PSA). The mechanism behind gel formation and its physiological significance is not known. We have studied phosphorylation and dephosphorylation of human semenogelins. Both were phosphorylated by protein kinases A and C (PKA and PKC, respectively) at a rate about 5 times less than that of histone. For PKA, incorporated (32P)phosphate into semenogelin approached a maximum above 1 mol/mol. Corresponding values for phosphorylation of the semenogelins with PKC were greater than 10. There was no change in the sensitivity of phosphosemenogelins to proteolysis by PSA. Serine (PKA) and serine and threonine (PKC) were the phosphate‐accepting amino acid residues, and all incorporated (32P)phosphate could be removed from the semenogelins with human acid phosphatase. Nil or very little phosphate could be detected in purified semenogelins isolated from seminal plasma. In vivo, about half the protein kinase activity in seminal plasma was bound to prostasomes. PKA but not PKC purified from prostasomes could phosphorylate specific substrates, but they could phosphorylate either of the semenogelins.
Localization of Androgen and Estrogen Receptors in Adult Male Mouse Reproductive Tract
Authors: ZHOU QING , NIE RONG , PRINS GAIL S. , SAUNDERS PHILIPPA T. K. , KATZENELLENBOGEN BENITA S. , HESS REX A.
Published: November 2023

ABSTRACT: There is considerable variation, both within and between species, in reports of nuclear steroid receptor localizations in the male reproductive tract. In this study, androgen receptor (AR) and estrogen receptors ERα and ERβ were visualized by immunohistochemistry in adult male mice reproductive tracts, including testes, efferent ductules; initial segment, caput, corpus, and cauda epididymides; and vas deferens. Antibody specificity was demonstrated by Western blot and antibody competition. In testis, AR was expressed in Leydig cells, Sertoli cells, and most peritubular cells, but not in germ cells; Sertoli cells showed more intense staining in stages VI‐VII; ERα was present in Leydig and some peritubular cells; ERβ was in Leydig, some peritubular, all Sertoli and germ cells except in spermatids and meiotic spermatocytes. In efferent ductules, AR was strongly expressed in ciliated and nonciliated epithelial cells and in stromal cells; ERα was strongly expressed in ciliated and nonciliated epithelial cells; stromal cells were negative; and ERβ was strongly expressed in ciliated and nonciliated epithelial cells and also in stromal cells. In epididymis, AR was strongly expressed in all epithelial cells (not in intraepithelial lymphocytes); ERα was strongly expressed in apical, narrow, and some basal cells of the initial segment, and in caput, principal cells of the caput, clear cells of the distal caput through cauda; stromal cells were negative in the initial segment, but more stromal cells were stained from caput to cauda; ERβ was strongly expressed in most of epithelial cells of the epididymis, but stromal cells were inconsistently stained. In vas deferens, AR was weakly expressed or absent in principal cells but moderately stained in basal cells, smooth muscle cells of stroma were stained intensely, ERα was absent in epithelial cells but present in a subepithelial smooth muscle layer, and ERβ was strongly expressed in all epithelial cells and most stromal cells. This study demonstrates that the reproductive tracts of male mice differ considerably from those of rats in expression of ARs and ERs and that caution is needed when extrapolating nuclear steroid receptor data across mammalian species.
Use of Computerized Karyometric Image Analysis for Evaluation of Human Spermatozoa
Authors: RAMOS LILIANA , HENDRIKS JAN C. M. , PEELEN PIM , BRAAT DIDI D. M. , WETZELS ALEX M. M.
Published: November 2023

ABSTRACT: The objective of this study was to evaluate a computer image system for its ability to determine morphological and nuclear semen characteristics in an integral and reproducible way. Semen samples from 19 normospermic fertile donors were used to estimate preliminary cutoff values for spermatozoa and to test the reproducibility of the system. Ten aliquots of 1 sample were used to investigate the sensitivity of the system for experimental conditions by exposure to different laboratory variables. Human spermatozoa were stained with Feulgen dye and analyzed with a magnification of 1000X. A panel of 21 parameters was measured for each sperm nucleus using the computerized karyometric image analysis (CKIA) system. Eight parameters were found to be sensitive for differentiating normal or abnormal human spermatozoa, and cutoff values for each parameter were defined for quantitative analysis. These 8 parameters were grouped into 3 categories depending on their descriptive value: morphometry, DNA condensation (stainability), and chromatin texture. Intrapatient and interpatient variabilities were tested by calculating the reliability coefficient for each of the 8 parameters as well as for each category. Reliability coefficients were all >70% (indicative of the suitability of the system to identify differences between spermatozoa). Interpatient variability (SD) was 5%. Although it was not statistically significant, a variation of 10.9% in measurements was found when the effects of experimental conditions were tested. We conclude that an objective description of the human sperm nucleus can be achieved with CKIA, yielding high interpatient and intrapatient reliability coefficients (reproducibility), thereby adding a new tool for the quantification of normal sperm.
Evaluation of Human Sperm Function After Repeated Freezing and Thawing
Authors: BANDULARATNE ENOKA , BONGSO ARIFF
Published: November 2023

