Synthesis and Evaluation of Cereblon-Recruiting HaloPROTACs

The development of proteolysis-targeting chimeras (PROTACs) is a useful approach to develop new therapeutics. PROTACs work by tagging proteins for degradation by the ubiquitin-proteasome system (UPS) in the cell. Especially, in this work, we use Halotag, a genetically modified bacterial dehalogenase that forms covalent bonds with ligands functionalized with terminal chlorohexyl moieties. Reported here the development of bifunctional HaloPROTAC ligands that recruit the cereblon (CRBN) E3 ubiquitin ligase to degrade target proteins fused with a HaloTag in the cell. The dissertation will start with a review of the ubiquitin-proteasome system (UPS) system, PROTACs, and induced protein degradation. Next, I will discuss the synthesis and evaluation of CRBN Recruiting HaloPROTACs for degrading proteins. In this collaborative effort, we found that the CRBN-recruiting HaloPROTAC demonstrated higher activities in inducing the degradation of HaloTagged EGFP than an existing VHL-recruiting ligand at sub-micromolar concentrations of the compound. We hypothesize that we can expand the use of the HaloPROTAC system various cell and tissue types for validating the degradation targets for therapeutic discovery. The final chapter of this dissertation is a brief review on the elucidation of the UPS cascade system and a report on the synthesis of unnatural amino acids for the synthesis of ubiquitin conjugates(diUBs) as activity-based probes for deubiquitinating enzymes

PERLINDUNGAN HUKUM TERHADAP AHLI WARIS KARENA PEWARIS MEWAKAFKAN SATU-SATUNYA HARTA WARISAN DITINJAU BERDASARKAN HUKUM ISLAM

ABSTRACKAn expert is a person who is entitled to inherit property after the heir dies due to several factors, such as due to blood relations, due to marriage, and because of Wala' or Hukmiah relationships. The heir during his lifetime, if he has or wants to make waqf of his inheritance, must not exceed one third of the entire property that he will inherit to his heirs, because if he will leave the heir in a poor condition because he has donated all of his inheritance, it is a big disadvantage which has fatal consequences. to the heirs he lives with. In the Qur'an it has been emphasized that the heir should never leave the heir in a state of deprivation and beg from others, and the heir must prioritize the welfare of the heir. The limitation on the size of the will shows that, even if it is prescribed to make a will to humans, the benefit or future of the children must still be a priority.Keywords: heirs, heir, waqf the only inheritance. ABSTRAK            Ahli merupakan orang yang berhak mendapatkan harta warisan setelah pewaris meningal dunia yang disebabkan oleh beberapa faktor, seperti karena adanya hubungan darah, karena perkawanian, dan karena Wala’ atau hubungan Hukmiah. Pewaris semasa hidupnya jika telah atau inigin mewakafkan harta warisannya tidak boleh melebihi sepertiga dari seluruh harta yang ia akan wariskan kepada ahli warisnya, karena jika ia akan meninggalkan ahli waris dalam keadaan miskin karena ia telah mewakafkan seluruh harta warisannya itu merupakan kemudharatan yang besar yang berakibat fatal terhadap ahli waris yang ia tinggal. Dalam Al-Qur’an sudah ditegaskan bahwa jangan sekali-kali pewaris meninggalkan ahli waris dalam keadaan serba kekurangan dan meminta-minta terhadap orang lain, dan pewaris harus lebih mengutamakan kesejahteraan ahli waris. Pembatasan besarnya wasiat tersebut menunjukkan bahwa, kalaupun disyari’atkan berwasiat kepada manusia, namun kemaslahatan atau masa depan Anak-anak tetap harus menjadi prioritas.Kata kunci: Ahli Waris, Pewaris, Mewakafkan satu-satunya harta warisan

