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Pentingnya independensi yang dimiliki Komisi Pemberantasan Korupsi (KPK) bertujuan untuk mempercepat kinerja lembaga KPK itu sendiri. Namun, pasca disahkannya Undang-Undang KPK, kedudukan KPK yang mulanya merupakan lembaga non pemerintah kini termasuk dalam rumpun cabang kekuasaan pemerintah dan beberapa revisi terkait kewenangannya yang saat ini diatur dalam UU KPK terbaru membuat banyak kalangan ahli mengkritik hal tersebut. Penelitian normatif, peneliti tidak melakukan pengumpulan data primer melalui observasi atau eksperimen, melainkan lebih fokus pada analisis terhadap dokumen-dokumen yang sudah ada. Dengan pendekatan ini, peneliti dapat menggali pemahaman yang mendalam mengenai isu hukum yang sedang diteliti. Ada tujuh poin utama yang menjadi penilaian mengapa dalam UU KPK terbaru justru membuat KPK menjadi lemah diantaranya: Pertama, terkait kedudukan KPK yang berada dalam rumpun eksekutif yang dalam pelaksanaan kewenangan dan tugasnya tetap independen; Kedua, mengenai pembentukan Dewan Pengawas KPK; Ketiga, terkait pelaksanaan fungsi penyadapan; Keempat, mengenai mekanisme penerbitan Surat Perintah Penghentian Penyidikan (SP3) oleh KPK; Kelima, terkait koordinasi kelembagaan KPK dengan penegak hukum sesuai dengan hukum acara pidana, kepolisian, kejaksaan, dan kementerian atau lembaga lainnya dalam pelaksanaan penyelidikan, penyidikan dan penuntutan perkara tindak pidana korupsi; Keenam, mengenai mekanisme penggeledahan dan penyitaan; Ketujuh, terkait sistem kepegawaian KPK.

Hukuman kebiri kimia yang diatur dalam undang-undang tentang perlindungan anak menjadi bentuk keseriusan negara dalam melindungi anak-anak dari kejahatan seksual, akan tetapi pada pelaksanaannya banyak terjadi penolakan pada hukuman kebiri tersebut karena dianggap sebagai hukuman yang kejam, tidak manusiawi, dan bertentangan dengan etika kedokteran. Penelitian ini bertujuan untuk menganalisis tentang perlindungan hukum terhadap anak dari tindak pidana kejahatan seksual pada anak dalam sistem hukum di Indonesia, dan untuk menganalisis kepastian hukum atas hukuman kebiri kimia sebagai pembaharuan hukum atas kejahatan seksual terhadap anak. Metode penelitian yang digunakan dalam penelitian ini adalah yuridis normatif yang dilakukan dengan cara penelitian terhadap kaidah hukum positif dan asas hukum yang dievaluasi terhadap kaidah-kaidah hukum (peraturan perundang-undangan) yang relevan. Hasil penelitian ini dapat disimpulkan bahwa hukuman kebiri kimia yang dikenakan kepada pelaku kejahatan seksual terhadap anak merupakan bentuk perlindungan hukum yang diberikan oleh pemerintah terhadap anak dalam melindungi anak-anak di Indonesia dari kejahatan seksual dan penegakan hukum atas hukuman kebiri yakni telah diberlakukannya Undang-Undang Nomor 17 Tahun 2016 tentang Penetapan Peraturan Pemerintah Pengganti Undang-Undang Nomor 1 Tahun 2016 tentang Perubahan Kedua Atas Undang-Undang Nomor 23 Tahun 2002 tentang Perlindungan Anak menjadi undang-undang dan digunakan sebagai dasar hukum oleh hakim dalam memberikan hukuman kebiri kimia kepada pelaku tindak pidana kekerasan seksual terhadap anak.

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30–38 µM).

The activation of the human cannabinoid receptor type II (CB2R) is known to mediate analgesic and anti-inflammatory processes without the central adverse effects related to cannabinoid receptor type I (CB1R). In this work we describe the synthesis and evaluation of a novel series of N-aryl-2-pyridone-3-carboxamide derivatives tested as human cannabinoid receptor type II (CB2R) agonists. Different cycloalkanes linked to the N-aryl pyridone by an amide group displayed CB2R agonist activity as determined by intracellular [cAMP] levels. The most promising compound 8d exhibited a non-toxic profile and similar potency (EC50 = 112 nM) to endogenous agonists Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) providing new information for the development of small molecules activating CB2R. Molecular docking studies showed a binding pose consistent with two structurally different agonists WIN-55212-2 and AM12033 and suggested structural requirements on the pyridone substituents that can satisfy the orthosteric pocket and induce an agonist response. Our results provide additional evidence to support the 2-pyridone ring as a suitable scaffold for the design of CB2R agonists and represent a starting point for further optimization and development of novel compounds for the treatment of pain and inflammation.

