Forward genetics combined with unsupervised classifications identified zebrafish mutants affecting biliary system formation.

Impaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested these 24 mutations affect 24 different genes. We applied unsupervised clustering algorithms to unbiasedly classify the recovered mutants into three classes. Further computational analysis revealed that each of the recovered mutations in these three classes has a unique phenotype on node-subtype composition and distribution within the intrahepatic biliary network. In addition, we found most of the recovered mutations are viable. In those mutant fish, which are already good animal models to study chronic cholestatic liver diseases, the biliary network phenotypes persist into adulthood. Altogether, this study provides unique genetic and computational toolsets that advance our understanding of the molecular pathways leading to biliary system malformation and cholestatic liver diseases.

Multiple Myeloma Therapy: Emerging Trends and Challenges.

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM. Cytopenias from cumulative treatment toxicity and disease refractoriness limit therapeutic options, hence creating an urgent need for innovative approaches effective against highly heterogeneous myeloma cell populations. Here, we present a comprehensive overview of the current and future treatment paradigm of MM, and highlight the gaps in therapeutic translations of recent advances in targeted therapy and immunotherapy. We also discuss the therapeutic potential of emerging preclinical research in multiple myeloma.

Photomediated Larvicidal Activity of Pheophorbide a against Cercaria Larvae of Fasciola gigantica.

Fasciolosis is a parasitic disease caused by Fasciola gigantica. The freshwater snail Lymnaea acuminata is the intermediate host of F. gigantica which cause endemic fasciolosis in the northern part of India. To investigate larvicidal activity of pure and laboratory extracted pheophorbide a (Pa) against cercaria larvae of F. gigantica, data were analyzed in different spectra of visible light, sunlight, and laboratory conditions. Photostimulation of chlorophyll derivative pheophorbide a (Pa) caused time and concentration dependent larvicidal activity against cercaria larvae of F. gigantica. Larvicidal activity of pure Pa under 650 nm and 400-650 nm (8 h LC50 0.006 mg/10 mL) was more pronounced than extracted Pa under same irradiations (650 nm LC50 0.12 mg/10 mL, 400-650 nm LC50 0.14 mg/10 mL). Lowest toxicity of pure (8 h LC50 0.14 mg/10 mL) and extracted Pa (8 h LC50 1.25 mg/10 mL) was noted under 400 nm. Pa was found to be toxic in laboratory conditions also. The results presented in this paper indicate that pheophorbide a possess potential larvicidal activity against Fasciola gigantica larvae in different wavelengths of visible light, sunlight, and laboratory conditions.

ANTHELMINTIC ACTIVITY OF CHLOROPHYLLIN AGAINST DIFFERENT LARVAL STAGES OF Fasciola gigantica.

Fasciolosis is a food borne zoonosis, caused by the digenetic trematode Fasciola. Freshwater lymnaeid snails are the intermediate host of the trematodes. Chlorophyllin, a semi-synthetic derivative of chlorophyll and its formulations obtained from freeze dried cow urine (FCU) had their toxicity tested against redia and cercaria larvae of F. gigantica. The larvicidal activity of chlorophyllin and its formulations were found to depend on both, time and concentration used against the larvae. Toxicity of chlorophyllin + FCU (1:1 ratio) in sunlight against redia larva (8 h LC50: 0.03 mg/mL) was more pronounced than using just chlorophyllin (8 h LC50: 0.06 mg/mL). Toxicity of chlorophyllin + FCU in sunlight against redia (8 h LC50: 0.03 mg/mL) was higher than against cercaria (8 h LC50: 0.06 mg/mL). The larvicidal activity of chlorophyllin in sunlight (redia/cercaria larvae: 8 h LC50: 0.06 mg/mL) was more pronounced than under laboratory conditions (redia: 8 h LC50: 22.21 mg/mL/, cercaria 8 h LC50: 96.21 mg/mL). Toxicity of FCU against both larvae was lower than that of chlorophyllin and chlorophyllin + FCU. Chlorophyllin and its formulations + FCU were 357.4 to 1603.5 times more effective against redia/cercaria larvae in sunlight than under laboratory conditions. The present study has shown that chlorophyllin formulations may be used as potent larvicides against fasciolosis.

Phytotherapy of chlorophyllin exposed Lymnaea acuminata: A new biotechnological tool for fasciolosis control.

Phytotherapy of chlorophyllin formulations against Fasciola gigantica infected Lymnaea acuminata under sunlight exposure was highly toxic against redia and cercaria larvae. Binary combinations (1:1 ratio) of chlorophyllin (CHL) + freeze dried cow urine (FCU) were more toxic against cercariae (8 h LC50: 9.6 mg L- 1) than single treatment with chlorophyllin (8 h LC50: 12.6 mg L- 1) in sunlight. The larvicidal activity of sunlight exposed CHL against rediae (8 h LC50: 13.5 mg L- 1) and cercariae (8 h LC50: 12.6 mg L- 1) was more pronounced than laboratory conditions CHL treatment (rediae- 8 h LC50: 305.9 mg L- 1; cercariae- 8 h LC50: 765.4 mg L- 1). Larvicidal activity of FCU was less than CHL and CHL + FCU against both redia and cercaria. Chlorophyllin and its formulations were more toxic against redia and cercaria larvae in sunlight than laboratory conditions. CHL and its different formulations may be used as potent larvicides against Fasciola gigantica larvae. Chlorophyllin formulations will be economical, ecologically sounder and their use in aquatic environment will be safe.

Toxicity of chlorophyllin in different wavelengths of visible light against Fasciola gigantica larvae.

Toxicity of chlorophyllin against redia and cercaria larvae of Fasciola gigantica was studied under irradiation of visible light. Highest and lowest toxicity of chlorophyllin against both larvae was noted under red (redia - 8 h LC50 7.88 mg/10 mL and cercaria - 11.99 mg/10 mL) and green (redia - 8 h LC50 32.12 mg/10 mL and cercaria - 8 h LC50 43.80 mg/10 mL) light irradiation respectively. The highest toxicity of chlorophyllin under red light irradiation against redia (8h LC50 7.88 mg/10 mL)/cercaria (8h LC50 11.99 mg/10 mL) was followed by white (8 h LC50 redia - 20.48 mg/10 mL, 8 h LC50 cercaria - 18.0 3mg/10 mL), blue (8 h LC50 redia - 33.10 mg/10 mL/ 8 h LC50 cercaria - 19.98 mg/10 mL) and yellow (8 h LC50 redia - 23.87 mg/10 mL/ 8 h LC50 cercaria - 23.48 mg/10 mL). Chlorophyllin treatment in darkness (control I) and without treatment of chlorophyllin, while all other conditions were same as treatment group (control II) caused no mortality of redia/cercaria larva. Chlorophyllin might be a promising new safe strategy to replace synthetic larvicide in fasciolosis control programme.