TRIM65 deficiency alleviates renal fibrosis through NUDT21-mediated alternative polyadenylation.

Chronic kidney disease (CKD) is a major global health concern and the third leading cause of premature death. Renal fibrosis is the primary process driving the progression of CKD, but the mechanisms behind it are not fully understood, making treatment options limited. Here, we find that the E3 ligase TRIM65 is a positive regulator of renal fibrosis. Deletion of TRIM65 results in a reduction of pathological lesions and renal fibrosis in mouse models of kidney fibrosis induced by unilateral ureteral obstruction (UUO)- and folic acid. Through screening with a yeast-hybrid system, we identify a new interactor of TRIM65, the mammalian cleavage factor I subunit CFIm25 (NUDT21), which plays a crucial role in fibrosis through alternative polyadenylation (APA). TRIM65 interacts with NUDT21 to induce K48-linked polyubiquitination of lysine 56 and proteasomal degradation, leading to the inhibition of TGF-ß1-mediated SMAD and ERK1/2 signaling pathways. The degradation of NUDT21 subsequently altered the length and sequence content of the 3'UTR (3'UTR-APA) of several pro-fibrotic genes including Col1a1, Fn-1, Tgfbr1, Wnt5a, and Fzd2. Furthermore, reducing NUDT21 expression via hydrodynamic renal pelvis injection of adeno-associated virus 9 (AAV9) exacerbated UUO-induced renal fibrosis in the normal mouse kidneys and blocked the protective effect of TRIM65 deletion. These findings suggest that TRIM65 promotes renal fibrosis by regulating NUDT21-mediated APA and highlight TRIM65 as a potential target for reducing renal fibrosis in CKD patients.

Gas6 Exerts Neuroprotective Effects via Restoring the Blood-Brain Barrier in Mice with Sepsis-Associated Encephalopathy.

OBJECTIVE: Sepsis-associated encephalopathy (SAE), characterized by cognitive and emotional impairments, is not well investigated in sepsis survivors. Growth arrest-specific gene 6 (Gas6) has been extensively used to treat cerebral diseases. This study aimed to evaluate the neuroprotective effects of Gas6 in post-septic mice and to determine the underlying mechanisms of action. METHODS: Mice underwent cecal ligation and puncture (CLP) for sepsis induction. Mice were then immediately injected with 6 µg of Gas6 via the tail vein, and the effect was evaluated after 24 hours. The neurological severity score (NSS) was used to assess neurological deficits in post-septic mice. In addition, brain edema was evaluated by measuring the brain water content and blood-brain barrier (BBB) permeability using Evans blue (EB) dye extravasation. Western blotting and immunofluorescence assays were performed to determine the expression of tight junction (TJ)-associated proteins such as occludin and zonula occludens-1 (ZO-1). RESULTS: Post-septic mice exhibited increased NSS, brain edema, and BBB permeability. However, acute Gas6 treatment attenuated the severe effects of sepsis on neurologic function in mice. Therefore, Gas6 attenuates brain edema and restores BBB permeability. These findings suggest that Gas6 could alleviate neurological deficits, brain edema, BBB damage, and reverse the decreased expression of occludin and ZO-1 in the brain tissue to protect against SAE. CONCLUSION: Gas6 protects against SAE by restoring the impaired BBB permeability.

The clinical implications and molecular features of intrahepatic cholangiocarcinoma with perineural invasion.

