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Microsomal triglyceride transfer protein (MTP) was first identified as a major cellular protein capable of transferring neutral lipids between membrane vesicles. Its role as an essential chaperone for the biosynthesis of apolipoprotein B (apoB)-containing triglyceride-rich lipoproteins was established after the realization that abetalipoproteinemia patients carry mutations in the MTTP gene resulting in the loss of its lipid transfer activity. Now it is known that it also plays a role in the biosynthesis of CD1, glycolipid presenting molecules, as well as in the regulation of cholesterol ester biosynthesis. In this review, we will provide a historical perspective about the identification, purification and characterization of MTP, describe methods used to measure its lipid transfer activity, and discuss tissue expression and function. Finally, we will review the role MTP plays in the assembly of apoB-lipoprotein, the regulation of cholesterol ester synthesis, biosynthesis of CD1 proteins and propagation of hepatitis C virus. We will also provide a brief overview about the clinical potentials of MTP inhibition.

In addition to sphingomyelin and ceramide, sugar derivatives of ceramides, hexosylceramides (HexCer) are the major circulating sphingolipids. We have shown that silencing of ABCA1 transmembrane protein function for instance in cases of loss of function of ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels. However, proteins involved in hepatic synthesis and egress of HexCer from cells is not well known although ABCA1 seems to be indirectly controlling the HexCer plasma levels by supporting HDL synthesis. In this study, we hypothesized that protein(s) other than ABCA1 are involved in the transport of HexCer to HDL. Using an unbiased knockdown approach, we found that ATP-binding cassette transporter protein C10 (ABCC10) participates in the synthesis of HexCer and thereby affects egress to HDL in human hepatoma Huh-7 cells. Furthermore, livers from ABCC10 deficient mice had significantly lower levels of HexCer compared to wild type livers. These studies suggest that ABCC10 partakes in modulating the synthesis and subsequent efflux of HexCer to HDL in liver cells.

Decreased sagittal-plane motion at the knee during dynamic tasks has been reported to increase impact forces during landing, potentially leading to knee injuries such as anterior cruciate ligament rupture. To describe the relationship between lower extremity muscle activity and knee-flexion angle during a jump-landing task. Cross-sectional study. Research laboratory. Thirty recreationally active volunteers (15 men, 15 women: age = 21.63 ± 2.01 years, height = 173.95 ± 11.88 cm, mass = 72.57 ± 14.25 kg). Knee-flexion angle and lower extremity muscle activity were collected during 10 trials of a jump-landing task. Simple correlation analyses were performed to determine the relationship between each knee-flexion variable (initial contact, peak, and displacement) and electromyographic amplitude of the gluteus maximus (GMAX), quadriceps (VMO and VL), hamstrings, gastrocnemius, and quadriceps : hamstring (Q : H) ratio. Separate forward stepwise multiple regressions were conducted to determine which combination of muscle activity variables predicted each knee-flexion variable. During preactivation, VMO and GMAX activity and the Q : H ratio were negatively correlated with knee-flexion angle at initial contact (VMO: r = 0.382, P = .045; GMAX: r = 0.385, P = .043; Q : H ratio: r = 0.442, P = .018). The VMO, VL, and GMAX deceleration values were negatively correlated with peak knee-flexion angle (VMO: r = 0.687, P = .001; VL: r = 0.467, P = .011; GMAX: r = 0.386, P = .043). The VMO and VL deceleration values were negatively correlated with knee-flexion displacement (VMO: r = 0.631, P = .001; VL: r = 0.453, P = .014). The Q : H ratio and GM activity predicted 34.7% of the variance in knee-flexion angle at initial contact (P = .006). The VMO activity predicted 47.1% of the variance in peak knee-flexion angle (P = .001). The VMO and VL activity predicted 49.5% of the variance in knee-flexion displacement (P = .001). Greater quadriceps and GMAX activation and less hamstrings and gastrocnemius activation were correlated with smaller knee-flexion angles. This landing strategy may predispose an individual to increased impact forces due to the negative influence on knee-flexion position.

