A diastereoselective palladium-catalyzed cyclization of allenyl hemiacetals is described. It permits the selective synthesis of 1,3-dioxane derivatives, precursors for syn-configured 1,3-diols which ...make an appearance in all of the statin representatives. The reaction allows the total synthesis of Rosuvastatin and Pitavastatin in a straightforward fashion.
•We provide a theoretical framework for variance based sensitivity analysis of time-dependent processes that guides analysis and method development.•We analyze, in the functional case, the effect of ...fixing inessential variables as determined by computing generalized Sobol’ indices both theoretically and numerically.•We present efficient approaches for computing of the generalized Sobol’ indices.•We present comprehensive numerical results that provide insight into sensitivity analysis of time-dependent processes and examine various aspects of our methods and show their effectiveness.
The global sensitivity analysis of time-dependent processes requires history-aware approaches. We develop for that purpose a variance-based method that leverages the correlation structure of the problems under study and employs surrogate models to accelerate the computations. The errors resulting from fixing unimportant uncertain parameters to their nominal values are analyzed through a priori estimates. We illustrate our approach on a harmonic oscillator example and on a nonlinear dynamic cholera model.
After the initial discovery of intermediate filament (IF)–forming proteins in 1968, a decade would elapse before they were revealed to comprise a diverse group of proteins which undergo tissue-, ...developmental stage-, differentiation-, and context-dependent regulation. Our appreciation for just how large (n = 70), conserved, complex, and dynamic IF genes and proteins are became even sharper upon completion of the human genome project. While there has been extraordinary progress in understanding the multimodal roles of IFs in cells and tissues, even revealing them as direct causative agents in a broad array of human genetic disorders, the link between individual IFs and cell differentiation has remained elusive. Here, we review evidence that demonstrates a role for IFs in lineage determination, cell differentiation, and tissue homeostasis. A major theme in this review is the function of IFs as sensors and transducers of mechanical forces, intersecting microenvironmental cues and fundamental processes through cellular redox balance.
Following the murders of George Floyd, Ahmaud Arberry, and Breonna Taylor, Black folks sought refuge within its community to experience collective healing and demand justice. A 2020 study reported ...that Black students at predominantly White institutions (PWIs) experienced racial microaggressions one to six times within 6 months time affirming the necessity for spaces that center the learning and development of Black students, like historically Black colleges and universities (HBCUs). This article explores the impact of racism on Black men's engagement with campus authority. The historic abuse Black men have faced by authority figures could have a direct impact on how they engage authority on campus. This study sought to identify if there were any significant mean differences in the likelihood of Black men engaging with Black authority figures versus White authority figures. An online survey collected data from 400 Black men assessing their preference in engagement with authority based on race. Analysis found a higher likelihood of engagement with Black authority rather than White authority regardless of the role they held on campus. This finding dispels the myth that Black men tend to be more disengaged from their academic pursuits and causes institutions to reflect on how representation effects students' willingness to engage. With Black educators making up 60% of faculty at HBCUs, HBCUs can serve as havens for Black men to find a village and safely engage in their academic experience.
To develop a reproducible animal model mimicking a novel 2-staged hepatectomy (ALPPS: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy) and explore the underlying ...mechanisms.
ALPPS combines portal vein ligation (PVL) with liver transection (step I), followed by resection of the deportalized liver (step II) within 2 weeks after the first surgery. This approach induces accelerated hypertrophy of the liver remnant to enable resection of massive tumor load. To explore the underlying mechanisms, we designed the first animal model of ALPPS in mice.
The ALPPS group received 90% PVL combined with parenchyma transection. Controls underwent either transection or PVL alone. Regeneration was assessed by liver weight and proliferation-associated molecules. PVL-treated mice were subjected to splenic, renal, or pulmonary ablation instead of hepatic transection. Plasma from ALPPS-treated mice was injected into mice after PVL. Gene expression of auxiliary mitogens in mouse liver was compared to patients after ALPPS or PVL.
