Integrin-Linked Kinase Is a Functional Mn2+-Dependent Protein Kinase that Regulates Glycogen Synthase Kinase-3β (GSK-3β) Phosphorylation

Integrin-linked kinase (ILK) is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain.Here, we have expressed full-length recombinant ILK, purified it to >94% homogeneity, and characterized its kinase activity. Recombinant ILK readily phosphorylates glycogen synthase kinase-3 (GSK-3) peptide and the 20-kDa regulatory light chains of myosin (LC(20)). Phosphorylation kinetics are similar to those of other active kinases, and mutation of the ATP-binding lysine (K220 within subdomain 2) causes marked reduction in enzymatic activity. We show that ILK is a Mn-dependent kinase (the K(m) for MnATP is approximately 150-fold less than that for MgATP).Taken together, our data demonstrate that ILK is a bona fide protein kinase with enzyme kinetic properties similar to other active protein kinases

Increased fidelity of protein synthesis extends lifespan

Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging

Adaptive strong-field control of chemical dynamics guided by three-dimensional momentum imaging.

Shaping ultrafast laser pulses using adaptive feedback can manipulate dynamics in molecular systems, but extracting information from the optimized pulse remains difficult. Experimental time constraints often limit feedback to a single observable, complicating efforts to decipher the underlying mechanisms and parameterize the search process. Here we show, using two strong-field examples, that by rapidly inverting velocity map images of ions to recover the three-dimensional photofragment momentum distribution and incorporating that feedback into the control loop, the specificity of the control objective is markedly increased. First, the complex angular distribution of fragment ions from the nω+C2D4→C2D3++D interaction is manipulated. Second, isomerization of acetylene (nω+C2H2→C2H22+→CH2++C+) is controlled via a barrier-suppression mechanism, a result that is validated by model calculations. Collectively, these experiments comprise a significant advance towards the fundamental goal of actively guiding population to a specified quantum state of a molecule

Angiomyofibroblastoma of the spermatic cord: a case report

<p>Abstract</p> <p>Introduction</p> <p>Angiomyofibroblastoma is a benign soft tissue tumor with tendency to arise in the vulva.</p> <p>Case presentation</p> <p>We report a 36-year-old Greek Caucasian man presenting with a left inguinal painless mass. This is the second case of angiomyofibroblastoma of the spermatic cord. At operation, a 4.5 cm well-circumscribed solid tumor was found adherent to the spermatic cord. The tumor consisted of spindle-shaped cells proliferating in short fascicles between numerous medium-sized blood vessels with thin and hyalinized walls. Neoplastic cells had eosinophilic cytoplasm with neither mitotic figures nor nuclear atypia. The stroma included abundant mast cells and few mature lypocytes. Immunostaining showed positivity for vimentin, CD34, desmin and smooth muscle actin. Our patient was treated by simple excision and was followed up for five years with clinical examination and ultrasonography, revealing no evidence of local recurrence or metastasis.</p> <p>Conclusion</p> <p>This unusual neoplasm should be distinguished from aggressive angiomyxoma and other myxoid malignant tumors with widespread metastatic potential.</p

Incorporating real time velocity map image reconstruction into closed-loop coherent control

We report techniques developed to utilize three-dimensional momentum information as feedback in adaptive femtosecond control of molecular dynamics. Velocity map imaging is used to obtain the three-dimensional momentum map of the dissociating ions following interaction with a shaped intense ultrafast laser pulse. In order to recover robust feedback information, however, the two-dimensional momentum projection from the detector must be inverted to reconstruct the full three-dimensional momentum of the photofragments. These methods are typically slow or require manual inputs and are therefore accomplished offline after the images have been obtained. Using an algorithm based upon an “onion-peeling” (also known as “back projection”) method, we are able to invert 1040 × 1054 pixel images in under 1 s. This rapid inversion allows the full photofragment momentum to be used as feedback in a closed-loop adaptive control scheme, in which a genetic algorithm tailors an ultrafast laser pulse to optimize a specific outcome. Examples of three-dimensional velocity map image based control applied to strong-field dissociation of CO and O2 are presented

