Understanding diet is critical for conservation of endangered predators. Southern Resident killer whales (SRKW) (Orcinus orca) are an endangered population occurring primarily along the outer coast ...and inland waters of Washington and British Columbia. Insufficient prey has been identified as a factor limiting their recovery, so a clear understanding of their seasonal diet is a high conservation priority. Previous studies have shown that their summer diet in inland waters consists primarily of Chinook salmon (Oncorhynchus tshawytscha), despite that species' rarity compared to some other salmonids. During other times of the year, when occurrence patterns include other portions of their range, their diet remains largely unknown. To address this data gap, we collected feces and prey remains from October to May 2004-2017 in both the Salish Sea and outer coast waters. Using visual and genetic species identification for prey remains and genetic approaches for fecal samples, we characterized the diet of the SRKWs in fall, winter, and spring. Chinook salmon were identified as an important prey item year-round, averaging ~50% of their diet in the fall, increasing to 70-80% in the mid-winter/early spring, and increasing to nearly 100% in the spring. Other salmon species and non-salmonid fishes, also made substantial dietary contributions. The relatively high species diversity in winter suggested a possible lack of Chinook salmon, probably due to seasonally lower densities, based on SRKW's proclivity to selectively consume this species in other seasons. A wide diversity of Chinook salmon stocks were consumed, many of which are also at risk. Although outer coast Chinook samples included 14 stocks, four rivers systems accounted for over 90% of samples, predominantly the Columbia River. Increasing the abundance of Chinook salmon stocks that inhabit the whales' winter range may be an effective conservation strategy for this population.
Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key ...cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway
. Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis.
Macrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of ...energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation.
We used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects.
We found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration.
Reduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.
We explored the application of a machine learning algorithm for the timely detection of potential abusive head trauma (AHT) using the first free-text note of an encounter and demographic information.
...First free-text physician notes and demographic information were collected for children under 5 years of age at a Level 1 Trauma Center. The control group, which included patients with head/neck injury, was compared to those with AHT diagnosed by the Child Protective Team. Differential scores accounted for words overrepresented in AHT patient vs. control notes. Sentiment scores were reflective of note positivity/negativity and subjectivity scores accounted for note subjectivity/objectivity. The composite scores reflected the patient’s differential score modified by the subjectivity score. Composite, sentiment, and subjectivity scores combined with demographic information trained a Random Forest (RF) machine learning algorithm to predict AHT.
Final composite scores with demographic information were highly associated with AHT in a test dataset. The control group included 587 patients and the test group included 193 patients. Combining composite scores with demographic information into the RF model improved AHT classification area under the curve (AUC) from 0.68 to 0.78, with an overall accuracy of 84%. Feature importance analysis of our RF model revealed that composite score, sentiment, age, and subjectivity were the most impactful predictors of AHT. The sentiment was not significantly different between control and AHT notes (p = 0.87), while subjectivity trended higher for AHT notes (p = 0.081).
We conclude that a machine learning algorithm can recognize patterns within free-text notes and demographic information that aid in AHT detection in children.
III
The complex cis-Ru(phpy)(phen)(CH3CN)2+ (phpy=2-phenylpyridine, phen=1,10–phenanthroline) was investigated as a potential photodynamic therapy (PDT) agent. This complex presents desirable ...photochemical characteristics including a low energy absorption tail extending into the PDT window (600–850nm) and photoinduced exchange of the CH3CN ligands, generating a species analogous to the chemotherapy drug cisplatin. Furthermore, photochemical reactivity can be controlled through selective irradiation into the Ru-phen singlet metal-to-ligand charge transfer (1MLCT) band (λirr=500nm) of Ru(phpy)(phen)(CH3CN)2+ in the presence of excess t-butylammonium chloride (TBACl) resulting in efficient photoinduced production of Ru(phpy)(phen)(CH3CN)Cl (Φ=0.25). This lower energy irradiation resulted in greater quantum yield of photosubstitution when compared to direct irradiation into the Ru-phpy 1MLCT peak (λirr=450nm; Φ=0.08) in CH2Cl2. It was found that the lower quantum yield observed for irradiation into the Ru→phpy−1MLCT band results from significant orbital mixing of the phpy− ligand with the t2g-type filled set in the metal, giving this state significant ligand-centered character. Lastly, this complex produced a decrease in the mobility of linearized ds-DNA when irradiated with λirr≥420nm, indicative of covalent binding by the transition metal complex similar to that observed for cisplatin. No change in mobility was found for the same samples kept in the dark indicating, unlike cisplatin, DNA binding of cis-Ru(phpy)(phen)(CH3CN)2+ only occurs with the activation of light. These observations support the use of cis-Ru(phpy)(phen)(CH3CN)2+ as a potential PDT agent by the photoinduced generation of a cisplatin analog.