Introduction. A safe and effective transition from hospital to post-acute care is a complex and important physician competency. Milestones and Entrustable Professional Activities (EPA) form the new educational rubric in Graduate Medical Education Training. \"A safe and effective discharge from the hospital\" is an EPA ripe for educational innovation. Methods. The authors collaborated in a qualitative process called mapping to define 22 of 142 Internal Medicine (IM) curricular milestones related to the transition of care. Fifty-five participant units at an Association for Program Directors in Internal Medicine (APDIM) workshop prioritized the milestones, using a validated ranking process called Q-sort. We analyzed the Q-sort results, which rank the milestones in order of priority. We then applied this ranking to three innovative models of training IM residents in the transitions of care: Simulation (S), Discharge Clinic Feedback (DCF) and TRACER (T). Results. We collected 55 Q-sort rankings from particpants at the APDIM workshop. We then identified which milestones are a focus of the three innovative models of training in the transition of care: Simulation = 5 of 22 milestones, Discharge Clinic Feedback = 9 of 22 milestones, and TRACER = 7 of 22 milestones. Milestones identified in each innovation related to one of the top 8 prioritized milestones 75% of the time; thus, more frequently than the milestones with lower priority. Two milestones are shared by all three curricula: Utilize patient-centered education and Ensure succinct written communication. Two other milestones are shared by two curricula: Manage and coordinate care transitions across multiple delivery systems and Customize care in the context of the patient's preferences. If you combine the three innovations, all of the top 8 milestones are included. Discussion. The milestones give us a context to share individual innovations and to compare and contrast using a standardized frame. We demonstrate that the three unique discharge curricula in aggregate capture all of the highest prioritized milestones for this discharge EPA.

Introduction Although the awareness of sleep deprivation and its impact on medical trainee and physician’s performance are gaining visibility in medical world, the training to help sleep related knowledge base and actionable plan are still lacking. The goal of this educational endeavor was to help measure the current level of knowledge regarding impact of sleep and conduct an educational session to facilitate learning amongst trainees. Methods: A sleep module was designed and introduced for the first time in the mandatory resident training at Hennepin Health Care Hospital, including training programs in Psychiatry, Internal Medicine, Surgery and Emergency Medicine. 54 residents were separated in small groups of about 6-12 people. Each session, an hour long, consisted of a clinical vignette involving a medical trainee struggling due to sleep deprivation. Interactive discussion was facilitated by moderator driven questions. Questions and answers were encouraged throughout. A 5-point Likert scale pre-session survey was administered to measure baseline level of knowledge regarding sleep deprivation, resulting impairment, recognition and mitigation strategies. Post session survey was also obtained to measure the impact of session. Results The survey results showed variance in different resident groups. Surgical specialties showed less variance in their pre- and post-survey training assessments. Of note, trainees rated their “recognition” of sleep deprivation as being largely unchanged. Trainees across the board, rated increase in their assessment of strategies and resources to improve sleep after the session. Lastly, the survey revealed that Emergency Medicine (EM) residents were the most affected in terms of their sleep. Conclusion Our sleep module demonstrated overall positive impact and a trend towards improvement in the parameters of knowledge of sleep related strategies and resources accessible to medical learners. The conduction of this module also instigated further interest in ED department to conduct separate tailored session for ED residents. It paved the way beyond the duty hour restriction checklist, moving from rules to actually engaging learners in an interactive environment to promote medical trainees' wellbeing. Support (If Any)

Before the heritable basis or fitness consequences of differences in decision-making can be explored, consistent variation in decision-making among individuals must be established. The presentation of conflicting stimuli in the form of a female and a male provides a unique situation that has not been widely explored in terms of consistent individual variation. To assess consistency and plasticity in decision-making, male Siamese fighting fish were presented with a single female, single male and paired male and female presented simultaneously both when they did and did not have nests. Having a nest had a marked effect on male response, but only towards the female. Males differed from one another in the strategies they used when faced with conflicting stimuli; some males focused on the male, others on the female, and still others divided their response between the two. Most importantly, males behaved consistently yet differed from one another when context and reproductive state were constant. Finally, some males exhibited consistent plasticity as a result of social environment and/or reproductive state, the first finding of this kind. This study demonstrates the presence of consistent individual variation in decision-making, providing the groundwork for further studies into the evolution of this trait.