BACKGROUND: Perineural invasion (PNI) is associated with metastasis in malignancies, including intrahepatic cholangiocarcinoma (ICC), and is correlated with poor prognosis. METHODS: The study included three large cohorts: ZS-ICC and TMA cohorts from our team, MSK cohort from a public database, and a small cohort named cohort 4. Prognostic implications of PNI were investigated in MSK cohort and TMA cohort. PNI-related genomic and transcriptomic profiles were analyzed in MSK and ZS-ICC cohorts. GO, KEGG, and ssGSEA analyses were performed. Immunohistochemistry was used to investigate the relationship between PNI and markers of neurons, hydrolases, and immune cells. The efficacy of adjuvant therapy in ICC patients with PNI was also assessed. RESULTS: A total of 30.6% and 20.7% ICC patients had PNI in MSK and TMA cohorts respectively. Patients with PNI presented with malignant phenotypes such as high CA19-9, the large bile duct type, lymph node invasion, and shortened overall survival (OS) and relapse-free survival (RFS). Nerves involved in PNI positively express tyrosine hydroxylase (TH), a marker of sympathetic nerves. Patients with PNI showed high mutation frequency of KRAS and an immune suppressive metastasis prone niche of decreased NK cell, increased neutrophil, and elevated PD-L1, CD80, and CD86 expression. Patients with PNI had an extended OS after adjuvant therapy with TEGIO, GEMOX, or capecitabine. CONCLUSION: Our study deciphered the genomic features and the immune suppressive metastasis-prone niche in ICC with PNI. Patients with PNI showed a poor prognosis after surgery but a good response to adjuvant chemotherapy.

Fibrous hamartoma of infancy with bone destruction of the tibia: A case report.

BACKGROUND: Fibrous hamartoma of infancy (FHI) is a rare disease of infancy with unknown etiology. The disease mainly involves soft tissue, has no specific clinical manifestations, and is difficult to diagnose. At present, the diagnosis is mainly confirmed by histopathological examination, and the main treatment is surgical resection of the pathological tissue, which is prone to recurrence. CASE SUMMARY: A five-month-old female patient was admitted to our hospital with swelling in the right calf. Two biopsies were performed in our hospital and another hospital, respectively, confirming the diagnosis as fibrous hamartoma. After exclusion of surgical contraindications, resection was performed with clear margins of 1 cm. Radiographic examination showed tumor recurrence more than four months after the operation, and surgery was performed again to extend the resection margins to 1.5 cm. The patient is recovering well, and after a follow-up of 36 mo, shows no signs of recurrence. CONCLUSION: Our case report demonstrates that FHI should be considered in the differential diagnosis for a lower extremity mass with bone destruction. For FHI with bone destruction and unclear boundaries, excision margins of 1.5 cm could be superior to margins of 1 cm.

Collective outbreak of severe acute histoplasmosis in immunocompetent Chinese in South America: the clinical characteristics and continuous monitoring of serum cytokines/chemokines.

BACKGROUND: Acute histoplasmosis is a rare fungal disease in China. This study is aimed to summarize the clinical characteristics of the first large-scale outbreak of imported acute histoplasmosis in Chinese, so as to provide suggestions for clinical diagnosis and treatment. METHODS: We collected the symptoms, signs, laboratory examination and imaging data of 10 patients in so far the biggest outbreak of imported acute histoplasmosis in immunocompetent Chinese. Their clinical characteristics and time-varying cytokine/chemokine levels were analyzed, and rank correlation analysis between these markers was utilized to show their condition. RESULTS: The 10 patients of imported acute histoplasmosis were working without any respiratory protection in an abandoned mine tunnel in Guyana. The most common symptoms were fever and cough. Their chest CT imaging showed multiple nodular shadows in lungs. Laboratory examination showed that at admission the CRP, PCT, LDH, CysC, G-test, ß2-MG were all increased in at least 9 patients, and the CD4/CD8 was decreased to < 1 in all patients. Most cytokines/chemokines (other than IL-4, IL-12, INF-α, TNF-α) varied widely with patients and time, but their overall trend is higher at admission and decreasing gradually during hospitalization, especially for the IL-6, IL-8, IL-10 and IFN-γ. The LDH, CysC, G-test, ß2-MG, N/L, IL-6, IL-8, IL-10, IFN-γ, IL-27 are in positive associations to both CRP and PCT. CONCLUSIONS: The diagnosis of acute histoplasmosis needs a comprehensive analysis of epidemiological history, clinical symptoms and signs, and results of imaging, laboratory, microbiological and pathological examinations. Although none of the CRP, PCT, G-test, N/L, LDH, CysC, ß2-MG, IL-6, IL-8, IL-10, IFN-γ shows specificity in the diagnosis of acute histoplasmosis, there is possibility that the above factors might help in the inflammation and prognosis estimation. However, more studies and further investigation are still required for the verification.