ABSTRACT: Sperm storage via freezing has been useful for men who have difficulty masturbating during assisted reproductive technology (ART) programs and before impotency caused by chemotherapy, vasectomy, and other procedures. Studies were undertaken to evaluate the extent of cryoinjury to sperm after repeated freezing and thawing. The results showed that normozoospermic and oligozoospermic sperm survived after 3 repeated freeze‐thaw cycles. The inclusion of seminal plasma did not seem to protect human sperm during freezing and thawing. There were no significant differences in recovery percentages for motile, vital, and morphologically normal sperm between slow and rapid freezing methods in thaws 1, 2, and 3 of normozoospermic and oligozoospermic unwashed (u), washed (w), and washed + seminal plasma (ws) samples. However, there were significant percentage drops in the recovery of motile and vital sperm between each thaw (ie, first to second thaw, and second to third thaw) using both slow and rapid freezing for u, w, and ws samples (P < .01). There were also no significant differences in percentage recovery of motile, vital, and morphologically normal sperm between u, w, and ws samples during thaws 1 to 3 in the normozoospermic and oligozoospermic groups. Sperm were capable of fertilizing hamster oocytes microinjected with single sperms after 3 freeze‐thaw cycles as evidenced by the formation of 2 distinct pronuclei and 2 polar bodies in 22.2% and 17.2% of normozoospermic and oligozoospermic samples, respectively. The numbers of normal vital motile sperm after 3 serial freeze‐thaw cycles are adequate for bringing about fertilization via intracytoplasmic sperm injection in ART programs. Thus, leftover washed sperm in laboratories that perform in vitro fertilization can be frozen, thawed, and refrozen several times without loss of the sperms' ability to fertilize. This approach has tremendous benefits for men who have difficulty producing sperm and for those with low and declining sperm counts.
Laser Oximetry: A Novel Noninvasive Method to Determine Changes in Penile Hemodynamics in an Anesthetized Rabbit Model
Authors: CHOI SEONG , MIN KWEONSIK , KIM NOEL N. , MUNARRIZ RICARDO , GOLDSTEIN IRWIN , TRAISH ABDULMAGED M.
Published: November 2023

ABSTRACT: This study was designed to determine the utility and validity of laser oximetry in measuring changes in penile hemodynamics. Anesthetized male New Zealand White Rabbits were divided into 2 groups, and penile hemodynamics were assessed by either laser oximetry (oxyhemoglobin, deoxyhemoglobin concentration, and oxygen saturation) or intracavernosal pressure (ICP) monitoring during penile erection induced by pelvic nerve stimulation (PNS) or intracavernosal administration of phentolamine, nitroprusside, papaverine, or sildenafil. PNS caused significant frequency‐dependent increases in penile ICP. PNS also caused significant increases in penile tissue oxyhemoglobin concentrations and tissue oxygen saturation in a frequency‐dependent manner. The changes in oxyhemoglobin concentrations and oxygen saturation correlated with frequency‐dependent increases in ICP. Intracavernosal vasoactive drug administration produced significant increases in ICP, tissue oxyhemoglobin concentration, oxygen saturation, and duration of response as a function of increasing drug concentration. Laser oximetry permits reproducible and valid assessment of changes in penile hemodynamics comparable to conventional ICP measurements. Thus, we consider laser oximetry a reliable technique in evaluating penile hemodynamics. Its sensitivity in detecting small changes in oxyhemoglobin concentration and its noninvasive nature make it advantageous over invasive methods such as ICP monitoring and laser Doppler flowmetry.
LncRNA SEMA3B‐AS1 suppresses the tumor‐initiating characteristics of triple negative breast cancer via engaging in MLL4‐mediated H3K4 trimethylation
Authors: Chen Debo , Chen Zhishan , Wang Zhitang , Hong Chengye , Wang Qinglan , Yang Peidong , Huang Zhidong , Lian Weibin , Huang Yiqin , Fu Wei , Li Junjing , Hong Zhipeng
Published: November 2023