Typically, when a taxpayer brings a case to the Tax Court, any documents submitted as part of that case become a matter of public record. As a result, potentially sensitive and otherwise private information, including tax returns and financial documents, are available for public inspection. In Anonymous v Commissioner, the Tax Court took an unprecedented step toward protecting taxpayer privacy by both sealing the record and allowing the taxpayer to litigate anonymously to protect the taxpayer and family from risk of kidnapping if their identities and financial circumstances were revealed. The Tax Court held that the taxpayer's need for anonymity outweighed the public's interest in knowing the taxpayer's identity and the potential prejudice to the opposing party. However, the Tax Court's opinion does not provide detailed reasoning and analysis to allow future Tax Court litigants and other interested parties to understand how they might protect their privacy by litigating anonymously.

The α/β-hydrolase fold family contains mostly esterases but includes other enzymes such as hydroxynitrile lyase from (rubber tree, HNL). HNL shares 44% sequence identity and a Ser-His-Asp catalytic triad with esterase SABP2 (salicylic acid binding protein 2 from (tobacco)). To identify how large a region within HNL influences the positions of the catalytic residues, we created variants where increasingly large regions surrounding the substrate-binding site had identical amino acid sequences to those in SABP2. Variant HNL40 contains 40 mutations (two inserted amino acid residues, 38 substitutions), shares 59% sequence identity with SABP2, and is identical in sequence to SABP2 within 10 Å of the substrate-binding site. Variant HNL71 contains 31 additional substitutions for a total of 71 changes (two insertions, 69 substitutions) and shares 71% sequence identity with SABP2. The sequences within 14 Å of the substrate-binding site are identical in SABP2 and HNL71. The crystal structures of HNL40 and HNL71 show that the positions of main chain Cɑ atoms move from their positions in HNL to more closely match those in SABP2 (RMSD = 0.51 Å over 235 Cɑ atoms for HNL40, 0.41 Å over 219 Cɑ atoms for HNL71) and even more closely in the region within 10 Å of the substrate-binding site (RMSD = 0.38 Å over 58 Cɑ atoms for HNL40, 0.28 Å over 53 Cɑ atoms for HNL71). The pattern of tunnels in HNL40 and HNL71 are similar to each other and intermediate between the pattern in HNL and SABP2. Variants HNL40 and HNL71 of hydroxynitrile lyase from contain 40 and 71 mutations, respectively, to make regions surrounding the substrate-binding site identical in sequence to esterase SABP2. X-ray structures reveal increasing similarities to SABP2 in HNL40 and HNL71. hydroxynitrile lyase from with forty mutations, 8SNI, hydroxynitrile lyase from with seventy-one mutations, 9CLR.

