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Bipedalism is unique among mammals. Until modern times, a fall and resulting leg fracture could be fatal. Balance maintenance after a destabilizing event requires instantaneous decision making. The vestibular system plays an essential role in this process, initiating an emergency response. The afferent otolithic neural response is the first directionally oriented information to reach the cortex, and it can then be used to initiate an appropriate protective response. Some vestibular efferent axons feed directly into type I vestibular hair cells. This allows for rapid vestibular feedback via the striated organelle (STO), which has been largely ignored in most texts. We propose that this structure is essential in emergency fall prevention, and also that the system of sensory detection and resultant motor response works by having efferent movement information simultaneously transmitted to the maculae with the movement commands. This results in the otolithic membrane positioning itself precisely for the planned movement, and any error is due to an unexpected external cause. Error is fed back via the vestibular afferent system. The efferent system causes macular otolithic membrane movement through the STO, which occurs simultaneously with the initiating motor command. As a result, no vestibular afferent activity occurs unless an error must be dealt with.

When controlling the process of improving the quality of seeds by separating on a spectrometric basis, the primary information about the state of Scots pine seeds is carried by the wavelengths of optical fluxes and their amplitudes. The algorithm for analyzing the required characteristics of small forest seeds in the infrared range is a corresponding sequence of logical terms that provide the ability to determine the specified seed parameters by a combination of spectral frequencies and light flux amplitudes taken from the corresponding photodetectors. At ΔС = 0.5, the efficiency of the algorithm was 77.6 %, and at ΔС = 0.9, respectively, 99.5 %. In this regard, the choice of ΔС is the result of a compromise between the cost of rejection of high-quality seeds and losses when using unrecognized low-quality seeds and it is made according to the results of relevant experiments.

Abstract Diprotodontians are the morphologically and ecologically most diverse order of marsupials. However, an approximately 30-million-year gap in the Australian terrestrial vertebrate fossil record means that the first half of diprotodontian evolution is unknown. Fossil taxa from immediately either side of this gap are therefore critical for reconstructing the early evolution of the order. Here we report the likely oldest-known koala relatives (Phascolarctidae), from the late Oligocene Pwerte Marnte Marnte Local Fauna (central Australia). These include coeval species of Madakoala and Nimiokoala, as well as a new probable koala (?Phascolarctidae). The new taxon, Lumakoala blackae gen. et sp. nov., was comparable in size to the smallest-known phascolarctids, with body-mass estimates of 2.2–2.6 kg. Its bunoselenodont upper molars retain the primitive metatherian condition of a continuous centrocrista, and distinct stylar cusps B and D which lacked occlusion with the hypoconid. This structural arrangement: (1) suggests a morphocline within Phascolarctidae from bunoselenodonty to selenodonty; and (2) better clarifies the evolutionary transitions between molar morphologies within Vombatomorphia. We hypothesize that the molar form of Lumakoala blackae approximates the ancestral condition of the suborder Vombatiformes. Furthermore, it provides a plausible link between diprotodontians and the putative polydolopimorphians Chulpasia jimthorselli and Thylacotinga bartholomaii from the early Eocene Tingamarra Local Fauna (eastern Australia), which we infer as having molar morphologies consistent with stem diprotodontians.

Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed “cyclo”R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), C-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. “Cyclo”R8 showed similar activity to that of R8 against α9α10 nAChR (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.