Long noncoding RNAs (lncRNAs) are crucial regulators of tumor‐initiating cells (TICs) and hold particular importance in triple negative breast cancer (TNBC). Yet, the precise mechanisms by which TIC‐associated lncRNAs influence TNBC remain unclear. Our research utilized The Cancer Genome Atlas Breast Cancer (BC) data set to identify prognostic lncRNAs. We then conducted extensive assays to explore their impact on the tumor‐initiating phenotype of TNBC cells and the underlying mechanisms. Notably, we found that low expression of lncRNA SEMA3B‐AS1 correlated with unfavorable survival in BC patients. SEMA3B‐AS1 was also downregulated in TNBC and linked to advanced tumor stage. Functional experiments confirmed its role as a TIC‐suppressing lncRNA, curtailing mammosphere formation, ALDH + TIC cell proportion, and impairing clonogenicity, migration, and invasion. Mechanistic insights unveiled SEMA3B‐AS1's nuclear localization and interaction with MLL4 (mixed‐lineage leukemia 4), triggering H3K4 methylation‐associated transcript activation and thus elevating the expression of SEMA3B, a recognized tumor suppressor gene. Our findings emphasize SEMA3B‐AS1's significance as a TNBC‐suppressing lncRNA that modulates TIC behavior. This study advances our comprehension of lncRNA's role in TNBC progression, advocating for their potential as therapeutic targets in this aggressive BC subtype.
Maternal and fetal safety outcomes after in utero stem cell injection: A systematic review
Authors: Sagar Rachel L. , Walther‐Jallow Lilian , Götherström Cecilia , Westgren Magnus , David Anna L.
Published: November 2023

Objective

To investigate the maternal and fetal safety of In utero stem cell transplantation (IUSCT).

Methods

Medline®, Embase and Cochrane library (1967−2023) search for publications reporting IUSCT in humans. Two reviewers independently screened abstracts and full‐text papers.

Results

Sixty six transplantation procedures in 52 fetuses were performed for haemoglobinopathies (n = 14), red cell/bleeding disorders (n = 4), immunodeficiencies (n = 15), storage disorders (n = 7), osteogenesis imperfecta (n = 2) and healthy fetuses (n = 10). The average gestational age was 18.9 weeks; of procedures reporting the injection route, cells were delivered by intraperitoneal (n = 37), intravenous (n = 19), or intracardiac (n = 4) injection or a combination (n = 3); most fetuses received one injection (n = 41). Haematopoietic (n = 40) or mesenchymal (n = 12) stem cells were delivered. The cell dose was inconsistently reported (range 1.8−3.3 × 109 cells total (n = 27); 2.7−5.0 × 109/kg estimated fetal weight (n = 17)). The acute fetal procedural complication rate was 4.5% (3/66); the acute fetal mortality rate was 3.0% (2/66). Neonatal survival was 69.2% (36/52). Immediate maternal and pregnancy outcomes were reported in only 30.8% (16/52) and 44.2% (23/52) of cases respectively. Four fetal/pregnancy outcomes would also classify as ≥ Grade 2 maternal adverse events.

Conclusions

Short‐, medium‐, and long‐term maternal and fetal adverse events should be reported in all IUSCT studies.
Examining the roles of labor factors, investment, and industrialization in poverty alleviation: Empirical evidence from Sumatra, Indonesia
Authors: Rambe Roosemarina Anggraini , Purmini Purmini , Alfansi Lizar , Armelly Armelly , Yusnida Yusnida
Published: November 2023

This article examines the effect of unemployment, laborer education, type of employment, gender, off‐farm worker vulnerability, investment, and industrialization levels on poverty in districts/cities in Sumatra, Indonesia. The study was conducted in 154 districts/cities in Sumatra from 2013 to 2018. Using a panel data regression model, this study found that laborer education, type of employment, gender, and industrialization level positively affected the poverty rate. By comparison, relatively higher levels of worker vulnerability and investment negatively influenced poverty. Unemployment rates did not influence poverty significantly. The policy recommendation for poverty alleviation, therefore, is the creation of jobs in sectors outside of agriculture, especially in the processing industry and service sectors, coupled with improving the quality of workers' performance through skill training. The study contributes to the literature on poverty reduction by providing insight into how labor factors, investment, and industrialization influence poverty.
Protective effects of melatonin on DEHP‐induced apoptosis and oxidative stress in prepubertal testes via the PI3K/AKT pathway
Authors: Chen Jiadong , Zhao Tianxin , Zheng Xiangqin , Kang Lian , Wang Junke , Wei Yuexin , Wu Yuhao , Shen Lianju , Long Chunlan , Wei Guanghui , Wu Shengde
Published: November 2023