Mars Express measurements of surface albedo changes over 2004 - 2010

The pervasive Mars dust is continually transported between the surface and the atmosphere. When on the surface, dust increases the albedo of darker underlying rocks and regolith, which modifies climate energy balance and must be quantified. Remote observation of surface albedo absolute value and albedo change is however complicated by dust itself when lifted in the atmosphere. Here we present a method to calculate and map the bolometric solar hemispherical albedo of the Martian surface using the 2004 - 2010 OMEGA imaging spectrometer dataset. This method takes into account aerosols radiative transfer, surface photometry, and instrumental issues such as registration differences between visible and near-IR detectors. Resulting albedos are on average 17% higher than previous estimates for bright surfaces while similar for dark surfaces. We observed that surface albedo changes occur mostly during the storm season due to isolated events. The main variations are observed during the 2007 global dust storm and during the following year. A wide variety of change timings are detected such as dust deposited and then cleaned over a Martian year, areas modified only during successive global dust storms, and perennial changes over decades. Both similarities and differences with previous global dust storms are observed. While an optically thin layer of bright dust is involved in most changes, this coating turns out to be sufficient to mask underlying mineralogical near-IR spectral signatures. Overall, changes result from apparently erratic events; however, a cyclic evolution emerges for some (but not all) areas over long timescales

The Electrophysiological Correlates of Processing Self- and Externally Generated Sensations

In order to interact effectively with the world, the brain must distinguish between sensations which are caused by one’s own actions and external sensations that are caused by the environment. This may be achieved through an efference copy-based forward model mechanism in which a copy of the motor command is sent to the relevant sensory cortices with a prediction for the action’s sensory outcome. Studies show that neural and behavioural responses to self-initiated sensations are modulated relative to identical but externally presented stimuli. In EEG studies, self-generated auditory stimuli elicit smaller early ERP components (N1 and P2) than identical but externally generated stimuli. Furthermore, pre-movement neural activity (RP and LRP) may encode the action’s sensory consequences. Previous EEG studies have focussed largely on the auditory domain, with inconsistent results coming from experiments with visual stimuli. These studies also lacked optimal control conditions with passive movements and behavioural measures of perception. In this dissertation, three studies with healthy subjects (two published and one submitted to a journal) were carried out to examine questions related to the neural and behavioural correlates of the forward model mechanism. Study I examined the sensory ERPs elicited by visual stimuli that were triggered by active (self-initiated) and passive (involuntary; finger moved by device) movements. Stimulus perception was measured using an intensity judgement task. Visual N1 and P2 ERP amplitudes were reduced in the active condition, indicating suppression of the self-initiated sensory input. There was no effect of movement in the behavioural task. However, suppression of the P2 component was correlated with behavioural suppression. This component might reflect higher-level processes such as conscious evaluation of perceived intensity. In Study II, it was investigated whether RP and LRP encode information related to anticipating action-effect contingency and stimulus modality. When the action was followed immediately by a stimulus, RP differed between active and passive movements approximately 200 ms before the button press. This difference was not there when the sensory consequences were delayed by one second. Conversely, LRP encoded the movement type but not the action-effect contingency. This demonstrates a dissociation between RP and LRP, with RP representing higher-level processes, including anticipation of upcoming stimuli and LRP being related to low-level preparation for the movement execution. MVPA was also used to investigate whether action-effect prediction was represented across the whole scalp. Movement decoding (active vs passive) showed ramping accuracy in all conditions from around -800 ms onwards up to an accuracy of ∼ 85% at the movement. Accuracy was lower in the control than in the visual and auditory conditions approximately 200 ms before the movement. Sensory modality (visual vs auditory) was also decodable for both active and passive conditions. The active condition showed increased accuracy shortly before the movement. The results suggest that pre-movement EEG activity encodes action-feedback prediction. In Study III, in addition to active (executed here with a minimum latency of 700 ms) and passive movements, participants made quick movements (as quickly as possible in response to a tone cue). The active and quick conditions showed reduced N1-P2 amplitudes relative to the passive condition and did not significantly differ from each other. Active and quick also showed comparable LRP amplitudes, which were significantly greater than passive. However, though all three conditions showed a negative shift in RP, the quick condition had lower amplitudes than the active condition, indicating differences in motor preparation. This may be related to additional preparatory processes for executing the movement as quickly as possible after the cue. The results showed that, even though active and quick were prepared differently, this did not ultimately lead to differences in feedback processing. Taken together, this thesis offers a finer-grained specification of the efference copy mechanism. There was robust evidence of neural sensory suppression in the visual domain. For the first time, it was shown that action-feedback processing is similar between active and quick movements that nonetheless differ in movement initiation, intention to move, task demand and preparation time. The studies have also demonstrated the dissociation between RP and LRP, with the novel result that LRP is significantly reduced preceding involuntary movements. Furthermore, across three studies, there was evidence that RP encodes higher-level motor preparation processes, including feedback anticipation, which was specific to the active condition. The thesis also contributed an innovative analysis approach using MVPA, which demonstrated prediction for the action’s outcome before the movement, taking into account patterns of activity across the entire scalp. The studies presented in this thesis enhance our understanding of the efference copy mechanism, with potential implications for future translational work which could contribute to understanding the deficits associated with major symptoms of psychosis