Hemangiopericytoma can occur anywhere in the body where capillaries are located. However, most often this tumor is detected in the subcutaneous soft tissues, pelvic ring, lower limbs and retroperitoneal space [2]. Hemangiopericytoma rarely affects the central nervous system. Because of the rarity of the disease, the clinical features, treatment, and outcomes are poorly understood. Patient M, 64 years old, male, applied to the polyclinic of the State University "Institute of Neurosurgery named after Acad. A.P. Romodanov of the National Academy of Medical Sciences of Ukraine" with complaints of pain in the thoracic spine with radiation to the left subscapular region of the body, numbness and weakness in the lower limbs. After an MRI, a diagnosis of a tumor of Th5-Th6 vertebrae was established. Given the presence of a spinal tumor in the patient with spinal cord compression, a decision was made to perform an operation to remove the tumor as a priority. After surgery, the patient's radicular pain and leg weakness immediately disappeared. CT was performed. The tumor was removed completely. Hemangiopericytomas are aggressive neoplasms with a high recurrence rate and a tendency to metastasize. The recurrence rate of hemangiopericytoma ranges from 50 to 80%, and metastases - from 14 to 30%, but can be as high as 23-64%, which makes the treatment of this disease very difficult. Surgical intervention and postoperative irradiation in a dose of up to 60 Gy, based on the data of the literature review, significantly improves treatment outcomes and reduces the number of recurrences compared to surgery alone. Surgical resection of the tumor should be total, if possible, in cases when the tumor cannot be removed completely, it should be removed as subtotal as possible.

Introduction. Building information modeling is key to the digital transformation of the construction industry. By maintaining a transparent and continuous flow of information between all stakeholders, BIM facilitates their collaboration at various stages of a project. This leads to significant efficiency gains at lower costs, faster delivery with fewer inaccuracies and delays, better business opportunities, and lower emissions and waste. The purpose of the study is to identify patterns in the formation of new industry-wide information processes and to formulate the main barriers to their implementation in the project practice.Materials and methods. The author studied the scholarly publications of domestic and foreign researchers. Since this scope of problems was formulated in the recent decade, materials, published during this period, were considered. Theoretical methods of research were employed: analysis, which allowed the author to break down an extensive information base on the EU countries; classification, which made it possible to identify the main levers for implementing new technologies; analogy, which identified similarities in the development of innovations; synthesis, which generated a general idea of the stages of forming new phenomena in the design of construction projects.Results. The author made a comparative analysis of the introduction of new technologies in the EU countries depending on the centre-periphery patterns, drew a parallel between the information processes in Russia and European. He also formulated the main drivers of the introduction of innovative development in the construction sector and decelerating factors based on a 10-year history of the implementation of BIM in European countries.Conclusions. The implementation of BIM in the construction sector is often limited. The main barriers are related to interoperability, compliance for all users, workflow changes, legal issues and training, and the emergence of new rights and responsibilities.

During the early years of spaceflight it was documented that astronauts were impaired and incapacitated upon return to earth. Computerized Dynamic Posturography (CDP) was devised to investigate and quantify this deficit, and eventually progressed into a clinical assessment tool. The current sprouting of virtual reality (VR) technologies has allowed for the development of an alternative approach that could be more informative. Many low-cost VR systems (including desktop gaming programs designed for rehabilitation) are now available. Continued improvements in this technology indicate a high probability that VR will become an integral component of posturography by replacing present mechanical CDP techniques. We researched the relevant literature to evaluate the strengths and weaknesses of CDP using the Equitest (Neurocom International; Clackamas USA), and the added benefits of incorporating VR to help clinicians assess the complex task of balance maintenance. VR is capable of manipulating task and environmental demands in order to assess functional postural behavior. VR is also a useful tool for clinical testing of postural disorders resulting from sensory mismatch. Although posturography is still a useful clinical tool, VR provides an inherent conflict between the visual and vestibular senses and can elevate the effectiveness of CDP for both assessment and intervention. We conclude that, when initially developed, CDP was innovative and ahead of its time. However, with the advent of VR, we have a chance to modernize CDP and enhance its value as a clinical instrument.