Renal pelvis mucosal artery hemorrhage after percutaneous nephrolithotomy: a rare case report and literature review.

BACKGROUND: Following a percutaneous nephrolithotomy (PCNL) procedure, the most common complications are considered to be intraoperative and postoperative bleeding. Many patients with postoperative bleeding can be treated conservatively, causing the perirenal hematoma to resolve spontaneously. The major causes of severe postoperative bleeding are pseudoaneurysms, arteriovenous fistula, and segmental arterial injury. Typically, the first choice of treatment to manage severe bleeding complications is selective angioembolization (SAE) because of the very high success rate associated with this procedure. CASE PRESENTATION: This clinical case involves a 56-year-old man who underwent dual-channel PCNL treatment after diagnosing a left kidney staghorn stone and urinary tract infection. The operation was successful, with no apparent signs of bleeding. Tests revealed continued decreasing hemoglobin levels following the procedure. After the conservative treatment failed, renal angiography was performed immediately, indicating renal pelvis mucosal artery hemorrhage. In the three hours post-surgery, the SAE still failed to prevent bleeding. Further discussions led to formulating a new surgical plan using a nephroscope to enter the initial channel where hemostasis began. The hemostasis origin was found precisely in the mucosal artery next to the channel during the operation and was successfully controlled. CONCLUSIONS: This case reveals there is poor communication and inadequate discussions about the potential failures of an SAE procedure. Swift clinical decision-making is imperative when dealing with high-level renal trauma to prevent delays in surgery that can threaten the safety of patients.

Analysis of the clinical efficacy of two-stage revision surgery in the treatment of periprosthetic joint infection in the knee: A retrospective study.

BACKGROUND: Periprosthetic joint infection (PJI) is a catastrophic complication that can occur following total knee arthroplasty (TKA). Currently, the treatment for PJI mainly includes the use of antibiotics alone, prosthetic debridement lavage, primary revision, secondary revision, joint fusion, amputation, etc. AIM: To explore the clinical effect of two-stage revision surgery for the treatment of PJI after TKA. METHODS: The clinical data of 27 patients (3 males and 24 females; age range, 47-80 years; mean age, 66.7 ± 8.0 years; 27 knees) with PJI treated with two-stage revision surgery in our hospital between January 1, 2010 and December 31, 2020 were analyzed retrospectively. The following outcomes were compared for changes between preoperative and last follow-up results: Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS) scores, Hospital for Special Surgery (HSS) scores, knee range of motion (ROM), and infection cure rates. RESULTS: All 27 patients were followed up (range, 13-112 mo). The ESR (14.5 ± 6.3 mm/h) and CRP (0.6 ± 0.4 mg/dL) of the patients at the last follow-up were significantly lower than those at admission; the difference was statistically significant (P < 0.001). The postoperative VAS score (1.1 ± 0.7), HSS score (82.3 ± 7.1), and knee ROM (108.0° ± 19.7°) were significantly improved compared with those before the surgery; the difference was statistically significant (P < 0.001). Of the 27 patients, 26 were cured of the infection, whereas 1 case had an infection recurrence; the infection control rate was 96.3%. CONCLUSION: Two-stage revision surgery can effectively relieve pain, control infection, and retain good joint function in the treatment of PJI after TKA.

The clinical efficacy of novel vacuum suction ureteroscopic lithotripsy in the treatment of upper ureteral calculi.