Topological Aspects of Spin and Statistics in Nonlinear Sigma Models

We study the purely topological restrictions on allowed spin and statistics of topological solitons in nonlinear sigma models. Taking as space the connected $d$-manifold $X$, and considering nonlinear sigma models with the connected manifold $M$ as target space, topological solitons are given by elements of $pi_d(M)$. Any topological soliton $\alpha \in \pi_d(M)$ determines a quotient \Stat_n(X,\alpha) of the group of framed braids on $X$, such that choices of allowed statistics for solitons of type $\alpha$ are given by unitary representations of \Stat_n(X,\alpha) when $n$ solitons are present. In particular, when $M = S^2$, as in the $O(3)$ nonlinear sigma model with Hopf term, and $\alpha \in \pi_2(S^2)$ is a generator, we compute that \Stat_n(\R^2,\alpha) = \Z, while \Stat_n(S^2,\alpha) = \Z_{2n}. It follows that phase $\exp(i\theta)$ for interchanging two solitons of type $\alpha$ on $S^2$ must satisfy the constraint $\theta = k\pi/n$, $k \in \Z$, when $n$ such solitons are present.Comment: 14 page

PERAN GURU KARAWITAN JAWA DALAM MENUMBUKAN SIKAP NASIONALISME SISWA ANGGOTA KEGIATAN KARAWITAN SMK NEGERI 10 SURABAYA

Abstrak Penelitian ini mengungkapkan tentang peran guru karawitan Jawa dalam menumbuhkan sikap Nasionalisme siswa anggota kegiatan karawitan di SMK Negeri 10 Surabaya. Permasalahan yang muncul pada penelitian ini adalah tentang rendahnya kecintaan terhadap budaya lokal remaja Indonesia yang menyebabkan rendahnya sikap Nasionalisme di kalangan remaja Indonesia saat ini. Remaja Indonesia saat ini lebih memilih mencintai kebudayaan asing daripada kebudayaan lokal. Ditengah kondisi yang memprihatinkan tersebut, SMK Negeri 10 Surabaya merupakan salah satu instansi pendidkan yang memberikan pembelajaran karawitan Jawa sebagai bentuk kepedulian terhadap lunturnya sikap Nasionalisme dikalangan remaja saat ini. Teori yang digunakan pada penelitian ini adalah teori belajar sosial Albert Bandura. Metode penelitian yang digunakan ialah metode kualitatif dengan model deskriptif. Lokasi penelitian dilakukan di SMK Negeri 10 Surabaya. Informan penelitian dalam penelitian ini ialah guru karawitan  Jawa SMK Negeri 10 Surabaya. Data dikumpulkan dengan metode observasi dan wawancara. Data dianalisis melalui reduksi data, penyajian data, dan penarikan kesimpulan atau verifikasi. Berdasarkan analisis data yang dilakukan dapat ditarik kesimpulan bahwa peran guru karawitan Jawa SMK Negeri dalam menumbuhkan sikap Nasionalisme siswaanggota karawitan dilakukan dengan cara memberikan pembelajaran teoritik di kelas, memberikan pembelajaran praktik latihan karawitan, memberikan penugasan yang dapat menumbuhkan sikap nasionalisme, serta dengan menampilkan sikap yang dapat dijadikan teladan bagi siswa dalam bersikap. Kata kunci : Peran guru karawitan, Sikap Nasionalisme, SMK Negeri 10 Surabay