Many soldiers who were wounded during the war in Ukraine with Russia increased the number of cases of spinal injury. As a result of the Russia-Ukraine war, the number of patients with spine and spinal cord injuries increased significantly. According to the literature, gunshot wounds to the spine and spinal cord accounted for 0.26% of all soldier injuries during the American Civil War, with a mortality rate of 55%. According to the U.S. military data, spinal and spinal cord injuries accounted for 1.2% of war-related deaths during the Korean War, 1.0% - during the Vietnam War and the Gulf War, 6.0% - during the US invasion of Panama, 11.1% - during the war in Afghanistan and Iraq. Disability related to spinal cord injuries (14.0%) is currently the leading cause of discharge from military service for U.S. soldiers who have been injured. Patient M., 32 years old, male sustained mine blast injury. Immediately after the injury there was tetraplegia. Surgery was performed to correct vertebrae С7–Тh1, decompression of the spinal cord at the level of vertebrae С7–Тh1. Sixteen days after surgery, the neurological deficit regressed to the Frankel C clinical group. The patient was transferred to rehabilitation treatment. A clear, consistent, rapid algorithm of action in spinal cord injuries allowed to provide highly qualified care, which allowed to achieve significant results in the regression of neurological deficits in the postoperative period.

New antibiotics are unquestionably needed to fight the emergence and spread of multidrug-resistant bacteria. To date, antibiotics targeting bacterial central metabolism have been poorly investigated. By determining the minimal inhibitory concentration (MIC) of desmethylphosphinothricin (Glu-γ-PH), an analogue of glutamate with a phosphinic moiety replacing the γ-carboxyl group, we previously showed its promising antibacterial activity on Escherichia coli. Herein, we synthetized and determined the growth inhibition exerted on E. coli by an L-Leu dipeptide derivative of Glu-γ-PH (L-Leu-D,L-Glu-γ-PH). Furthermore, we compared the growth inhibition obtained with this dipeptide with that exerted by the free amino acid, i.e., Glu-γ-PH, and by their phosphonic and non-desmethylated analogues. All the tested compounds were more effective when assayed in a chemically-defined minimal medium. The dipeptide L-Leu-D,L-Glu-γ-PH had a significantly improved antibacterial activity (2 μg/mL), at a concentration between the non-desmethytaled (0.1 μg/mL) and the phosphonic (80 μg/mL) analogues. Also, in Bacillus subtilis, the dipeptide L-Leu-D,L-Glu-γ-PH displayed an activity comparable to that of the antibiotic amoxicillin. This work highlights the antibacterial relevance of the phosphinic pharmacophore and proposes new avenues for the development of novel antimicrobial drugs containing the phosphinic moiety.

The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation of vitally important cellular functions. Polyamine analogs and derivatives are a traditional and important instrument for the investigation of the cellular functions of polyamines, enzymes of their metabolism, and the regulation of the biosynthesis of antizyme—a key downregulator of polyamine homeostasis. Here, we describe convenient gram-scale syntheses of a set of C-methylated analogs of Spd. The biochemical properties of these compounds and the possibility for the regulation of their activity by moving a methyl group along the polyamine backbone and by changing the stereochemistry of the chiral center(s) are discussed.

Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication, and DNA repair. However, the contribution of these complexes to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of the Snf2h gene during the development of the mammalian retina. We show that Snf2h is expressed in both retinal progenitors and post-mitotic retinal cells. Using Snf2h conditional knockout mice (Snf2h cKO), we found that when Snf2h is deleted, the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. The depletion of Snf2h did not influence the ability of retinal progenitors to generate all the differentiated retinal cell types. Instead, the Snf2h function is critical for the proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although all retinal cell types appear to be specified in the absence of the Snf2h function, cell-cycle defects and concomitantly increased apoptosis in Snf2h cKO result in abnormal retina lamination, complete destruction of the photoreceptor layer, and consequently, a physiologically non-functional retina.

The fast spread of bacteria that are resistant to many classes of antibiotics (multidrug resistant) is a global threat to human and animal health with a worrisome scenario ahead. Novel therapeutical strategies are of crucial importance to combat this phenomenon. For this purpose, we investigated the antimicrobial properties of the naturally occurring tripeptide Bialaphos and a dipeptide L-leucyl-L-phosphinoithricin, the synthesis and diastereomers separation of which are herein described. We demonstrate that these compounds are effective on clinical isolates of the human pathogen Klebsiella pneumoniae, causing hospital-acquired and community-acquired infections. The tested isolates were remarkable for their resistance to more than 20 commercial antibiotics of different classes. Based on previous literature data and our experiments consisting of glutamine supplementation, we suggest that both compounds release phosphinothricin—a well-known nanomolar inhibitor of glutamine synthetase—after their penetration in the bacterial cells; and, in this way, exert their antibacterial effect by negatively affecting nitrogen assimilation in this pathogen.