Di(2‐ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, is one of the most common plasticizers and is widely used in various plastic products. DEHP induces apoptosis and oxidative stress and has been shown to have androgenic toxicity. However, the methods to combat DEHP‐induced testicular damage and the mechanisms involved remain to be elucidated. In the present study, we used melatonin, which has strong antioxidant properties, to intervene in prepubertal mice and mouse Leydig cells (TM3) treated with DEHP or its metabolite mono(2‐ethylhexyl) phthalate (MEHP). The results showed that melatonin protected against DEHP‐induced testicular damage in prepubertal mice, mainly by protecting against DEHP‐induced structural destruction of the germinal tubules and by attenuating the DEHP‐induced decrease in testicular organ coefficients and testosterone levels. Transcriptomic analysis found that melatonin may attenuate DEHP‐induced oxidative stress and apoptosis in prepubertal testes. In vitro studies further revealed that MEHP induces oxidative stress injury and increases apoptosis in TM3 cells, while melatonin reversed this damage. In vitro studies also found that MEHP exposure inhibited the expression levels of molecules related to the PI3K/AKT signaling pathway, and melatonin reversed this change. In conclusion, these findings suggest that melatonin protects against DEHP‐induced prepubertal testicular injury via the PI3K/AKT signaling pathway, and provide a theoretical basis and experimental rationale for combating male reproductive dysfunction.
Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations
Authors: Petersen Ronald C. , Graf Ana , Brady Chris , De Santi Susan , Florian Hana , Landen Jaren , Pontecorvo Mike , Randolph Christopher , Sink Kaycee M. , Carrillo Maria C. , Weber Christopher J.
Published: November 2023

Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well‐defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the basis of biomarker features and the two need to be coordinated. The Alzheimer's Association Research Roundtable (AARR) Spring 2021 meeting discussed the implementation of preclinical AD staging criteria, and provided recommendations for how they may best be incorporated into clinical trials research. Discussion also included what currently available tools for global clinical trials may best define populations in preclinical AD trials, and if are we able to differentiate preclinical from clinical stages of the disease. Well‐defined AD staging criteria are key to improving early detection, diagnostics, clinical trial enrollment, and identifying statistically significant clinical changes, and researchers discussed how emerging blood biomarkers may help with more efficient screening in preclinical stages.
Antimicrobial resistance: should vets have prescriber autonomy or formulary restriction in small animal practice?
Authors: Allerton Fergus , Granick Jennifer
Published: November 2023

Fergus Allerton and Jennifer Granick discuss the different approaches to antimicrobial stewardship and the potential implications of the ‘carrot’ (enablement) versus ‘stick’ (legislative change) strategies.
Diary of a parliamentary intern: debate around welfare of fish at slaughter
Authors: Davenport Harriet
Published: November 2023

Vet and parliamentary intern Harriet Davenport reports on the Veterinary Policy Research Foundation's work to drive awareness of the need to stun farmed fish before slaughter.
Worldsheet description of a massive type IIA superstring in
10D
Authors: Garcia del Moral M. P. , León P. , Restuccia A.
Published: November 2023

Abstract

We construct, following [1,
2], a massive M2-brane
(supermembrane) as the limit of a genus two M2-brane that becomes a twice punctured
Riemann surface with particular boundary conditions on the fields defined on the
punctures. The target space is M9 × LCD,
where LCD is a genus one light cone diagram. It
contains mass terms and a topological term associated with the non-triviality of the
target surface that, at low energies, can be associated with the presence of a
cosmological constant. We show that the supergravity background of the M2-brane
considered in this formulation requires the presence of M9-branes acting as sources.
They correspond to the 11D uplift of the characteristic D8’s of Romans supergravity.
To this end, we explicitly show that some of the background singularities of the
massive M2-brane can be reproduced by the M9-branes found by [3]. This establishes a relation between the
Romans mass and the moduli of the massive M2-brane.