OBJECTIVE: To investigate the clinical efficacy of a novel vacuum suction ureteroscopic approach in the treatment of upper ureteral calculi and to compare it with traditional rigid and flexible ureteroscopic approaches. SUBJECTS AND METHODS: A total of 160 patients with impacted upper ureteral calculi were included in this study. 50 patients underwent rigid ureteroscopic lithotripsy, 54 patients underwent flexible ureteroscopic lithotripsy, and 56 patients underwent vacuum suction ureteroscopic lithotripsy. The operative time, length of hospitalization, stone-free rate, the incidence of postoperative complications, and total treatment cost were compared among the three groups. Subgroup analysis was performed based on the stone diameter over and below 1.5 cm. RESULTS: All operations were performed successfully, and there were no cases converted to open surgery. Compared with the other 2 groups, the vacuum suction ureteroscopy group had a higher stone-free rate at 3-5 days (90.0% vs. 61.9% vs. 55.6%, P < 0.05) and 1 month (96.4% vs. 77.7% vs. 74.0%, P < 0.05) postoperatively. In subgroup analysis, the stone-free rate of the vacuum suction ureteroscopy group was significantly higher when the stone diameter was > 1.5 cm at 1 month postoperatively (P < 0.05) compared with that in the other 2 groups; however, there were no differences in postoperative complications. (P > 0.05). CONCLUSION: The novel vacuum suction ureteroscopic lithotripsy has significantly improved the stone-free rate especially in complicated cases, compared with that in rigid and flexible approaches; however, the complication and cost were not increased.

Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice.

OBJECTIVES: The activation of brown adipose tissue (BAT) is considered as a promising therapeutic target for obesity. APPL1 (Adaptor protein containing the Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif) is an intracellular adaptor protein and its genetic variation is correlated with BMI and body fat distribution in diabetic patients. However, little is known about the roles of APPL1 in BAT thermogenesis. MATERIALS/METHODS: In this study, adipose tissue specific knockout (ASKO) mice were generated to evaluate APPL1's role in BAT thermogenesis in vivo, and possible signaling pathways were further explored in cultured brown adipocytes. RESULTS: After high fat diet challenge, APPL1 ASKO mice developed more severe obesity, glucose intolerance and insulin resistance compared with control mice. Metabolic cage study showed that APPL1 deficiency impaired energy expenditure and adaptive thermogenesis in ASKO mice. PET-CT analysis showed decreased standardized uptake value (SUV) in the inter-scapular region which indicated impaired BAT activity in ASKO mice. Further study showed deletion of APPL1 attenuated brown fat specific gene expression, such as UCP1 and PGC1α in both BAT and brown adipocytes. In cultured brown adipocytes, upon cAMP stimulation, APPL1 shuttled from cytosol to nuclei. Co-IP and ChIP study showed that APPL1 could directly interact with histone deacetylase 3 (HDAC3) to mediate chromatin remodeling and UCP1 gene expression. CONCLUSIONS: Our data demonstrated the essential role of APPL1 in regulating brown adipocytes thermogenesis via interaction with HDAC3, which may have potential therapeutic implications for treatment of obesity.

Butenolide, a Marine-Derived Broad-Spectrum Antibiofilm Agent Against Both Gram-Positive and Gram-Negative Pathogenic Bacteria.

Bacterial biofilm can cause nosocomial recurrent infections and implanted device secondary infections in patients and strongly promotes development of pathogenic drug resistance in clinical treatments. Butenolide is an effective anti-macrofouling compound derived from a marine Streptomyces sp., but its antibiofilm efficacy remains largely unexplored. In the present study, the antibiofilm activities of butenolide were examined using biofilms formed by both Gram-positive and Gram-negative pathogenic model species. Four Escherichia coli strains, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA) were used as targets in antibiofilm assays that examined the effects of butenolide, including the following: (i) on bacterial growth; (ii) in inhibiting biofilm formation and eradicating mature biofilm; (iii) on biofilm structures. In addition, the synergistic effect between butenolide with tetracycline was also examined. Butenolide not only effectively inhibited the biofilm formation but also eradicated pre-formed biofilms of tested bacteria. Fractional inhibitory concentration index (FICI) indicated that butenolide was a potential tetracycline enhancer against E. coli, P. aeruginosa, and MRSA. These results indicated that butenolide may hold a great potential as an effective antibiofilm agent to control and prevent biofilm-associated infections in future clinical treatments.

Benthodytes marianensis, a new species of abyssal elasipodid sea cucumbers (Elasipodida: Psychropotidae) from the Mariana Trench area.