The automated grading of Scots pine seeds in the near-infrared wavelength region (NIR grading) is a starting point for further actions, such as coating and priming. This reduces the time and financial costs and increases the accuracy of seed viability classification compared to invasive techniques. The NIR-based wave reflected from each pine seed must be detected and processed with sufficient accuracy. To focus the reflected beam, we used fiber-optic Bragg grating, a Bragg mirror, and diffraction grating. For each focusing option based on the DOE matrix, one experiment of 20 runs (n = 20) and three replicas (m = 3) in each run was conducted. In each replica, we used 100 conditioned and 100 non-conditioned seeds (NC + NNC = 200) selected randomly from five samples weighing 50 g from a seedlot weighing 1 kg extracted from cones collected from a natural tree stand. Three experiments were conducted on the NIR grading of Scots pine seeds using an optoelectronic device. An adequate DOE regression model of the grading efficiency function was obtained. The functions included the following arguments: angle of incidence of the optical beam, NIR wavelength reflected from the seed, and height of the seed pipeline. The influence of the inclination angle of the light source relative to the plane of pine seed movement on the grading quality prevails over other factors. The NIR grading of Scots pine seeds allows the separation of seeds according to the viability index, which is important, since dead petrified seeds (possibly up to 25%) may occur in the seed batch, which cannot be eliminated by either seed size or mass. The peak of NIR grading is achieved by combining the average grader engineering parameters: 968–973 nm for the wavelength and 44–46 degrees for the inclination angle of the reflected beam at a seed pipe size of 0.18–0.23 m.

Currently, one of the most effective algorithms for state estimation of stochastic systems is a Kalman filter. This filter provides an optimal root-mean-square error in state vector estimation only when the parameters of the dynamic system and its observer are precisely known. In real conditions, the observer’s parameters are often inaccurately known; moreover, they change randomly over time. This in turn leads to the divergence of the Kalman estimation process. The problem is currently being solved in a variety of ways. They include the use of interval observers, the use of an extended Kalman filter, the introduction of an additional evaluating observer by nonlinear programming methods, robust scaling of the observer’s transmission coefficient, etc. At the same time, it should be borne in mind that, firstly, all of the above ways are focused on application in specific technical systems and complexes, and secondly, they fundamentally do not allow estimating errors in determining the parameters of the observer themselves in order to compensate them for further improving the accuracy and stability of the filtration process of the state vector. To solve this problem, this paper proposes the use of accurate observations that are irregularly received in a complex measuring system (for example, navigation) for adaptive evaluation of the observer’s true parameters of the stochastic system state vector. The development of the proposed algorithm is based on the analytical dependence of the Kalman estimate variation on the observer’s parameters disturbances obtained using the mathematical apparatus for the study of perturbed multidimensional dynamical systems. The developed algorithm for observer’s parameters adaptive estimation makes it possible to significantly increase the accuracy and stability of the stochastic estimation process as a whole in the time intervals between accurate observations, which is illustrated by the corresponding numerical example.

Osteoblasts and adipocytes are derived from a common precursor, mesenchymal stem cells (MSCs). Alterations in the normal fate of differentiating MSCs are involved in the development of obesity and osteoporosis. Here, we report that viable motheaten (mev) mice, which are deficient in the SH2-domain-containing phosphatase-1 (SHP1), develop osteoporosis spontaneously. Consistently, MSCs from mev/mev mice exhibit significantly reduced osteogenic potential and greatly increased adipogenic potential. When MSCs were transplanted into nude mice, SHP1-deficient MSCs resulted in diminished bone formation compared with wild-type MSCs. SHP1 was found to bind to GSK3β and suppress its kinase activity by dephosphorylating pY216, thus resulting in β-catenin stabilization. Mice, in which SHP1 was deleted in MSCs using SHP1fl/flDermo1-cre, displayed significantly decreased bone mass and increased adipose tissue. Taken together, these results suggest a possible role for SHP1 in controlling tissue homeostasis through modulation of MSC differentiation via Wnt signaling regulation.