Recent evidence has raised in discussion the possibility that cannabidiol can act as a negative allosteric modulator of the cannabinoid type 1 receptor. Here we have used computational methods to study the modulation exerted by cannabidiol on the effects of delta-9-tetrahydrocannabinol in the cannabinoid receptor type 1 and the possibility of direct receptor blockade. We propose a putative allosteric binding site that is located in the N-terminal region of receptor, partially overlapping the orthosteric binding site. Molecular dynamics simulations reveled a coordinated movement involving the outward rotation of helixes 1 and 2 and subsequent expansion of the orthosteric binding site upon cannabidiol binding. Finally, changes in the cytoplasmic region and high helix 8 mobility were related to impaired receptor internalization. Together, these results offer a possible explanation to how cannabidiol can directly modulate effects of delta-9-tetrahydrocannabinol on the cannabinoid receptor type 1.

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a–o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a–l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure–activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).

Molecular hybridisation using cloned hepatitis B virus DNA (HBV DNA) was applied to liver and serum samples from 46 children (39 with liver diseases and seven controls) for detection of HBV DNA sequences, free and integrated into the liver cell genome. HBV DNA integration was observed in 10 children. The young age of some of these cases indicates that such integration can occur early in liver disease and is not related to the duration of viral infection. Thirteen children exhibited serological evidence of active viral multiplication. All but one had free HBV DNA in liver tissue and integrated HBV DNA sequences were found in four cases. Integrated HBV DNA sequences alone were also detected in three children with neither HBV-antigens nor HBV DNA in serum. One had inactive cirrhosis, and the two others, chronic active hepatitis. Consequently DNA hybridisation may be useful for diagnosis, in the absence of serological signs of HBV infection; its specificity was enhanced in the present investigation by negative results in six children with autoimmune chronic active hepatitis. Taken together, the above results imply that HBV-DNA integration can occur in both active and inactive liver disease. Integrated HBV DNA was also observed in the liver of three children with fatal hepatic failure who presented with antibodies to HBsAg and/or to hepatitis B core antigen in the serum. This finding raises the question of the relationship between the host immune factors and the state of HBV DNA. [ABSTRACT FROM PUBLISHER]

Fatty Acid Amide Hydrolase (FAAH) is one of the main enzymes responsible for endocannabinoid metabolism. Inhibition of FAAH increases endogenous levels of fatty acid ethanolamides such as anandamide (AEA) and thus consitutes an indirect strategy that can be used to modulate endocannabinoid tone. In the present work, we present a three-dimensional quantitative structure-activity relationships/comparative molecular similarity indices analysis (3D-QSAR/CoMSIA) study on a series of 90 reported irreversible inhibitors of FAAH sharing a piperazine-carboxamide scaffold. The model obtained was extensively validated (q2 = 0.734; r2 = 0.966; r2m = 0.723). Finally, based on the information derived from the contour maps we designed a series of 10 new compounds with high predicted FAAH inhibition (predicted pIC50 of the best-proposed compounds = 12.196; 12.416).

The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

Background: Incidence of breast cancer is rising in Asian countries, and breast cancer is the most common cancer among Asian women. However, there are few recent descriptive reports on the epidemiology of breast cancer among Eastern and Southeastern Asian populations., Methods: We examined incidence trends for invasive breast cancer in women aged ≥20 years from 15 registries in Eastern (China, Japan, the Republic of Korea, Taiwan) and Southeastern Asia (the Philippines, Singapore, Thailand) for the period 1993-2002 mainly using data from Cancer Incidence in Five Continents, Volumes VIII and IX. We compared trends in annual incidence rates and age-specific incidence curves over a 10-year period. We also compared the incidence rates of Asian-Americans with the rates of their Asian counterparts., Results: Breast cancer incidence rates increased gradually over time in all study populations. Rates were relatively high in Southeastern Asia and became progressively lower along a south-to-north gradient, with a fourfold geographic variation within the study populations. Age-specific incidence curves showed patterns that gradually changed according to incidence rates. Breast cancer incidence among Asian women living in the United States was 1.5-4 times higher than the corresponding incidence rate in the women's respective countries of origin., Conclusion: Breast cancer incidence is expected to continue to increase for the next 10 years in Asia and may approach rates reported among Asian-Americans. The number and mean age of breast cancer cases is expected to increase as the female Asian population ages, the prevalence of certain risk factors changes (early menarche, late menopause, low parity, late age at first live birth, and low prevalence of breastfeeding), and as Asian countries introduce mass screening programs.

Breast cancer risk is increasing in most Asian female populations, but little is known about the long-term mortality trend of the disease among these populations. We extracted data for Hong Kong (1979-2005), Japan (1963-2006), Korea (1985-2006), and Singapore (1963-2006) from the World Health Organization (WHO) mortality database and for Taiwan (1964-2007) from the Taiwan cancer registry. The annual age-standardized, truncated (to > or =20 years) breast cancer death rates for 11 age groups were estimated and joinpoint regression was applied to detect significant changes in breast cancer mortality. We also compared age-specific mortality rates for three calendar periods (1975-1984, 1985-1994, and 1995-2006). After 1990, breast cancer mortality tended to decrease slightly in Hong Kong and Singapore except for women aged 70+. In Taiwan and Japan, in contrast, breast cancer death rates increased throughout the entire study period. Before the 1990s, breast cancer death rates were almost the same in Taiwan and Japan; thereafter, up to 1996, they rose more steeply in Taiwan and then they began rising more rapidly in Japan than in Taiwan after 1996. The most rapid increases in breast cancer mortality, and for all age groups, were in Korea. Breast cancer mortality trends are expected to maintain the secular trend for the next decade mainly as the prevalence of risk factors changes and population ages in Japan, Korea, and Taiwan. Early detection and treatment improvement will continue to reduce the mortality rates in Hong Kong and Singapore as observed in Western countries.