Benthodytes marianensis sp. nov., is described from the Mariana Trench at the depth of 5567 m. This is the thirteenth species in Benthodytes Théel, 1882. The new species has a broad brim around the body, dark violet skin, 9 pairs of large dorsal papillae with other papillae of equal or smaller size situated elsewhere, forming two zigzag rows, and some minute papillae scattered around the anterior region. Body wall ossicles are rods, crosses with three or four arms and central apophyses, and crosses of an unusual type. Crosses with four arms and central bipartite, tripartite and tetrapartite apophyses and peculiar cross-shaped ossicles with high apophyses ending in two horizontal arms are present in the dorsum. Large rod-shaped ossicles with bipartite apophyses and crosses with three or four arms and rudimentary apophyses are present on the ventrum. B. marianensis is morphologically most similar to B. incerta, but it is distinguished from B. incerta by the number and arrangement of dorsal large papillae, the broad brim and details of ossicle morphology. The phylogenetic analyses based on (16S, COI) and nuclear genes (H3) all confirm the morphological identification.

Acuticoccus kandeliae sp. nov., isolated from rhizosphere soil of the mangrove plant Kandelia, and emended description of Acuticoccus yangtzensis.

A novel bacterial strain, J103T, was isolated from rhizosphere soil of the mangrove plant Kandelia in Mai Po Inner Deep Bay Ramsar Site, Hong Kong. The strain was aerobic, Gram-stain-negative, oval-shaped with folds in the middle, non-motile and non-spore-forming. It grew at temperatures of 20-30 °C (optimum, 25-30 °C), at pH 6.0-9.0 (optimum pH 6.0) and at NaCl concentrations of 0.5-5.0 % (w/v) (optimum 1.0-2.0 %). Strain J103T was able to reduce nitrate to nitrite, and hydrolyse urea, Tween 40 and Tween 60. The major polar lipids were aminolipid, glycolipid, phosphatidylcholine and phosphatidylglycerol. The major fatty acids were C18 : 1ω7c and C19 : 0 cyclo ω8c. The respiratory quinone was Q-10. The DNA G+C content was 68.5 mol%. Sequence analysis of the 16S rRNA gene indicated that strain J103T belongs to the genus Acuticoccus, within the family Rhodobacteraceae. The closest phylogenetic neighbour was Acuticoccus yangtzensis JL1095T, showing 96.2 % 16S rRNA gene sequence similarity. The genome size of strain J103T was 6 478 100 bp. The average nucleotide identity and digital DNA-DNA hybridization values between strain J103T and Acuticoccus yangtzensis JL1095T were 75.44 and 16.43 %, respectively. Characterization based on phylogenetic, phenotypic, chemotaxonomic and genomic evidence demonstrated that strain J103T represents a novel species of the genus Acuticoccus, for which the name Acuticoccus kandeliae sp. nov. is proposed. The type strain is J103T (=DSM 104434T=MCCC 1K03288T).

Euzebya rosea sp. nov., a rare actinobacterium isolated from the East China Sea and analysis of two genome sequences in the genus Euzebya.

Rare Actinobacteria, known as non-Streptomyces, hold great potential to produce new bioactive compounds for drug development. A strain designated DSW09T, which belongs those rare Actinobacteria, was isolated from surface seawater of the East China Sea. The cells were aerobic, Gram-positive, non-motile, non-spore-forming and rod-shaped (0.4 µm wide and 1.5-4.0 µm long). The closest relative was Euzebya tangerina F10T (96.46 % of 16S rRNA gene similarity). Cell growth occurred at 15-45 °C (optimum, 25-30 °C), at pH 6.0-9.0 (pH 6.0-7.0) and at NaCl concentrations of 0.5-5.0 % (w/v; 1.0-4.0 %). The major cellular fatty acids were summed feature 3 (comprising C16 : 1ω7c and/or C15 : 0iso 2OH), C17 : 1ω8c and C16 : 0. The predominant polar lipid was diphosphatidylglycerol. The predominant menaquinone was MK-9(H4). The cell-wall peptidoglycan was A1 γ-type, containing meso-DPA. The major cell-wall sugars were rhamnose and ribose. The genome size was 5 509 297 bp with a 71.29 mol% G+C content for strain DSW09T, while 4 781 440 bp with a 68.87 mol% G+C content for E. tangerina F10T. The average nucleotide identity and digital DNA-DNA hybridization values between strain DSW09T and E. tangerina F10T were 73.44 % and 16.43 %, respectively. Based on phylogenetic, phenotypic, chemotaxonomic evidence and genomic analyses, strain DSW09T is a novel species of genus Euzebya, for which the name Euzebya rosea sp. nov. is proposed. The type strain is DSW09T (=DMS 104446T=MCCC 1K03290T).