Discrete feeding of forest seeds is an urgent task for accurate detection of seeds during grading and reducing the seeding rate. The study used Pinus sylvestris L. seeds from cones collected in a natural stand of the Lisinsky educational-and-experimental forestry farm, Leningrad region, Russia, in 2017. Well-known methods for determining the properties of bulk materials were used; the results were processed by mathematical statistics using the MS Excel program. The physical and mechanical properties of uncalibrated seeds as a bulk material were determined. The angle of repose of Pinus sylvestris L. seeds, determined using a hollow cylinder by calculation, is 24.92°. The angle of repose of Pinus sylvestris L. seeds, determined using a hollow cylinder and a goniometer, is 32.7°. The significant discrepancy (~8°) in the values obtained by these methods is explained by the seeds shape. The flowability of Pinus sylvestris L. seeds corresponds to an excellent (free) category. The study will enable correct seed treatment protocols for sustainable forest management. However, some questions remained unresolved: how to orient a single seed in the right direction? How does seed-size calibration affect the angle of repose?

Research Highlights: There is a problem of forest seeds quality assessment and grading afield in minimal costs. The grading quality of each seed coat color class is determined by the degree of its separation with a mobile optoelectronic grader. Background and Objectives: Traditionally, pine seeds are graded in size, but this can lead to a loss of genetic diversity. Seed coat color is individual for each forest seed and is caused to a low error in identifying the genetic features of seedling obtained from it. The principle on which the mobile optoelectronic grader operates is based on the optical signal detection reflected from the single seed. The grader can operate in scientific (spectral band analysis) mode and production (spectral feature grading) mode. When operating in production mode, it is important to determine the optimal engineering parameters of the grader that provide the maximum value of the separation degree of seed-color classes. For this purpose, a run of experiments was conducted on the forest seeds separation using a mobile optoelectronic grader and regression models of the output from factors were obtained. Materials and Methods: Scots pine (Pinus sylvestris L.) seed samples were obtained from cones of the 2019 harvest collected in a natural stand. The study is based on the Design of Experiments theory (DOE) using the Microsoft Excel platform. In each of three replications of each run from the experiment matrix, a mixture of 100 seeds of light, dark and light-dark fraction (n = 300) was used. Results: Interpretation of the obtained regression model of seed separation in the visible wavelength range (650–715 nm) shows that the maximum influence on the output—separation degree—is exerted by the angle of incidence of the detecting optical beam. Next in terms of the influence power on the output are paired interactions: combinations of the wavelength with the angle of incidence and the wavelength with the grader’s seed pipe height. The minimum effect on the output is the wavelength of the detecting optical beam. Conclusions: The use of a mobile optoelectronic grader will eliminate the cost of transporting seeds to and from forest seed centers. To achieve a value of 0.97–1.0 separation degree of Scots pine seeds colored fractions, it is necessary to provide the following optimal engineering parameters of the mobile optoelectronic grader: the wavelength of optical radiation is 700 nm, the angle of incidence of the detecting optical beam is 45° and the grader’s seed pipe height is 0.2 m.

Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT), CYP2E1 knockout (KO) or CYP2E1 humanized transgenic knockin (KI), mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA), an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These results suggest that autophagy is protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. We speculate that autophagy-dependent processes such as mitophagy and lipophagy help to minimize ethanol-induced CYP2E1-dependent oxidative stress and therefore the subsequent liver injury and steatosis. Attempts to stimulate autophagy may be helpful in lowering ethanol and CYP2E1-dependent liver toxicity.