When dimensionally reduced, we obtain a worldsheet Hamiltonian of a N=2
type IIA closed superstring in 10D. We denote it massive string. The corresponding massive string inherits a non-vanishing constant term from the
topological massive M2-brane that shifts the Hamiltonian. The non-vanishing
parameter is related to the non-trivial structure of the massive M2-brane background
and it can be related to the Romans mass term. It also contains a modified tension
due to the non-trivial dependence on the moduli and on the punctures associated with
the target torus.
Quantum theory of dark matter scattering
Authors: Kamada Ayuki , Kuwahara Takumi , Patel Ami
Published: November 2023

Abstract

Dark matter self-scattering is one of key ingredients for small-scale structure of the Universe, while dark matter annihilation is important for the indirect measurements. There is a strong correlation between the velocity-dependent self-scattering cross section and the Sommerfeld enhancement factor for the dark matter annihilation cross section. In this study, we formulate a direct relation between them by the use of Watson’s (initial state/final state) theorem and Omnès solution, and our formulation reproduces the Sommerfeld enhancement factor, which directly computed by solving the Schrödinger equation, from the scattering phase shift.
Dai-Freed anomaly in the standard model and topological inflation
Authors: Kawasaki Masahiro , Yanagida Tsutomu T.
Published: November 2023

Abstract

When we impose discrete symmetries in the standard model we have Dai-Freed global anomalies. However, interestingly if we introduce three right-handed neutrinos we can have an anomaly-free discrete Z4 gauge symmetry. This Z4 symmetry should be spontaneously broken down to the Z2 symmetry to generate the heavy Majorana masses for the right-handed neutrinos. We show that this symmetry breaking naturally generates topological inflation, which is consistent with the CMB observations at present and predicts a significant tensor mode with scalar-tensor ratio r > 0.03. The right-handed neutrinos play an important role in reheating processes. The reheating temperature is as high as ∼ 108 GeV, and non-thermal leptogenesis successfully takes place.
Dark dimension gravitons as dark matter
Authors: Gonzalo Eduardo , Montero Miguel , Obied Georges , Vafa Cumrun
Published: November 2023

Abstract

We consider cosmological aspects of the Dark Dimension (a mesoscopic dimension of micron scale), which has recently been proposed as the unique corner of the quantum gravity landscape consistent with both the Swampland criteria and observations. In particular we show how this leads, by the universal coupling of the Standard Model sector to bulk gravitons, to massive spin 2 KK excitations of the graviton in the dark dimension (the “dark gravitons”) as an unavoidable dark matter candidate. Assuming a lifetime for the current de Sitter phase of our universe of order Hubble, which follows from both the dS Swampland Conjecture and TCC, we show that generic features of the dark dimension cosmology can naturally lead to the correct dark matter density and a resolution of the cosmological coincidence problem, where the matter/radiation equality temperature (T ~ 1 eV) coincides with the temperature where the dark energy begins to dominate. Thus one does not need to appeal to Weinberg’s anthropic argument to explain this coincidence. The dark gravitons are produced at T ~ 4 GeV, and their composition changes as they mainly decay to lighter gravitons, without losing much total mass density. The mass of dark gravitons is mDM ∼ 1 − 100 keV today.
Superdensity with Respect to a Radon Measure on $${\mathbb {R}}^n$$
Authors: Delladio Silvano
Published: November 2023

We introduce and investigate superdensity and the density degree of sets with respect to a Radon measure on $${\mathbb {R}}^n$$

R

n

. Some applications are provided. In particular, we prove a result on the approximability of a set by closed subsets of small density degree and a generalization of Schwarz’s theorem on cross derivatives.
A Note on Invariant Description of SU(2)–Structures in Dimension 5
Authors: Niedziałomski Kamil
Published: November 2023

We develop an invariant approach to SU(2)–structures on spin 5–manifolds. We characterize (via spinor approach) the subspaces in the spinor bundle which induce the same group isomorphic to SU(2). Moreover, we show how to induce quaternionic structure on the contact distribution of the considered SU(2)–structure. We show the invariance of certain components of the covariant derivative $$\nabla \varphi $$