Tbx5 is required for forelimb bud formation and continued outgrowth

Tbx5 is a T-box transcription factor expressed exclusively in the developing forelimb but not in the developing hindlimb of vertebrates. Tbx5 is first detected in the prospective forelimb mesenchyme prior to overt limb bud outgrowth and its expression is maintained throughout later limb development stages. Direct evidence for a role of Tbx5 in forelimb development was provided by the discovery that mutations in human TBX5 cause Holt-Oram Syndrome (HOS), a dominant disorder characterised predominantly by upper(fore) limb defects and heart abnormalities. Misexpression studies in the chick have demonstrated a role for this gene in limb-type specification. Using a conditional knockout strategy in the mouse to delete Tbx5 gene function in the developing forelimb, we demonstrate that this gene is also required at early limb bud stages for forelimb bud development. In addition, by misexpressing dominant-negative and dominant-activated forms of Tbx5 in the chick wing we provide evidence that this gene is also required at later stages of limb bud development for continued limb outgrowth. Our results provide a context to understand the defects observed in HOS caused by haploinsufficiency of TBX5 in human. Moreover, our results also demonstrate that limb bud outgrowth and specification of limb identity are linked by a requirement for Tbx5

Medical students’ pattern of self-directed learning prior to and during the coronavirus disease 2019 pandemic period and its implications for Free Open Access Meducation within the United Kingdom

PURPOSE: Self-directed learning (SDL) has been increasingly emphasized within medical education. However, little is known about the SDL resources medical students use. This study aimed to identify patterns in medical students’ SDL behaviors, their SDL resource choices, factors motivating these choices, and the potential impact of the coronavirus disease 2019 (COVID-19) pandemic on these variables. Methods: An online cross-sectional survey comprising multiple-choice, ranked, and free-text response questions were disseminated to medical students across all 41 UK medical schools between April and July 2020. Independent study hours and sources of study materials prior to and during the COVID-19 pandemic were compared. Motivational factors guiding resource choices and awareness of Free Open Access Meducation were also investigated. Results: The target sample was 75 students per medical school across a total of 41 medical schools within the United Kingdom (3,075 total students), and 1,564 responses were analyzed. University-provided information comprised the most commonly used component of independent study time, but a minority of total independent study time. Independent study time increased as a result of the COVID-19 pandemic (P<0.001). All sub-cohorts except males reported a significant increase in the use of resources such as free websites and question banks (P<0.05) and paid websites (P<0.05) as a result of the pandemic. Accessibility was the most influential factor guiding resource choice (Friedman’s μrank=3.97, P<0.001). Conclusion: The use of learning resources independent of university provision is increasing. Educators must ensure equitable access to such materials while supporting students in making informed choices regarding their independent study behaviors

Multiarticular chronic tophaceous gout with severe and multiple ulcerations: a case report

<p>Abstract</p> <p>Introduction</p> <p>Gout is a common inflammatory arthritis caused by articular precipitation of monosodium urate crystals. It usually affects the first metatarsophalangeal joint of the foot and less commonly other joints, such as wrists, elbows, knees and ankles.</p> <p>Case presentation</p> <p>We report the case of a 75-year-old Caucasian man with tophaceous multiarticular gout, soft-tissue involvement and ulcerated tophi on the first metatarsophalangeal joint of the left foot, on the first interphalangeal joint of the right foot and on the left thumb.</p> <p>Conclusion</p> <p>Ulcers due to tophaceous gout are currently uncommon considering the positive effect of pharmaceutical treatment in controlling hyperuricemia. Surgical treatment is seldom required for gout and is usually reserved for cases of recurrent attacks with deformities, severe pain, infection and joint destruction.</p