The cytochrome P450 mixed function oxidase enzymes play a major role in the metabolism of important endogenous substrates as well as in the biotransformation of xenobiotics. The liver P450 system is the most active in metabolism of exogenous substrates. This review briefly describes the liver P450 (CYP) mixed function oxidase system with respect to its enzymatic components and functions. Electron transfer by the NADPH-P450 oxidoreductase is required for reduction of the heme of P450, necessary for binding of molecular oxygen. Binding of substrates to P450 produce substrate binding spectra. The P450 catalytic cycle is complex and rate-limiting steps are not clear. Many types of chemical reactions can be catalyzed by P450 enzymes, making this family among the most diverse catalysts known. There are multiple forms of P450s arranged into families based on structural homology. The major drug metabolizing CYPs are discussed with respect to typical substrates, inducers and inhibitors and their polymorphic forms. The composition of CYPs in humans varies considerably among individuals because of sex and age differences, the influence of diet, liver disease, presence of potential inducers and/or inhibitors. Because of such factors and CYP polymorphisms, and overlapping drug specificity, there is a large variability in the content and composition of P450 enzymes among individuals. This can result in large variations in drug metabolism by humans and often can contribute to drug–drug interactions and adverse drug reactions. Because of many of the above factors, especially CYP polymorphisms, there has been much interest in personalized medicine especially with respect to which CYPs and which of their polymorphic forms are present in order to attempt to determine what drug therapy and what dosage would reflect the best therapeutic strategy in treating individual patients.

The cytochrome P450 mixed function oxidase enzymes are the major catalysts involved in drug metabolism. There are many forms of P450. CYP2E1 metabolizes many toxicologically important compounds including ethanol and is active in generating reactive oxygen species. Since several of the contributions in the common theme series “Role of CYP2E1 and Oxidative/Nitrosative Stress in the Hepatotoxic Actions of Alcohol” discuss CYP2E1, this methodology review describes assays on how CYP2E1 catalytic activity and its induction by ethanol and other inducers can be measured using substrate probes such as the oxidation of para-nitrophenol to para-nitrocatechol and the oxidation of ethanol to acetaldehyde. Approaches to validate that a particular reaction e.g. oxidation of a drug or toxin is catalyzed by CYP2E1 or that induction of that reaction is due to induction of CYP2E1 are important and specific examples using inhibitors of CYP2E1, anti-CYP2E1 IgG or CYP2E1 knockout and knockin mice will be discussed.

Purpose To report the outcomes of patients with pathologic T4 UTUC and investigate the potential impact of peri-operative chemotherapy combined with radical nephroureterectomy (RNU) and regional lymph node dissection (LND) on oncologic outcomes. Materials and Methods Patients with pathologic T4 UTUC were identified from the cohort of 1464 patients treated with RNU at 13 academic centers between 1987 and 2007. Oncologic outcomes were stratified according to utilization of perioperative systemic chemotherapy and regional LND as an adjunct to RNU. Results The study included 69 patients, 42 males (61%) with median age 73 (range 43-98). Median follow-up was 17 months (range: 6-88). Lymphovascular invasion was found in 47 (68%) and regional lymph node metastases were found in 31 (45%). Peri-operative chemotherapy was utilized in 29 (42%) patients. Patients treated with peri-operative chemotherapy and RNU with LND demonstrated superior oncologic outcomes compared to those not treated by chemotherapy and/or LND during RNU (3Y-DFS: 35% vs. 10%; P = 0.02 and 3Y-CSS: 28% vs. 14%; P = 0.08). In multivariate Cox regression analysis, administration of peri-operative chemotherapy and utilization of LND during RNU was associated with lower probability of recurrence (HR: 0.4, P = 0.01), and cancer specific mortality (HR: 0.5, P = 0.06). Conclusions Pathological T4 UTUC is associated with poor prognosis. Peri-operative chemotherapy combined with aggressive surgery, including lymph node dissection, may improve oncological outcomes. Our findings support the use of aggressive multimodal treatment in patients with advanced UTUC.