The complex cis-Ru(phpy)(phen)(CH3CN)2+ (phpy=2-phenylpyridine, phen=1,10–phenanthroline) was investigated as a potential photodynamic therapy (PDT) agent. This complex presents desirable photochemical characteristics including a low energy absorption tail extending into the PDT window (600–850nm). Furthermore, photochemical reactivity can be controlled through selective irradiation into the Ru-phen 1MLCT band of Ru(phpy)(phen)(CH3CN)2+ resulting in efficient photoinduced production of Ru(phpy)(phen)(CH3CN)Cl (Φ=0.25). Display omitted
► Ligand exchange and covalent DNA binding with irradiation in the PDT window by ruthenium complex. ► Significant ligand-metal orbital mixing results in irradiation at lower energies producing greater reactivity than those at higher energies. ► Decrease in mobility is observed upon irradiation of ds-DNA in the presence of the complex and no change in mobility is observed in the dark.
Cytotoxicity of cyclometallated ruthenium complexes: the role of ligand exchange on the activity Palmer, Alycia M.; Peña, Bruno; Sears, R. Bryan ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
07/2013, Letnik:
371, Številka:
1995
Journal Article
Recenzirano
Odprti dostop
The cyclometallated Ru(II) complexes cis-Ru(phpy)(phen)(CH3CN)2(PF6) (1; phpy−=deprotonated 2-phenylpyridine, phen=1,10-phenanthroline) and cis-Ru(phpy)(bpy)(CH3CN)2(PF6) (2; bpy=2,2′-bipyridine) ...were investigated as potential agents for photodynamic therapy. The presence of phpy− in the coordination sphere results in a red-shift of the Ru→phen and Ru→bpy metal-to-ligand charge transfer of 1 and 2, respectively, thus improving the tissue penetration of light while maintaining the efficient photo-induced ligand exchange required for DNA binding. The 14-fold enhancement of OVCAR-5 cell death that occurs upon irradiation with 690 nm light can be attributed to photo-aquation. The role of glutathione (GSH) on the toxicity of the complex was also explored. Complexes 1 and 2 undergo ligand substitution in the presence of GSH in the dark, such that the metal may covalently bind to biomolecules. The combination of photo-induced ligand exchange and GSH-facilitated ligand exchange may explain the observed cytotoxicity.
The cyclometallated Ru(II) complexes cis-Ru(phpy) (phen)(CH₃CN)₂(PF₆) (1; phpy ̅ = deprotonated 2-phenylpyridine, phen = 1,10-phenanthroline) and cis-Ru(phpy)(bpy)(CH₃CN)₂(PF₆) (2; bpy = ...2,2'-bipyridine) were investigated as potential agents for photodynamic therapy. The presence of phpy ̅ in the coordination sphere results in a red-shift of the Ru → phen and Ru → bpy metal-to-ligand charge transfer of 1 and 2, respectively, thus improving the tissue penetration of light while maintaining the efficient photo-induced ligand exchange required for DNA binding. The 14-fold enhancement of OVCAR-5 cell death that occurs upon irradiation with 690 nm light can be attributed to photo-aquation. The role of glutathione (GSH) on the toxicity of the complex was also explored. Complexes 1 and 2 undergo ligand substitution in the presence of GSH in the dark, such that the metal may covalently bind to biomolecules. The combination of photo-induced ligand exchange and GSH-facilitated ligand exchange may explain the observed cytotoxicity.
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