Small molecule-mediated upregulation of G3BP1 as a therapy for ALS

Les troubles neurodégénératifs, tels que la sclérose latérale amyotrophique (SLA) et la démence frontotemporale (DFT), ont été associés aux protéines de liaison à l'ARN (RBP). Les principales caractéristiques de la SLA sont l'agrégation d'une protéine de liaison à l'ARN appelée protéine de liaison TAR (TDP-43). Il a été démontré que TDP-43 se lie à G3BP1, un facteur de nucléation pour l'assemblage des granules de stress, pour le stabiliser. Les granules de stress sont des structures séparées par phases qui se forment dans des conditions stressantes et favorisent la survie cellulaire. Une altération de l’assemblage des granules de stress et une réduction du G3BP1 sont signalées dans la SLA. Cette réduction est due à un défaut dans les transcriptions codantes pour G3BP1 stabilisant TDP-43. Par conséquent, une réponse défaillante des granules de stress pourrait jouer un rôle majeur dans la maladie. Ainsi, ce projet de recherche se concentre sur la restauration de G3BP1, dont la déplétion est liée à la perte de fonction de TDP-43. En utilisant des composés de petites molécules identifiés lors d'une campagne de dépistage de médicaments, nous cherchons à augmenter l'expression de G3BP1, rétablissant ainsi le mécanisme SG endogène et favorisant la survie neuronale. La découverte de candidats principaux (NPX-047, NPX-000-115 et NPX-001-280) qui sauvent efficacement l'expression et la fonction de G3BP1 est prometteuse pour des thérapies potentielles contre la SLA. Ces composés ont été testés sur des cellules SHSY5Y traitées avec du si-TDP, mais aucune récupération de l'ARNm de G3BP1 n'a été observée malgré des niveaux plus élevés de signaux de luciférase. Ainsi, une enquête approfondie sur les divergences dans nos résultats constitue notre prochaine étape, ce qui n’a pas été possible pendant la durée limitée de cette mémoire. De plus, les cibles non ciblées de ces composés seront étudiées à l’aide du séquençage Bru Chase. Dans l’ensemble, cette étude explore de nouvelles stratégies pour restaurer l’expression de G3BP1, offrant ainsi une voie potentielle d’intervention thérapeutique dans la SLA.Neurodegenerative disorders, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), have been associated with RNA-binding proteins (RBPs). Major hallmark of ALS is aggregation of an RNA-binding protein called TAR binding protein (TDP-43). TDP-43 has shown to bind to G3BP1, a nucleating factor for stress granule assembly, to stabilize it. Stress granules (SGs) are phase separated structures that form under stressful conditions and promote cell survival. Impaired stress granules assembly and reduced G3BP1 is reported in ALS. This reduction is due to a defect in TDP-43 stabilizing G3BP1 encoding transcripts; thus, a failed stress granule response could have a major role in the disease. Thus, this research focuses on restoring G3BP1, whose depletion is linked to TDP-43 loss of function. By utilizing small-molecule compounds identified through a drug screening campaign, we seek to increase G3BP1 expression, consequently reinstating the endogenous SG mechanism and promoting neuronal survival. The discovery of lead candidates (NPX-047, NPX-000-115, and NPX-001-280) that effectively rescue G3BP1 expression and function offers promise for potential ALS therapies. These compounds were tested on SH-SY5Y cells treated with si-TDP however no rescue of G3BP1 mRNA was observed despite higher levels of luciferase signals. Thus, in-depth investigation of discrepancies in our results is our next step which was not possible during the limited timeline of this thesis. In addition, off-targets of these compounds will be investigated using BruChase-sequencing. Overall, this study explores novel strategies to restore G3BP1 expression, providing a potential avenue for therapeutic intervention in ALS

Key success factor of lean six sigma implementation in oil and gas industry: Case study in MBU, strategic business unit of XYZ

Merdeka Business Unit (MBU) is subsidiary of XYZ, Inc in Indonesia.As a global oil and gas company, XYZ, Inc had been implementing Lean Six Sigma since 1990s and cascaded down to its business units gradually.Since its first deployment in 2000, MBU Lean Sigma experienced steady if not unsatisfactory performance looking at the acrrued financial benefit (AFB) only. But with new leadership and governance, it’s AFB rose to MM $46 (6 times) compared to average AFB in the past eleven years in 2011, MM$ 206 (30 times) in 2012, and MM $ 392 (57 times) in 2013.Within three years, MBU successfully occupying the top position among other business unit in XYZ,inc on its AFB achievement. This paper presents the strategy in reinventing MBU Lean Six Sigma, its governance, best practices. XYZ’s five component model, will be tested with existing Critical Success Factor developed by Jeyaraman,K. and Teo, L.K (2010) based on manufacturing company practices LSS in Malaysia with more than 80% corresponding factors. Five component model will then be used to analyze MBU LSS implementation and its performance during the period of 2000-2010 and find the root causes. In addition, this paper will outline best practices to revamp LSS implementation in MBU and its Lean Six Sigma Success implementation Mode

Dynamics of Matrix-Fracture Coupling During Shale Gas Production

In this work, a dynamic permeability model for organic-rich shale matrix is constructed and implemented into a flow simulation to investigate the impact on production. Effective stress and molecular transport effects on the permeability are considered during the flow in the matrix. Using a sector model with a single hydraulically-induced fracture, we investigate the dynamic nature of fracture-matrix coupling during the first year of production. The proposed apparent permeability shows improved transport near the fracture due to adsorption capacity of the rock and molecular transport of the adsorbed phase. This fosters drainage and leads eventually to a larger cumulative production. Away from the fracture, however, within the region of depletion, sensitivity to the stress is more pronounced which may impair the local permeability and reduce the production. Overall the shale matrix typically yields more fluid than that with the constant-permeability case. When the fracture-matrix coupling is considered during the production, an infinite conductivity fracture has negligible effect on the production trends, and that production optimization efforts should focus to considerations to improve the flow rates in the matrix

A sexual difference in the chromosomes of two species of agamid lizards

The diploid number of chromosomes in Calotes versicolor is 34 in the male and 33 in the female. The numerical difference in the two sexes is based on the condition of the sex chromosome; in the male it is present as a homologous pair, while in the female it remains unpaired. The sex chromosome was identified as one of the micro-chromosomes (the chromosome No. 7) in this species. Sitana ponticeriana possesses the diploid number of 46 in the male and 45 in the female. The sex chromosome identified in this form is also one of the micro-chromosomes (chromosome No. 13), which has no partner in the female, whereas in the male it is in the paired state having a homologous mate. It was established therefore that, in both species studied, the female is heterogametic as regards the sex chromosome. The chromosome complement of Calotes versicolor consists of 12 V-shaped macro-chromosomes and 22 dot-like micro-chromosomes, while in Sitana ponticeriana there are 24 rod-shaped macro-chromosomes and 22 dot-like micro-chromosomes. The difference in the karyotypes of these two species can be accounted for on the basis of the formation of V-shaped multiple chromosomes by means of the fusion of two rods at the point of fibre attachment. The karyological relationships in the Family Agamidae were discussed. The chromosome number previously reported for Uromastix hardwicki was found to be erroneous; the diploid number in this species is 34

Kebijakan Pertahanan Indonesia terhadap Pulau-Pulau Kecil Terluar sebagai Beranda Depan Kedaulatan Negara: Pada Masa Pemerintahan Joko Widodo

Dari 17.506 lebih pulau, 92 di antaranya adalah pulau-pulau kecil terluar yang berbatasan laut langsung dengan 10 negara lain yakni Malaysia, Singapura, Filipina, Vietnam, Thailand, Timor Leste, Papua New Guinea, Republik Palau, Australia, dan India. Dari 92 pulau tersebut, menurut Badan Nasional Pengelola Perbatasan (BNPP), ada 12 pulau-pulau kecil terluar yang rawan secara pertahanan dan keamanan karena merupakan titik koordinat terluar. Kekalahan Indonesia dalam memperebutkan Pulau Sipadan dan Ligitan juga menjadi salah satu titik terhadap kesadaran negara tentang pentingnya pulau-pulau kecil terluar. Dengan kehadiran Joko Widodo bersama Doktrin Poros Maritim Dunia, menjadikan pulau-pulau kecil terluar sebagai kajian strategis bagi penyusunan kebijakan pertahanan Indonesia. Penelitian ini merupakan upaya untuk menggambarkan kebijakan pertahanan yang diterapkan Indonesia terhadap pulau-pulau kecil terluar sebagai beranda kedaulatan negara. Dengan menggunakan konstruktivisme, penulis melihat adanya kekuatan ide yang dituangkan Joko Widodo melalui Doktrin Poros Maritim Dunia, yang kemudian membentuk wajah baru Indonesia dalam memperlakukan pulau-pulau kecil terluar yang merupakan salah satu komponen penting pada sektor maritim. Konsep maritime security juga digunakan penulis dalam menganalisa kebijakan pertahanan karena mengingat militer tetap menjadi satu bagian penting dalam menjaga kedaulatan wilayah NKRI, khususnya di wilayah perbatasan. Dengan menggunakan metode wawancara dan telaah pustaka, penulis menyajikan penelitian ini dengan pendekatan kualitatif. Dari penelitian yang dilakukan, ditemui bahwa Joko Widodo berhasil menuangkan idenya ke dalam kebijakan pertahanan Indonesia, bahkan hingga melahirkan berbagai peraturan nasional yang berpatok pada UNCLOS 1982. Joko Widodo juga berhasil menggerakkan Kementerian/Lembaga terkait yakni Kementerian Pertahanan, Kementerian Kelautan dan Perikanan, dan Badan Nasional Pengelola Perbatasan untuk menjalankan perannya di pulau-pulau kecil terluar. Namun demikian, pemerintahan Joko Widodo masih jauh dari kata aktif dalam keterlibatannya di forum internasional untuk membawa isu pulau-pulau kecil terluar.From more than 17.506 islands, 92 among them are the outermost small islands which have sea border with ten neighbor states including Malaysia, Singapura, Phillippines, Vietnam, Thailand, Timor-Leste, Papua New Guinea, Republic of Palau, Australia and India. According to The National Agency for Border Management (BNPP), from 92 of the outermost small islands above, 12 are having the vulnerability in security and defense because they were in the outermost coordinate point. After The International Court of Justice decided that sovereignty over Sipadan and Ligitan Island belongs to Malaysia, Indonesia puts the outermost small islands as one of the most important issues. Joko Widodo with his Global Maritime Axis Doctrine puts the outermost small islands as strategic studies in defense policy. This research aims to describe Indonesian defense policy of Joko Widodo's era toward the outermost small islands as state sovereign verandah. By using constructivism, the author saw that Joko Widodo’s ideas of Global Maritime Axis Doctrine have shaped Indonesian new forms toward how it treat the outermost small islands which one of the most important components in maritime. The author also using maritime security concept to analyze Indonesia defense policy because military existence still plays an important role in protecting Indonesian sovereignty, especially in the border region. By using research methods of interviews and literature review, this research presented in a qualitative approach. Through this research, the author found that Joko Widodo transfers his idea in Indonesian defense policy successfully, and moreover can make some national constitutions which are based on UNCLOS 1982. The Ministry and/or Institution under Joko Widodo's era, such as Ministry of Defense, Ministry of Marine Affairs and Fisheries, and The National Agency for Border Management also played their roles into the outermost small islands. Even though, Indonesian defense policy in Joko Widodo's era still far from involvement into the international forum to bring the outermost small islands issues

Outcome of Diode Laser Cyclophotocoagulation in Neovascular Glaucoma in Nigerians: A short-term follow-up