Autophagy has been shown to be protective against drug and alcohol-induced liver injury. CYP2E1 plays a role in the toxicity of ethanol, carcinogens and certain drugs. Inhibition of autophagy increased ethanol-toxicity and accumulation of fat in wild type and CYP2E1 knockin mice but not in CYP2E1 knockout mice as well as in HepG2 cells expressing CYP2E1 (E47 cells) but not HepG2 cells lacking CYP2E1 (C34 cells). The goal of the current study was to evaluate whether modulation of autophagy can affect CYP2E1-dependent cytotoxicity in the E47 cells. The agents used to promote CYP2E1 –dependent toxicity were a polyunsaturated fatty acid, arachidonic acid (AA), buthionine sulfoximine (BSO), which depletes GSH, and CCl4, which is metabolized to the CCl3 radical. These three agents produced a decrease in E47 cell viability which was enhanced upon inhibition of autophagy by 3-methyladenine (3-MA) or Atg 7 siRNA. Toxicity was lowered by rapamycin which increased autophagy and was much lower to the C34 cells which do not express CYP2E1. Toxicity was mainly necrotic and was associated with an increase in reactive oxygen production and oxidative stress; 3-MA increased while rapamycin blunted the oxidative stress. The enhanced toxicity and ROS formation produced when autophagy was inhibited was prevented by the antioxidant N-Acetyl cysteine. AA, BSO and CCl4 produced mitochondrial dysfunction, lowered cellular ATP levels and elevated mitochondrial production of ROS. This mitochondrial dysfunction was enhanced by inhibition of autophagy with 3-MA but decreased when autophagy was increased by rapamycin. The mitogen activated protein kinases p38 MAPK and JNK were activated by AA especially when autophagy was inhibited and chemical inhibitors of p38 MAPK and JNK lowered the elevated toxicity of AA produced by 3-MA. These results show that autophagy was protective against the toxicity produced by several agents known to be activated by CYP2E1. Since CYP2E1 plays an important role in the toxicity of ethanol, drugs and carcinogens and is activated under various pathophysiological conditions such as diabetes, NASH and obesity, attempts to stimulate autophagy may be beneficial in preventing/lowering CYP2E1/ethanol liver injury.

OBJECTIVES: Urine based tumor markers have uncertain utility in diagnosis or surveillance of patients with bladder cancer while cytology is commonly used. We evaluated whether cytology provides additional diagnostic information in patients with a negative NMP22® BladderChek® test (BladderChek) and negative cystoscopy. MATERIALS AND METHODS: We performed subset analyses of 2 large prospective multi-center databases evaluating BladderChek for UCB detection and surveillance. These cohorts were analyzed for presence of cancer and result of urine cytology in setting of a negative cystoscopy and negative BladderChek. Subsequently, we prospectively performed cystoscopy, cytology and BladderChek on 434 patients at our institution being evaluated for UCB. RESULTS: In the detection database (n = 1331), 1065 patients had a negative cystoscopy and BladderChek. There were 3 cancers (stages Ta, Tis and T1) and cytology was atypical in one and reactive in two. In the surveillance cohort (n = 668) patients, 437 patients had negative cystoscopy and BladderChek. Cancer was found in 2 patients (stages Tis and Ta). The patient with Tis has dysplastic cytology and Ta tumor had reactive cytology. In our cohort of 434 patients, 288 pts had negative cystoscopy and BladderChek. One cancer was missed, a Ta ureteral urothelial carcinoma with a reactive cytology. CONCLUSIONS: In patients with negative cystoscopy and BladderChek, very few cancers are missed and cytology was not effective in detection. Use of a point-of-care test in conjunction with cystoscopy in lieu of cytology could decrease cost, provide immediate results, improve negative predictive value and reduce the uncertainty that results from inconclusive cytologic results.