Hydroxynitrile lyase from rubber tree (HbHNL) shares 45% identical amino acid residues with the homologous esterase from tobacco, SABP2, but the two enzymes catalyze different reactions. The x-ray structures reveal a serine-histidine-aspartate catalytic triad in both enzymes along with several differing amino acid residues within the active site. Previous exchange of three amino acid residues in the active site of HbHNL with the corresponding amino acid residue in SABP2 (T11G-E79H-K236M) created variant HNL3, which showed low esterase activity toward p-nitrophenyl acetate. Further structure comparison reveals additional differences surrounding the active site. HbHNL contains an improperly positioned oxyanion hole residue and differing solvation of the catalytic aspartate. We hypothesized that correcting these structural differences would impart good esterase activity on the corresponding HbHNL variant. To predict the amino acid substitutions needed to correct the structure, we calculated shortest path maps for both HbHNL and SABP2, which reveal correlated movements of amino acids in the two enzymes. Replacing four amino acid residues (C81L-N104T-V106F-G176S) whose movements are connected to the movements of the catalytic residues yielded variant HNL7TV (stabilizing substitution H103V was also added), which showed an esterase catalytic efficiency comparable to that of SABP2. The x-ray structure of an intermediate variant, HNL6V, showed an altered solvation of the catalytic aspartate and a partially corrected oxyanion hole. This dramatic increase in catalytic efficiency demonstrates the ability of shortest path maps to predict which residues outside the active site contribute to catalytic activity.Hydroxynitrile lyase from rubber tree (HbHNL) shares 45% identical amino acid residues with the homologous esterase from tobacco, SABP2, but the two enzymes catalyze different reactions. The x-ray structures reveal a serine-histidine-aspartate catalytic triad in both enzymes along with several differing amino acid residues within the active site. Previous exchange of three amino acid residues in the active site of HbHNL with the corresponding amino acid residue in SABP2 (T11G-E79H-K236M) created variant HNL3, which showed low esterase activity toward p-nitrophenyl acetate. Further structure comparison reveals additional differences surrounding the active site. HbHNL contains an improperly positioned oxyanion hole residue and differing solvation of the catalytic aspartate. We hypothesized that correcting these structural differences would impart good esterase activity on the corresponding HbHNL variant. To predict the amino acid substitutions needed to correct the structure, we calculated shortest path maps for both HbHNL and SABP2, which reveal correlated movements of amino acids in the two enzymes. Replacing four amino acid residues (C81L-N104T-V106F-G176S) whose movements are connected to the movements of the catalytic residues yielded variant HNL7TV (stabilizing substitution H103V was also added), which showed an esterase catalytic efficiency comparable to that of SABP2. The x-ray structure of an intermediate variant, HNL6V, showed an altered solvation of the catalytic aspartate and a partially corrected oxyanion hole. This dramatic increase in catalytic efficiency demonstrates the ability of shortest path maps to predict which residues outside the active site contribute to catalytic activity.

First-generation college student success is a matter of significance to college leaders across the United States. According to a recent study, over half of all undergraduate students are first-generation (RTI International, 2019). The problem, however, is that first-generation college students are more likely than continuing-generation students to drop out of college and never return (Cataldi et al., 2018). College leaders must find ways to retain and graduate the first-generation college students who enroll in their schools. College leaders can address retention issues by ensuring their students are socially integrated into their college and feel they belong there (Strayhorn, 2019; Tinto, 1975). Therefore, leaders of colleges that enroll first-generation college students need to actively provide academic and social engagement opportunities for their students. In this explanatory sequential mixed-methods study, I deployed a three-pronged theoretical framework to investigate how social engagement affected first-generation college students’ success and sense of belonging at a small, Catholic, private, all women’s college in the Midwest. I collected quantitative data first and then collected qualitative data to further explain the quantitative results. To conduct the study, I used the work of Ishitani (2003) to define the status of first-generation college students. I then framed my study in Tinto’s (1975) theory of student integration that concluded that students must be academically and socially integrated into their college to succeed. I also positioned my research in the context of Strayhorn’s (2019) work on student sense of belonging and supported that by applying Nodding’s (2012) work on caring as an additional lens. Through my research, I studied how first-generation college students chose to engage socially at their college. I examined the impact of their social engagement on their social integration and their sense of belonging. Through quantitative research, I found that the participants were actively engaging socially. Then, my qualitative follow-up revealed how the students became socially integrated and developed a sense of belonging through their engagement. College leaders can use the results to inform their student engagement strategies, recognizing that social engagement affects the social integration and sense of belonging for first-generation college students, as displayed in my study.