∇
φ

, where $$\varphi $$
φ
is any spinor field defining SU(2)–structure. This shows, as expected, that (at least some of) the intrinsic torsion modules can be derived invariantly with the spinorial approach. We conclude with the explicit description of the intrinsic torsion and the characteristic connection.
Epidemiology of Tumor-Induced Osteomalacia in Germany Based on Real World Data
Authors: May Melanie , Oheim Ralf , Bovy Leonore , Doess Axel , Maessen Dirk , Neukirch Benno , Norris Raeleesha , Williams Angela , Abrahamsen Bo
Published: November 2023

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO’s incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.
Reproductive behavior, seasonality, and distribution of three devil ray species (Mobula mobular, M. thurstoni, and M. munkiana) in the Southern Gulf of California, Mexico
Authors: Palacios Marta D. , Trejo-Ramírez Abel , Velázquez-Hernández Sidharta , Huesca-Mayorga Scarlett A. K. , Stewart Joshua D. , Cronin Melissa R. , Lezama-Ochoa Nerea , Zilliacus Kelly M. , González‑Armas Rogelio , Galván‑Magaña Felipe , Croll Donald A.
Published: November 2023

We examined the reproductive behavior (courtship and mating), seasonality and its distribution in three Mobula species, spinetail, bentfin, and Munk’s devil rays (M. mobular, M. thurstoni, and M. munkiana) in the southwestern Gulf of California, Mexico, using boat surveys (with drone and in-water observations) (n = 69 survey days), spotter planes (n = 428 flights), and citizen science observations (n = 31). We examined whether (1) reproductive grounds existed within the area for any of these species, (2) whether reproductive behavior followed seasonal patterns, and (3) if this behavior was similar among all mobula rays. We observed reproductive behavior in 221 events in 2017 and 2021–2022, for M. mobular (n = 10), M. thurstoni (n = 3), and M. munkiana (n = 208) dispersed along 312 km of the eastern Baja California Peninsula between 4 m and 6.3 km away from the coast. Most events (n = 209) occurred in the La Ventana and Ensenada de Muertos areas. Courtship was observed for M. mobular and M. thurstoni and a copulation attempt for M. munkiana, with reproductive behavior following a seasonal pattern occurring from March to August, with a peak during May (81.9% of the events). Mobula munkiana displayed previously undescribed behaviors, such as the “piggyback leaps” as a pre-copulatory position and the “courtship vortex”, where 122 individuals were observed circling in a clockwise direction for 5 h with courtship groups joining and leaving the main vortex formation. This study highlights the areas of La Ventana and Ensenada de Muertos as critical habitats for reproductive behavior of two endangered and one vulnerable devil ray species.
Split scar sign to predict complete response in rectal cancer after neoadjuvant chemoradiotherapy: systematic review and meta-analysis
Authors: Torri Giovanni Brondani , Wiethan Camila Piovesan , Langer Felipe Welter , de Oliveira Guilherme Strieder , Meirelles Alice Villa Bella , Horvat Natally , Tse Justin Ruey , Dias Adriano Basso , Altmayer Stephan
Published: November 2023

Objectives

Magnetic resonance imaging (MRI) is the modality of choice for rectal cancer initial staging and restaging after neoadjuvant chemoradiation. Our objective was to perform a meta-analysis of the diagnostic performance of the split scar sign (SSS) on rectal MRI in predicting complete response after neoadjuvant therapy.

Methods

MEDLINE, EMBASE, and Cochrane databases were searched for relevant published studies through June 2023. Primary studies met eligibility criteria if they evaluated the diagnostic performance of the SSS to predict complete response on pathology or clinical follow-up in patients undergoing neoadjuvant chemoradiation. A meta-analysis with a random-effects model was used to estimate pooled sensitivity and specificity, area under the curve (AUC), and diagnostic odds ratio (DOR) of the SSS.

Results

A total of 4 studies comprising 377 patients met the inclusion criteria. The prevalence of complete response in the studies was 21.7–52.5%. The pooled sensitivity and specificity of the SSS to predict complete response were 62.0% (95% CI, 43.5–78.5%) and 91.9% (95% CI, 78.9–97.2%), respectively. The estimated AUC for SSS was 0.83 (95% CI, 0.56–0.94) with a DOR of 18.8 (95% CI, 3.65–96.5).

Conclusion

The presence of SSS on rectal MRI demonstrated high specificity for complete response in patients with rectal cancer after neoadjuvant chemoradiation. This imaging pattern can be a valuable tool to identify potential candidates for organ-sparing treatment and surveillance.