The issue of blindness and legally blind is becoming a global issue. Based on the last statistics from American Foundation for the blind, there are approximately 10 million blind and visually impaired people in the United States alone. Over 45 million people around the world are completely blind. 180 million more people are legally blind, and approximately 7 million people are diagnosed as blind or legally blind every year. One of the greatest stumbling blocks in the ability of the blind to enter careers in science, technology, engineering or mathematics is the paucity of tools to help them read and write equations. Over the years there have been numerous projects around the world with the goal of building special tools to help the visually impaired student read and write equations. In the current work, we describe some of the most interesting work in this domain and then attempt to make recommendations and/or predictions about the future.

The mechanisms by which alcohol causes cell injury are not clear. A major mechanism is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol elevated production of lipopolysaccharide (LPS) and TNFα and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other; however, interactions between them, have not been extensively evaluated. Increased oxidative stress from induction of CYP2E1 sensitizes hepatocytes to LPS and TNFα toxicity and oxidants, activation of inducible nitric oxide synthase and p38 and JNK MAP kinases, and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNFα-potentiated hepatotoxicity. This paper will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved including activation of the mitogen-activated kinase kinase kinase ASK-1. Decreasing either cytosolic or mitochondrial thioredoxin in HepG2 cells expressing CYP2E1 causes loss of cell viability and elevated oxidative stress via an ASK-1/JNK-dependent mechanism. We hypothesize that similar interactions occur as a result of ethanol induction of CYP2E1 and TNFα.

As more reports emerge of improved mortality and morbidity rates in infants born at the edge of viability, there may be need to reassess protocols and recommendations that encourage only comfort care for infants who are born at less than 24 weeks’ gestation. Analysis of those studies that report extremely poor survival of these infants reveals that, all too often, the results are measures of a self-fulfilling prophesy that reflects a predetermined non-aggressive global policy of no resuscitation and minimal investment in intensive care. Furthermore, little distinction is made between high- and low-risk infants of the same gestational age despite repeated studies that indicate that one can identify subpopulations that have as much as a 20–50% increased chance of surviving with little if any long-term neurodevelopmental impairment. Thus, the need to reassess current policies is discussed.

Species richness generally promotes ecosystem productivity, although the shape of the relationship varies and remains the subject of debate. One reason for this uncertainty lies in the multitude of methodological approaches to sampling biodiversity and productivity, some of which can be subjective. Remote sensing offers new, objective ways of assessing productivity and biodiversity. In this study, we tested the species richness–productivity relationship using a common remote sensing index, the Normalized Difference Vegetation Index (NDVI), as a measure of productivity in experimental prairie grassland plots (Cedar Creek). Our study spanned a growing season (May to October, 2014) to evaluate dynamic changes in the NDVI–species richness relationship through time and in relation to environmental variables and phenology. We show that NDVI, which is strongly associated with vegetation percent cover and biomass, is related to biodiversity for this prairie site, but it is also strongly influenced by other factors, including canopy growth stage, short-term water stress and shifting flowering patterns. Remarkably, the NDVI-biodiversity correlation peaked at mid-season, a period of warm, dry conditions and anthesis, when NDVI reached a local minimum. These findings confirm a positive, but dynamic, productivity–diversity relationship and highlight the benefit of optical remote sensing as an objective and non-invasive tool for assessing diversity–productivity relationships.

The number of fat cells contained in the rat epididymal fat pad was found to increase rapidly as the rats grew to a weight of about 300 g. Additional increases in cell number above this weight were minimal. By contrast, cell size, as measured by the amount of triglyceride per cell, increased linearly until the rats reached about 600 g. Glycerol release per 106 cells in response to norepinephrine in vitro was observed to be independent of cell size. Basal release expressed in this manner showed a slight but significant positive correlation with increasing cell size. When the rate of lipolysis was based either on the amount of triglyceride in the incubation medium, as is the usual custom, or on the cell surface area, lipolysis was inversely related to cell size. In addition to these observations on lipolysis, it was also demonstrated that norepinephrine-activated adenyl cyclase activity expressed per 106 cells was unaffected by cell size. This leads to the suggestion that the number of adrenergic receptors in the fat cell is fixed and is independent of the size of the cell; as the cell enlarges, these receptors are merely distributed over a greater surface area.