Immediate loading of oral implants has been reported as a beneficial treatment protocol in implant dentistry that increases the comfort of the patient. However, documentation in the literature is poor regarding the clinical outcome and the peri-implant bone response of immediately loaded implants compared with the conventional loading protocol placed in different bone qualities. The aim of this report was to present the role of bone quality in the survival rate of implants using conventional or immediate loading according to the literature. A literature search analysis was performed to demonstrate the survival rate of immediately loaded implants, as well as data from the histologic and histomorphometric evaluation in comparison with conventional loaded implants. This analysis showed high survival rates of immediately loaded implants along with osseointegration, with high percentages of bone-to-implant contacts based on histologic evaluation from human and animal studies of immediately and conventionally loaded implants. This study may provide histologic and clinical evidence of the immediate loading protocol for different bone qualities.

We sought to determine the pathway of HIV-1 entry into human astrocytes and the fate of HIV-1 by detecting viral DNA and GFP-tagged HIV-1 in HIV-1-infected primary astrocytes. Immunochemistry and FACS analysis were used to assess the expression of DC-SIGN in human purified cultures of astrocytes. HIV-1 LTR was detected by PCR in infected cultures of human embryonic astrocytes at their third passage. GFP-Vpr-labeled R5 tropic HIV-1 was used to infect astrocytes, and was followed by confocal microscopy. Forty percent of astrocytes expressed DC-SIGN at the membrane level. Viral DNA was detected 5 days after infection in human astrocytes, but not in the presence of anti-CCR5 and anti-DC-SIGN mAbs. T20, NH4Cl, and bafilomycin had no effect on viral DNA detection. We found that 67% of the fluorescent GFP-Vpr-labeled R5 tropic HIV-1 viruses were present in the endosomes of astrocytes at 24 h, but not in the presence of anti-CCR5 or DC-SIGN mAbs. Bafilomycin and NH(4)Cl each increased the amount of fluorescent HIV-1 detected outside endosomes. Titers of p24 remained low from day 1 to day 5 postinfection, in the presence or absence of NH4Cl. Astrocytes express DC-SIGN and HIV-1 penetrates into these cells through CCR5- and/or DCSIGN- mediated endocytosis, via a pH-dependent pathway, with a delayed reverse transcription after infection without productive infection.

Within the brain, glial cells are target cells for human cytomegalovirus (HCMV) and HIV. We infected cultures of unstimulated human microglial cells and astrocytes of embryonic origin and of monocyte-derived macrophages (MDM) with HCMV strain AD169 and observed down-regulation of the plasma membrane expression of CCR5 in the three cell types, and of CXCR4 and CD4 in microglial cells only. Cells were then coinfected simultaneously or at a 24-h interval with both AD169 and two different HIV-1 monocytotropic strains. HCMV late antigens and HIV-1 tat protein colocalized in the cytoplasm of 5-10% of microglia and MDM. p24 antigen levels decreased 10- to 40-fold in supernatants of MDM and the reduction was greater when HCMV infection was performed 24 h before HIV-1 infection. These data suggest that HCMV-induced reduction in the cell-surface expression of the primary co-receptor of HIV-1 monocytotropic strains may impair the ability of HIV to infect these cells.

The regulation of the thyroid gland by TSH is mediated by a heterotrimeric G protein-coupled receptor. Nonthyroid effects of TSH have been reported, and expression of its receptor has been described in adipocytes and lymphocytes. We have previously reported the existence of specific and saturable binding sites of TSH and specific TSH effects in primary cultured rat brain astroglial cells. We now report expression of the TSH receptor gene in these cells; the coding sequence of the corresponding complementary DNA is identical to that previously established in thyroid. Using specific antisense RNA probe, expression of this gene was detected in some isolated or clustered glial fibrillary acidic protein-positive primary cultured cells by in situ hybridization. With this technique, we further detected TSH receptor messenger RNA (mRNA) expression in rat brain cryoslices in both neuronal cells and astrocytes. Its presence predominated in neuron-rich areas (pyriform and postcingulate cortex, hippocampus, and hypothalamic nuclei) and was mostly colocalized with neuron-specific enolase. In astrocytes, this mRNA was detected in the ependymal cell layer and the subependymal zone, and several isolated cells were also found in the brain parenchyma. We also detected TSH receptor mRNA and protein in primary cultured human astrocytes. The protein was detected as well in both rat and human brain cryoslices. Together, these findings clearly demonstrate the expression of the TSH receptor gene in the brain in both neuronal cells and astrocytes.