Phospholipase Cδ4 is required for Ca2+ mobilization essential for acrosome reaction in sperm

Zona pellucida (ZP)–induced acrosome reaction in sperm is a required step for mammalian fertilization. However, the precise mechanism of the acrosome reaction remains unclear. We previously reported that PLCδ4 is involved in the ZP-induced acrosome reaction in mouse sperm. Here we have monitored Ca2+ responses in single sperm, and we report that the [Ca2+]i increase in response to ZP, which is essential for driving the acrosome reaction in vivo, is absent in PLCδ4−/− sperm. Progesterone, another physiological inducer of the acrosome reaction, failed to induce sustained [Ca2+]i increases in PLCδ4−/− sperm, and consequently the acrosome reaction was partially inhibited. In addition, we observed oscillatory [Ca2+]i increases in wild-type sperm in response to these acrosome inducers. Calcium imaging studies revealed that the [Ca2+]i increases induced by exposure to ZP and progesterone started at different sites within the sperm head, indicating that these agonists induce the acrosome reaction via different Ca2+ mechanisms. Furthermore, store-operated channel (SOC) activity was severely impaired in PLCδ4−/− sperm. These results indicate that PLCδ4 is an important enzyme for intracellular [Ca2+]i mobilization in the ZP-induced acrosome reaction and for sustained [Ca2+]i increases through SOC induced by ZP and progesterone in sperm

A Comprehensive Study of Repetitive Transcranial Magnetic Stimulation in Parkinson's Disease

The clinical benefits of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's disease (PD) remain controversial. We performed a comprehensive study to examine whether rTMS is a safe and effective treatment for PD. Twelve PD patients received rTMS once a week. The crossover study design consisted of 4-week sham rTMS followed by 4-week real rTMS. The Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoehn and Yahr Stage, Schwab and England ADL Scale, Actigraph, Mini-Mental State Examination, Hamilton Depression Scale, Wechsler Adult Intelligence Scale-revised, and cerebral blood flow (CBF) and cerebrospinal fluid (CSF) examinations were used to evaluate the rTMS effects. Under both drug-on and drug-off conditions, the real rTMS improved the UPDRS scores significantly, while the sham rTMS did not. There were no significant changes in the results of the neuropsychological tests, CBF and CSF. rTMS seems to be a safe and effective therapeutic option for PD patients, especially in a wearing-off state

Human Blood Feeding Activity of Female Hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus（Diptera: Culicidae）

Human blood feeding activity was examined in females of hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus during long photoperiod at 25℃. Blood feeding rates of hybrids were lower than in Culex pipiens quinquefasciatus and Culex pipiens pallens, and higher than in Culex pipiens pipiens, because no females fed on human blood in Culex pipiens pipiens

Real-world clinical outcomes of nivolumab and taxane as a second- or later-line therapy for recurrent or unresectable advanced esophageal squamous cell carcinoma

BackgroundNivolumab is approved in Japan as a second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC) resistant to fluoropyrimidine and platinum-based drugs. It is also used in adjuvant and primary postoperative therapies. This study aimed to report real-world data on nivolumab use for esophageal cancer treatment.MethodsIn total, 171 patients with recurrent or unresectable advanced ESCC who received nivolumab (n = 61) or taxane (n = 110) were included. We collected real-world data of patients treated with nivolumab as a second- or later-line therapy and evaluated treatment outcomes and safety.ResultsMedian overall survival was longer and progression-free survival (PFS) was significantly longer (p = 0.0172) in patients who received nivolumab than in patients who received taxane as a second- or later-line therapy. Furthermore, subgroup analysis for second-line treatment only showed the superiority of nivolumab in increasing the PFS rate (p = 0.0056). No serious adverse events were observed.ConclusionsIn real-world practice, nivolumab was safer and more effective than taxane in patients with ESCC with diverse clinical profiles who did not meet trial eligibility criteria, including those with poor Eastern Cooperative Oncology Group performance status, comorbidities, and receiving multiple treatments

Metabolic activation of CaMKII by coenzyme A

Active metabolism regulates oocyte cell death via calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation of caspase-2, but the link between metabolic activity and CaMKII is poorly understood. Here we identify coenzyme A (CoA) as the key metabolic signal that inhibits Xenopus laevis oocyte apoptosis by directly activating CaMKII. We found that CoA directly binds to the CaMKII regulatory domain in the absence of Ca(2+) to activate CaMKII in a calmodulin-dependent manner. Furthermore, we show that CoA inhibits apoptosis not only in X. laevis oocytes but also in Murine oocytes. These findings uncover a direct mechanism of CaMKII regulation by metabolism and further highlight the importance of metabolism in preserving oocyte viability

Cryptosporidium oocyst検出法

The protozoa Cryptosporidium parvum has been identified as one of the agents responsible for numerous outbreaks of diarrheal diseases. Detection of C.parvum oocysts in clinical and environmental samples is the key in the diagnosis of cryptosporidiosis in human and in identifying a water-borne and/or food-borne outbreaks. Therfore, it is very important and necessary to have simples, sensitive and specific methods. However, no such perfect methods are available as yet. In this context, we studies the various methods available by modifying at different aspects and steps using samples collected in Nepal. This study revealed that morphological test using microscopy in combination with specific immunological is valuable for quick screening and the genetic method is effective method for identifying Cryptosporidium species

Regulation of Oocyte Apoptosis: A View from Gene Knockout Mice

Apoptosis is a form of programmed cell death that plays a critical role in cellular homeostasis and development, including in the ovarian reserve. In humans, hundreds of thousands of oocytes are produced in the fetal ovary. However, the majority die by apoptosis before birth. After puberty, primordial follicles develop into mature follicles. While only a large dominant follicle is selected to ovulate, smaller ones undergo apoptosis. Despite numerous studies, the mechanism of oocyte death at the molecular level remains elusive. Over the last two and a half decades, many knockout mouse models disrupting key genes in the apoptosis pathway have been generated. In this review, we highlight some of the phenotypes and discuss distinct and overlapping roles of the apoptosis regulators in oocyte death and survival. We also review how the transcription factor p63 and its family members may trigger oocyte apoptosis in response to DNA damage

Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance