Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif

Heterotrimeric G proteins are quintessential signalling switches activated by nucleotide exchange on Gα. Although activation is predominantly carried out by G-protein-coupled receptors (GPCRs), non-receptor guanine-nucleotide exchange factors (GEFs) have emerged as critical signalling molecules and therapeutic targets. Here we characterize the molecular mechanism of G-protein activation by a family of non-receptor GEFs containing a Gα-binding and -activating (GBA) motif. We combine NMR spectroscopy, computational modelling and biochemistry to map changes in Gα caused by binding of GBA proteins with residue-level resolution. We find that the GBA motif binds to the SwitchII/α3 cleft of Gα and induces changes in the G-1/P-loop and G-2 boxes (involved in phosphate binding), but not in the G-4/G-5 boxes (guanine binding). Our findings reveal that G-protein-binding and activation mechanisms are fundamentally different between GBA proteins and GPCRs, and that GEF-mediated perturbation of nucleotide phosphate binding is sufficient for Gα activation

Sum-rate maximisation comparison using incremental approaches with different constraints

In this work, the problem of rate maximisation of multichannel systems is considered. Two greedy allocation approaches using power (GPA) and bit (GBA) loading schemes with a slight difference in design constraints that aiming to maximise the overall system throughput are compared. Both algorithms use incremental bit loading whereby, the GPA is designed with main interest of efficient power utilisation. Whereas, the GBA sacrifices power utilisation to another design issue of achieving an average bit error ratio (BER) less than the target BER. Simulation results shows that with GPA algorithm better throughput is gained over the GBA algorithm while the latter guaranteed less BER

Incremental rate maximisation power loading with BER improvements

This paper aims to maximise the rate over a MIMO link using incremental power and bit allocation. Two different schemes, greedy power allocation (GPA) and greedy bit allocation (GBA), are addressed and compared with the standard uniform power allocation (UPA). The design is constrained by the target BER, the total power budget, and fixed discrete modulation orders. We demonstrate through simulations that GPA outperforms GBA in terms of throughput and power conservation,while GBA is advantageouswhen a lower BER is beneficial. Once the design constraints are satisfied, remaining power is utilised in two possible ways, leading to improved performance of GPA and UPA algorithms. This redistribution is analysed for fairness in BER performance across all active subchannels using a bisection method

Discrete rate maximisation power allocation with enhanced BER

This study aims to maximise the rate over a multiple-in multiple-out (MIMO) link using incremental power and bit allocation. Two different schemes, greedy power allocation (GPA) and greedy bit allocation (GBA), are addressed and compared with the standard uniform power allocation (UPA). The design is constrained by the target bit error ratio (BER), the total power budget and fixed discrete modulation orders. The authors demonstrate through simulations that GPA outperforms GBA in terms of throughput and power conservation, whereas GBA is advantageous when a lower BER is beneficial. Once the design constraints are satisfied, remaining power is utilised in two possible ways, leading to improved performance of GPA and UPA algorithms. This redistribution is analysed for fairness in BER performance across all active subchannels using a bisection method

Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles.

Targeted delivery of lysosomal enzymes to the endocytic compartment of human cells represents a transformative technology for treating a large family of lysosomal storage diseases (LSDs). Gaucher disease is one of the most common types of LSDs caused by mutations to the lysosomal β-glucocerebrosidase (GBA). Here, we describe a genetic strategy to produce engineered exosomes loaded with GBA in two different spatial configurations for targeted delivery to the endocytic compartment of recipient cells. By fusing human GBA to an exosome-anchoring protein: vesicular stomatitis virus glycoprotein (VSVG), we demonstrate that the chimeric proteins were successfully integrated into exosomes which were secreted as extracellular vesicles (EVs) by producer cells. Isolation and molecular characterization of EVs confirmed that the fusion proteins were loaded onto exosomes without altering their surface markers, particle size or distribution. Further, enzyme-loaded exosomes/EVs added to cultured medium were taken up by recipient cells. Further, the endocytosed exosomes/EVs targeted to endocytic compartments exhibited a significant increase in GBA activity. Together, we have developed a novel method for targeting and delivery of lysosomal enzymes to their natural location: the endocytic compartment of recipient cells. Since exosomes/EVs have an intrinsic ability to cross the blood-brain-barrier, our technology may provide a new approach to treat severe types of LSDs, including Gaucher disease with neurological complications

Genre-Based Approach As A Method to Build Students’ Critical Thinking in Comprehending Narrative Text for Senior High School

Abstrak Membaca teks naratif memerlukan kemampuan berpikir kritis guna memahami isi teks secara mendalam. Genre Based Approach (GBA) atau pendekatan berbasis genre adalah sebuah metode dalam pengajaran bahasa yang memiliki empat tahapan, yaitu: BKOF, MOT, JCOT, dan ICOT. Dalam pengajaran membaca, penggunaan GBA akan mendorong siswa untuk memahami teks secara keseluruhan bukan kalimat per kalimat dan hal tersebut berhubungan dengan kemampuan berpikir kritis. Oleh karenanya, penelitian ini akan menunjukkan penggunaan GBA dalam pembentukan kemampuan berpikir siswa khususnya dala memahami teks naratif. Penelitian ini berupa penelitian deskriptif yang bertujuan untuk mendeskripsikan implementasi GBA sebagai metode untuk membangun kemampuan berpikir kritis siswa dalam memahami teks naratif, hasil kerja siswa penerapan GBA, dan respon siswa terhadap proses belajar mengajar yang menggunakan GBA. Subjek penelitian sejumlah 36 siswa dan seorang guru. Peneliti melakukan observasi terhadap proses belajar mengajar di kelas guna mendeskripsikan implementasi GBA dan bagaimana hal tersebut membangun kemampuan berpikir kritis siswa. Peneliti juga mengumpulkan hasil kerja siswa untuk menunjukkan sejauh mana kemampuan berpikir kritis mereka berkembang setelah penerapan GBA. Selanjutnya, peneliti melakukan wawancara untuk mendeskripsikan respon siswa tentang proses belajar mengajar menggunakan GBA. Hasil observasi menunjukkan bahwa guru telah menerapkan seluruh tahapan GBA, meskipun terdapat sedikit ketidaksesuaian dengan teori. Hasil kerja siswa menunjukkan siswa mampu menjawab soal-soal berbasis HOTS khususnya pada tahapan analisis dan evaluasi. Terakhir, hasil wawancara menujukkan siswa mampu menikmati dan merasa proses belajar mengajar menggunakan GBA sangat menarik serta lebih komprehensif. Kata kunci: pemahaman membaca, pendekatan berbasis genre, kemampuan berpikir kritis siswa, teks naratif. Abstract Reading narrative text requires critical thinking ability to comprehend the text deeply. Genre-Based Approach (GBA) is a language teaching method that consists of 4 stages: BKOF, MOT, JCOT, and ICOT. In teaching reading, GBA will encourage the students to comprehend the whole of the text rather than sentence by sentence which relates to critical thinking ability. Therefore, this research is designed as descriptive research aims to describe the implementation of GBA as a method to build students critical thinking in comprehending narrative text, the students work after they are taught by GBA, and the students responses toward teaching and learning process with GBA. The subjects are 36 students and an English teacher. The researcher observed the teaching and learning process to describe the implementation of GBA and how it built students critical thinking. Moreover, she collected the students work to investigate whether the method was successful in encouraging students’ critical thinking or not. Likewise, the researcher conducted an interview to describe the students responses to the teaching and learning process by GBA. The observation showed that the teacher implemented all stages in GBA, although there were some points which were not in line with the theory. The students works showed that the students could answer the HOTS test especially for analyzing and evaluating stage. In addition, the interview result showed that the students felt the teaching and learning process was interesting, enjoyable, and more comprehensive. Keywords: reading comprehension, genre-based approach, students critical thinking, narrative text

The Effect of the Gauss-Bonnet term to Hawking Radiation from arbitrary dimensional Black Brane

We investigate the probabilities of the tunneling and the radiation spectrums of the massive spin-1 particles from arbitrary dimensional Gauss-Bonnet-Axions (GBA) Anti-de Sitter (AdS) black brane, via using the WKB approximation to the Proca spin-1 field equation. The tunneling probabilities and Hawking temperature of the arbitrary dimensional GBA AdS black brane is calculated via the Hamilton-Jacobi approach. We also compute the Hawking temperature via Parikh-Wilczek tunneling approach. The results obtained from the two methods are consistent. In our setup, the Gauss-Bonnet (GB) coupling affects the Hawking temperature if and only if the momentum of axion fields is non-vanishing.Comment: 11 pages; version 2,references added; published versio

Advancing the knowledge on the GBA gene and its role on the pathogenesis of Parkinson disease

Since its first description in the XIV century, the understanding of Parkinson disease (PD) has advanced significantly. However, a considerable part of its pathogenesis remains elusive, and no disease modifying therapy has been successfully developed yet and partly because of this lack of knowledge. The genetic background of PD is diverse, accounting for both mendelian, familial and sporadic forms of the disease. One of the main contributors to the genetic risk of PD is the GBA gene, which encodes for a lysosomal enzyme and is also linked to Gaucher disease, an autosomal recessive storage disorder. GBA variants are relatively frequent in sporadic PD, making it a promising target for disease modifying therapies. However, the penetrance of GBA variants is low and mostly unexplained, with only a minority of GBA variants carriers developing PD. In addition, the study of GBA is complicated by difficulties in sequencing the gene, due to the presence of a highly homologous pseudogene (GBAP1) in close proximity to GBA. The aim of this PhD research is to study potential modifiers of risk of PD among GBA variant carriers. First, I collaborated in the development of RAPSODI, an online tool to assess and follow-up a cohort of GBA carriers, both with and without PD, and analysed the data produced, showing interesting differences between GBA carriers and non-carries. The main outcome of this preliminary assessment is that GBA carriers with PD have significantly worse motor and non-motor symptoms compared to GBA-negative PD patients. Further, I refined a method to sequence the GBA gene with Oxford Nanopore’s MinION and developed a novel method for detecting reciprocal recombinants between the gene and pseudogene. By applying these tools, I was able to detect complex structural variants that might modify the risk of PD, as well as explore the role of intronic variants in GBA

Promoting Students’ Writing Skill: Genre-Based Approach in Indonesia EFL Context

This paper aimed to critically examine the effectiveness of Genre-Based Approach (GBA) to teaching writing in EFL context of Indonesia. Although several studies have discussed the effectiveness of GBA in teaching writing, those studies put emphasize how GBA focuses on genre or text types rather than the basic principles of GBA that aims for socially functioning language skills. This paper draws on the relevant literature to investigates how GBA suits the teaching of writing in EFL context of Indonesia. Moreover, the discussion focuses on the benefits of GBA which mainly derived from five key principles of Genre proposed by Hyland (2007). Through the exploration of existing empirical studies, this paper found that GBA offer three main benefits in teaching writing under the EFL context. These benefits are: (1) the offer of practical writing skill; (2) the build of students’ confidence in English writing; and (3) stimulation on students’ critical thinking as part of their English literacy. Nevertheless, the benefits of GBA in teaching writing could only be attained if teachers implement GBA according to its full-fledged teaching and learning cycles