Aim: To find out the short-term outcome of ciliary ablation with diode laser contact cyclophotocoagulation in Nigerians with neovascular glaucoma.Methods: The study is a retrospective, non-comparative, interventional case series. Demographic data, ocular and systemic history were obtained. Clinical examination included visual acuity, intraocular pressure, number ofintraocular pressure-lowering medications and type of treatment administered at the time of NVG diagnosis. Treatment with diode laser cyclophotocoagulation was instituted. Short-term outcomes were observed and patients were followed-up for three months.Results: The study included 3 eyes of 3 patients; all above 40 years, 1 female and 2 male. At the time of NVG diagnosis, all three patients presented with severe ocular pain, and had VA between PL and NPL. Intraocular pressure on the average was 33mmHg at presentation,and associated with corneal oedema. At 3 months after initial diode laser photocoagulation (DLPC), the VA remained the same in all patients. No patient required repeat treatment. Pain reduction and lowering of theintraocular pressure were achieved at 3 months followup post-DLPC without anti-glaucoma medication. Conjunctival burns and chemosis were seen. All three eyes had corneal oedema and spontaneous hyphema by the 7 day; with subsequent s th evere corneal blood stain.Conclusions: Diode laser photocoagulation can be used as an acceptable non-invasive surgical intervention for the reduction of pain and lowering of intraocular pressure in Nigerians with neovascular glaucoma. Most shortterm complications are uneventful. The presence of hyphema with corneal oedema may enhance the occurrence of corneal blood stain in black people. The presence of corneal oedema may thus be a risk factor for corneal blood staining.Key words: short-term outcome, diode laser, corneal stainin

Effect of COVID-19 on Academic Performance in Four CORE Subjects of selected Senior Secondary School Students in Upper West Region of Ghana

COVID-19 created lots of distortions in the world. This study investigated effect of COVID-19 on academic performance among selected senior secondary school students from Ghana. WASSCE results from 2017/2018 through 2021/2022 academic sessions were considered to determine order in academic performance before, during and after COVID-19. Two research questions and hypotheses were stated, while a descriptive correlational survey was adopted, and convenience sampling technique employed to select needed sample for the study. WASSCE results of five (5) academic sessions were extracted for core subjects in senior high schools for pre-, during, and after COVID-19. Data used are standardized scores with reliability coefficients of 0.5, 0.6 and 0.7 respectively at p=0.01 (2-tailed). Data collected were analyzed using frequency and percentages. Results revealed that highest and lowest mean scores recorded occurred in 2017/2018 and 2021/2022 academic sessions respectively. Also, the relationship between academic performance after COVID-19 was established to be significant and stronger than the relationship between academic performance before COVID-19 which was weak but, not significant. Models introduced into the school system during COVID-19 should continue since academic performance in the core subjects is improving as desired by stakeholders in education

Ocular effects of chronic exposure to welding light on calabar welders

It was generally observed that welders in Calabar, Nigeria did not always wear their protective goggles during welding. Since chronic exposure to welding light can impair vision this study was done to assess the effect of exposure to welding light on ocular function of welders in Calabar, Nigeria. There were 195 subjects comprising 110welders (test) and 85 control subjects. Both groups were all male and had similar age range. The tests employed were clinical examination for ocular disorders, assessment of visual acuity, and opthalmoscopy. Test questionnaire was also used to record information on length of service, precautionary measures at work place, age and past ocular illnesses.The study also compared incidence of ocular disorders between the two groups of welders (arc and carbide welders). The mean ages of the welders and their control were not significantly different (27.53 10.0 vs 27.78 8.5 yrs respectively). There was a significantly (P<0.01) higher incidence of pingueculum, cataract, allergic conjunctivitis,corneal opacity, and keratoconjunctivitis (arc eye) in welders than in their control subjects. However, visual acuity, incidence of pterygium and glaucoma were similar. Between the two groups of welders, the incidence of pterygium, corneal opacity and keratoconjunctivitis was significantly (P< 0.01) higher in arc welders than carbide welders. Theincidence of pingueculum and glaucoma were however, similar. In conclusion, chronic exposure to welding light without adequate precaution may cause ocular disorders. Arc welding is more dangerous to ocular function than carbide welding. Length of service and age are predisposing factors to ocular disorders in the welding business

Somatic chromosomes and microsporogenesis in Cobra or Snake Lily, Arisama murrayi (Aracea)

This article does not have an abstract