The hypertrophy of the remnant liver after ALPPS doubled relative to PVL, whereas mice with transection alone disclosed minimal signs of regeneration. Markers of hepatocyte proliferation were 10-fold higher after ALPPS, when compared with controls. Injury to other organs or ALPPS-plasma injection combined with PVL induced liver hypertrophy similar to ALPPS. Early initiators of regeneration were significantly upregulated in human and mice.
ALPPS in mice induces an unprecedented degree of liver regeneration, comparable with humans. Circulating factors in combination with PVL seem to mediate enhanced liver regeneration, associated with ALPPS.
•The HNGD model was found to be unable to predict the hydride rim thickness under temperature gradient.•Two hypotheses, targeting the supersolubility and solubility, were proposed to address this ...issue.•The modified HNGD model accurately predicts the thickness of the hydride rim in a sample submitted to a temperature gradient.•The modified HNGD model predicts the hydride distribution in the case of a Zircaloy cladding with an inner Zr liner.•The modified HNGD model has been implemented and verified and is now available for general use in Bison.
Display omitted
During operation of a light water reactor, waterside corrosion of the Zircaloy nuclear fuel cladding causes hydrogen pickup. The absorbed hydrogen can redistribute in the cladding driven by existing concentration, stress, and temperature gradients. When the concentration reaches the solubility limit, hydrides precipitate. These hydrides can be more brittle than the Zircaloy matrix, so they can endanger the cladding integrity during a transient if their concentration is too high. In recent years, extensive efforts have been made to understand hydrogen behavior and to develop simulation tools able to predict hydrogen diffusion and hydride precipitation and dissolution. These efforts led to the development of the Hydride Nucleation-Growth-Dissolution (HNGD) model and its implementation into the nuclear fuel performance code Bison. While it offers a significant improvement and accurately predicts the amount of precipitates, this model fails to predict the thickness of the hydride rim under a temperature gradient. The current work presents the limitation of the HNGD model and proposes two hypotheses to improve the model’s accuracy. The first hypothesis introduces a time dependency to the supersolubility to reduce the nucleation barrier as hydrogen atoms find more favorable nucleation sites. The second one introduces a hydride content dependency to the solubility. These hypotheses were validated and implemented into Bison and are now available to the user community. The modified HNGD model accurately predicts the hydride rim thickness, and it was demonstrated that this updated model can be used in Bison to model Zircaloy cladding with a zirconium inner liner. Finally, potential experimental and numerical methods are discussed to further validate these hypotheses.
A study by Saraiva et al. (2011) demonstrated the presence of Angiotensin II receptors on the erythrocyte membrane. This little-known information should be deemed as crucial as the SARS-CoV-2 ...relationships with oxygen saturation and the Renine Angiotensin System but it currently remains unexploited. The pulmonary and cardiovascular systems are involved in any typical complications of COVID-19 but numerous other unrelated symptoms may occur. To fill the gap, we shall first emphasize some similarities between the complications of this infectious disease and Decompression Illness (DCI), which involves bubble formation. We theorized that the Angiotensin II clearance by the red blood cells could trigger the release of its oxygen content in the bloodstream. The resulting foam would worsen the widespread endotheliitis, worsen the gas exchange, trigger the coagulation process, the inflammation process and the complement pathway as typically occurs in DCI. At the end, we propose a plausible mechanism.
The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under ...specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms.
A GGGGCC
hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), fatal neurodegenerative ...diseases with no cure or approved treatments that substantially slow disease progression or extend survival. Mechanistic underpinnings of neuronal death include C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. Here, we used an adeno-associated viral vector system to deliver CRISPR/Cas9 gene-editing machineries to effectuate the removal of the HRE from the C9ORF72 genomic locus. We demonstrate successful excision of the HRE in primary cortical neurons and brains of three mouse models containing the expansion (500-600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, major hallmarks of C9-ALS/FTD, making this a promising therapeutic approach to these diseases.
PDF