Ruegeria kandeliae sp. nov., isolated from the rhizosphere soil of a mangrove plant Kandelia candel.

A Gram-negative, rod-shaped and motile bacterium, designated strain J95T, was isolated from the rhizosphere soil of a mangrove plant Kandeliacandel (L.) Druce in Mai Po Nature Reserve, Hong Kong. Growth of strain J95T was observed at pH 5.0-8.5 (optimum, 6.0-7.0), between 10-40 °C (30-37 °C) and in the presence of 0-9 % (w/v) NaCl (0.5-3 %). Chemotaxonomic analysis showed ubiquinone-10 as the predominant respiratory quinone and C18 : 1ω7c and C19 : 0 cycloω8c as the major fatty acids. The major polar lipids were lipid, aminolipid, phospholipid, phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine. The genomic contained a circular chromosome of 5.48 Mb with a DNA G+C content of 65.7 mol%. The genome included 5299 genes. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain J95T belongs to the genus Ruegeria with highest sequence similarity (96.8 %) to the type strain Ruegeria marina ZH17T. The combined phenotypic, chemotaxonomic and phylogenetic data suggested that strain J95T represents a novel species of the genus Ruegeria, for which the name Ruegeria kandeliae sp. nov. is proposed. The type strain is J95T (=MCCC 1K03284T=DSM 104293T).

PKA-RIIB Deficiency Induces Brown Fatlike Adipocytes in Inguinal WAT and Promotes Energy Expenditure in Male FVB/NJ Mice.

Obesity has become the most common metabolic disorder worldwide. Promoting brown adipose tissue (BAT) and beige adipose tissue formation, and therefore, a functional increase in energy expenditure, may counteract obesity. Mice lacking type IIß regulatory subunit of adenosine 3',5' cyclic monophosphate (cAMP)-dependent protein kinase A (PKA-RIIB) display reduced adiposity and resistance to diet-induced obesity. PKA-RIIB, encoded by the Prkar2b gene, is most abundant in BAT and white adipose tissue (WAT) and in the brain. In this study, we show that mice lacking PKA-RIIB have increased energy expenditure, limited weight gain, and improved glucose metabolism. PKA-RIIB deficiency induces brownlike adipocyte in inguinal WAT (iWAT). PKA-RIIB deficiency also increases the expression of uncoupling protein 1 and other thermogenic genes in iWAT and primary preadipocytes from iWAT through a mechanism involving increased PKA activity, which is represented by increased phosphorylation of PKA substrate, cAMP response element binding protein, and P38 mitogen-activated protein kinase. Our study provides evidence for the role of PKA-RIIB deficiency in regulating thermogenesis in WAT, which may potentially have therapeutic implications for the treatment of obesity and related metabolic disorders.

Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats.

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-∞ of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb-drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.

Migraine in the era of precision medicine.

Migraine is a common neurovascular disorder in the neurologic clinics whose mechanisms have been explored for several years. The aura has been considered to be attributed to cortical spreading depression (CSD) and dysfunction of the trigeminovascular system is the key factor that has been considered in the pathogenesis of migraine pain. Moreover, three genes (CACNA1A, ATP1A2, and SCN1A) have come from studies performed in individuals with familial hemiplegic migraine (FHM), a monogenic form of migraine with aura. Therapies targeting on the neuropeptids and genes may be helpful in the precision medicine of migraineurs. 5-hydroxytryptamine (5-HT) receptor agonists and calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated efficacy in the acute specific treatment of migraine attacks. Therefore, ongoing and future efforts to find new vulnerabilities of migraine, unravel the complexity of drug therapy, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with migraine.

Three new species of freshwater Macrostomum (Platyhelminthes, Macrostomida) from southern China.