Clinical relevance statement

SSS presents high specificity for complete response post-neoadjuvant. This MRI finding enhances rectal cancer treatment assessment and aids clinicians and patients in choosing watch-and-wait over immediate surgery, which can potentially reduce costs and associated morbidity.

Key Points

•Fifteen to 50% of rectal cancer patients achieve complete response after neoadjuvant chemoradiation and may be eligible for a watch-and-wait strategy.

•The split scar sign has high specificity for a complete response.

•This imaging finding is valuable to select candidates for organ-sparing management.
Cytosolic nucleic acid sensing and mitochondrial transcriptomic changes as early triggers of metabolic disease in db/db mice
Authors: Ludwig-Słomczyńska Agnieszka H. , Seweryn Michał T. , Wiater Jerzy , Borys Agnieszka , Ledwoń Anna , Druszczyńska Magdalena , Łabieniec-Watała Magdalena , Lis Grzegorz J. , Wołkow Paweł P.
Published: November 2023

Animal models of diabetes, such as db/db mice, are a useful tool for deciphering the genetic background of molecular changes at the initial stages of disease development. Our goal was to find early transcriptomic changes in three tissues involved in metabolism regulation in db/db mice: adipose tissue, muscle tissue and liver tissue. Nine animals (three per time point) were studied. Tissues were collected at 8, 12 and 16 weeks of age. Transcriptome-wide analysis was performed using mRNA-seq. Libraries were sequenced on NextSeq (Illumina). Differential expression (DE) analysis was performed with edgeR. The analysis of the gene expression profile shared by all three tissues revealed eight upregulated genes (Irf7, Sp100, Neb, Stat2, Oas2, Rtp4, H2-T24 and Oasl2) as early as between 8 and 12 weeks of age. The most pronounced differences were found in liver tissue: nine DE genes between 8 and 12 weeks of age (Irf7, Ly6a, Ly6g6d, H2-Dma, Pld4, Ly86, Fcer1g, Ly6e and Idi1) and five between 12 and 16 weeks of age (Irf7, Plac8, Ifi44, Xaf1 and Ly6a) (adj. p-value < 0.05). The mitochondrial transcriptomic profile also changed with time: we found two downregulated genes in mice between 8 and 12 weeks old (Ckmt2 and Cox6a2) and five DE genes between 12 and 16 weeks of age (Mavs, Tomm40L, Mtfp1, Ckmt2 and Cox6a2). The KEGG pathway analysis showed significant enrichment in pathways related to the autoimmune response and cytosolic DNA sensing. Our results suggest an important involvement of the immunological response, mainly cytosolic nucleic acid sensing, and mitochondrial signalling in the early stages of diabetes and obesity.
Niclosamide, but not ivermectin, inhibits anoctamin 1 and 6 and attenuates inflammation of the respiratory tract
Authors: Ousingsawat Jiraporn , Centeio Raquel , Schreiber Rainer , Kunzelmann Karl
Published: November 2023

Inflammatory airway diseases like cystic fibrosis, asthma and COVID-19 are characterized by high levels of pulmonary cytokines. Two well-established antiparasitic drugs, niclosamide and ivermectin, are intensively discussed for the treatment of viral inflammatory airway infections. Here, we examined these repurposed drugs with respect to their anti-inflammatory effects in airways in vivo and in vitro. Niclosamide reduced mucus content, eosinophilic infiltration and cell death in asthmatic mouse lungs in vivo and inhibited release of interleukins in the two differentiated airway epithelial cell lines CFBE and BCi-NS1.1 in vitro. Cytokine release was also inhibited by the knockdown of the Ca2+-activated Cl− channel anoctamin 1 (ANO1, TMEM16A) and the phospholipid scramblase anoctamin 6 (ANO6, TMEM16F), which have previously been shown to affect intracellular Ca2+ levels near the plasma membrane and to facilitate exocytosis. At concentrations around 200 nM, niclosamide inhibited inflammation, lowered intracellular Ca2+, acidified cytosolic pH and blocked activation of ANO1 and ANO6. It is suggested that niclosamide brings about its anti-inflammatory effects at least in part by inhibiting ANO1 and ANO6, and by lowering intracellular Ca2+ levels. In contrast to niclosamide, 1 µM ivermectin did not exert any of the effects described for niclosamide. The present data suggest niclosamide as an effective anti-inflammatory treatment in CF, asthma, and COVID-19, in addition to its previously reported antiviral effects. It has an advantageous concentration–response relationship and is known to be well tolerated.