Macrostomum is a diverse genus of turbellarians with more than 180 species described from around the world. However, the Macrostomum fauna in China is poorly known. In this study, three new species of freshwater Macrostomum were described from southern China based on morphology of the penis stylet, an important character for species identification in this genus. In M. heyuanensis n. sp., the penis stylet bends 108° leftwards at its 1/2 length then backwards besides the distal opening, and the terminal region is thicker than other parts of penis stylet. In M. dongyuanensis n. sp., the penis stylet is J-shaped, with the opening at the tail end. In M. bicaudatum n. sp., the penis stylet is C-shaped, with the upper margin of the distal end longer but slimmer than the lower margin. In addition, molecular phylogenetic analyses were conducted to aid the classification of the novel species. Finally, their habitat and taxonomic status are compared and discussed.

Pacific white shrimp (Litopenaeus vannamei) vitellogenesis-inhibiting hormone (VIH) is predominantly expressed in the brain and negatively regulates hepatopancreatic vitellogenin (VTG) gene expression.

Ovarian maturation in crustaceans is temporally orchestrated by two processes: oogenesis and vitellogenesis. The peptide hormone vitellogenesis-inhibiting hormone (VIH), by far the most potent negative regulator of crustacean reproduction known, critically modulates crustacean ovarian maturation by suppressing vitellogenin (VTG) synthesis. In this study, cDNA encoding VIH was cloned from the eyestalk of Pacific white shrimp, Litopenaeus vannamei, a highly significant commercial culture species. Phylogenetic analysis suggests that L. vannamei VIH (lvVIH) can be classified as a member of the type II crustacean hyperglycemic hormone family. Northern blot and RT-PCR results reveal that both the brain and eyestalk were the major sources for lvVIH mRNA expression. In in vitro experiments on primary culture of shrimp hepatopancreatic cells, it was confirmed that some endogenous inhibitory factors existed in L. vannamei hemolymph, brain, and eyestalk that suppressed hepatopancreatic VTG gene expression. Purified recombinant lvVIH protein was effective in inhibiting VTG mRNA expression in both in vitro primary hepatopancreatic cell culture and in vivo injection experiments. Injection of recombinant VIH could also reverse ovarian growth induced by eyestalk ablation. Furthermore, unilateral eyestalk ablation reduced the mRNA level of lvVIH in the brain but not in the remaining contralateral eyestalk. Our study, as a whole, provides new insights on VIH regulation of shrimp reproduction: 1) the brain and eyestalk are both important sites of VIH expression and therefore possible coregulators of hepatopancreatic VTG mRNA expression and 2) eyestalk ablation could increase hepatopancreatic VTG expression by transcriptionally abolishing eyestalk-derived VIH and diminishing brain-derived VIH.

The type III secretion system of Vibrio alginolyticus induces rapid apoptosis, cell rounding and osmotic lysis of fish cells.

Vibrio alginolyticus is a Gram-negative bacterium and has been recognized as an opportunistic pathogen in humans as well as marine animals. However, the virulence mechanisms for this species of Vibrio have not been elucidated. This study characterized multiple mechanisms that induce cell death in fish cells upon infection with a V. alginolyticus strain, ZJO. The bacterium required its type III secretion system (T3SS) to cause rapid death of infected fish cells. Dying cells exhibited some features of apoptotic cells, such as membrane blebbing, nuclear condensation and DNA fragmentation. Further studies showed that caspase-3 was activated by the T3SS of the ZJO strain, confirming that infection with V. alginolyticus rapidly induces T3SS-dependent apoptosis in fish cells. Infection with the ZJO strain also led to membrane pore formation and release of cellular contents from infected fish cells, as evidenced by lactate dehydrogenase release and the uptake of a membrane-impermeable dye. Importantly, inhibition of apoptosis did not prevent ZJO-infected cells from releasing cellular contents and did not block cell rounding. Taken together, these data demonstrate that infection with V. alginolyticus may promote at least three different T3SS-dependent events, which lead to the death of fish cells. This study provides an important insight into the mechanism used by Vibrio species to cause host-cell death.