Structure-based design of MptpB inhibitors that reduce multi-drug-resistant mycobacterium tuberculosis survival and infection burden in vivo

Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatmen

Efficient self-timed interfaces for crossing clock domains

We accept this thesis as conformin

Efficient self-timed interfaces for crossing clock domains

With increasing integration densities, large chip designs are commonly partitioned into multiple clock domains. While the computation within each individual domain may be synchronous, the interfaces between these domains often use asynchronous methods. One such approach is the STARI technique[Gre93, Gre95] where a self-timed FIFO compensates for clock-skew between the sender and receiver. This dissertation presents implementations of STARI where the FIFO consists of a single, handshaking stage. I start with the simplest case where the sender and receiver operate at exactly the same frequency with an unknown skew. I then generalize this design for links with clocks whose frequencies are rational multiples of each other, clocks whose frequencies are closely matched, and arbitrary clocks. In each of these cases, the STARI interface can exploit the stability of typical clocks to achieve low latencies and negligible probabilities of synchronization failure using very simple hardware. I have designed and tested a proof-of-concept chip fabricated with the TSMC 0.18μ CMOS process for the scenario where clocks of different domains are exactly matched in frequency. The tests have demonstrated our claims about the skew tolerance of the design and I am now in the process of designing the interface for further generalizations.Science, Faculty ofComputer Science, Department ofGraduat

A minimalist source-synchronous interface

data PLL Figure 1. Multiple Clock Domains in a SOC Abstract We present a novel implementation of source syn-chronous communication. Our design appears to the designer as a latch with two clock inputs, one from the trans-mitter and the other from the receiver. Our circuit is simple and provides a skew tolerance of nearly two clock periods.The analog dynamics of our circuit provide a simple initialization mechanism that maximizes the robustness of theinterface to skew variations

Efficient Self-Timed Interfaces for Crossing Clock Domains

With increasing integration densities, large chip designs are commonly partitioned into multiple clock domains. While the computation within each individual domain may be synchronous, the interfaces between these domains often use asynchronous methods. One such approach is the STARI technique[12, 13] where a self-timed FIFO compensates for clock-skew between the sender and receiver. We present implementations of STARI where the FIFO consists of a single, handshaking stage. We start with the simplest case where the sender and receiver operate at exactly the same frequency with an unknown skew. We then generalize this design for links with clocks whose frequencies are rational multiples of each other, clocks whose frequencies are closely matched, and arbitrary clocks. We show that in each of these cases, the STARI interface can exploit the stability of typical clocks to achieve low latencies and negligible probabilities of synchronization failure using very simple hardware

A Minimal Source-Synchronous Interface data PLL

We present a novel implementation of source synchronous communication. Our design appears to the designer as a latch with two clock inputs, one from the transmitter and the other from the receiver. Our circuit is simple and provides a skew tolerance of nearly two clock periods. The analog dynamics of our circuit provide a simple initialization mechanism that maximizes the robustness of the interface to skew variations.

Heterochromatin extension: a possible cytogenetic fate of primary amenorrhea along with normal karyotype

Primary amenorrhoea (PA) is considered to be one of the challenging and taxing problems for the gynaecologist. Previous studies suggested that different numerical and structural chromosome abnormalities are associated with this. Heterochromatin polymorphisms are considered to be normal variant but considering the recent research on crucial cellular effects of heterochromatin, we have aimed to find out the prevalence of heteromorphism along with other standard chromosomal abnormalities. This was an observational study which was conducted in Diamond Harbour Govt. Medical College and Hospital, West Bengal during March 2019–February 2021. Clinical features of 178 patients were noted and peripheral venous blood was taken following informed consent. This comprehensive study reveals that there are 10.11% of the females among 178 females having a heterochromatin extension which is significantly high. We hence suggest that heteromorphism may be associated with ovarian dysfunction leading to amenorrhoea as the region of heterochromatin acts as a key part in chromosome structure, histone modification and gene regulation. Analysis at the molecular level may be needed to unveil any relationship between heteromorphism and PA. Impact Statement What is already known on this subject? Primary amenorrhoea (PA) is a menstrual abnormality found in females with the prevalence of 1–3%. It may be associated with different types of numerical and structural chromosomal anomalies. Among them Turner’s syndrome (pure and in variant form) is the commonest chromosomal aberration associated with PA. Some patients with PA are found to have a normal karyotype with heterochromatin extension on the large arm (q) of either chromosome 9 or chromosome 16. Chromosomal polymorphism with increase in heterochromatin region consists of highly repetitive sequences of satellite DNA, which normally does not encode any protein and thus considered to be a normal variant. What do the results of this study add? This comprehensive study reveals that there are 10.11% of the females among 178 females having a heterochromatin extension which is significantly high. PA and certain association of phenotypical stigmata like short stature in these patients with heterochromatin extension can be explained on the basis of histone modification and gene regulation by heterochromatin. What are the implications of these findings for clinical practice and/or further research? We will be able to know about involved transcription factors those are responsible for the histone modification directly linked to the heterochromatin extension by further molecular study. That will definitely help to find out the reason for PA as well as implementation of gene therapy in these cases

Anticancer activities of pterostilbene-isothiocyanate conjugate in breast cancer cells: involvement of PPARγ.

Trans-3,5-dimethoxy-4'-hydroxystilbene (PTER), a natural dimethylated analog of resveratrol, preferentially induces certain cancer cells to undergo apoptosis and could thus have a role in cancer chemoprevention. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor whose activation results in growth arrest and/or apoptosis in a variety of cancer cells. Here we investigated the potential of PTER-isothiocyanate (ITC) conjugate, a novel class of hybrid compound (PTER-ITC) synthesized by appending an ITC moiety to the PTER backbone, to induce apoptotic cell death in hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cell lines and to elucidate PPARγ involvement in PTER-ITC action. Our results showed that when pre-treated with PPARγ antagonists or PPARγ siRNA, both breast cancer cell lines suppressed PTER-ITC-induced apoptosis, as determined by annexin V/propidium iodide staining and cleaved caspase-9 expression. Furthermore, PTER-ITC significantly increased PPARγ mRNA and protein levels in a dose-dependent manner and modulated expression of PPARγ-related genes in both breast cancer cell lines. This increase in PPARγ activity was prevented by a PPARγ-specific inhibitor, in support of our hypothesis that PTER-ITC can act as a PPARγ activator. PTER-ITC-mediated upregulation of PPARγ was counteracted by co-incubation with p38 MAPK or JNK inhibitors, suggesting involvement of these pathways in PTER-ITC action. Molecular docking analysis further suggested that PTER-ITC interacted with 5 polar and 8 non-polar residues within the PPARγ ligand-binding pocket, which are reported to be critical for its activity. Collectively, our observations suggest potential applications for PTER-ITC in breast cancer prevention and treatment through modulation of the PPARγ activation pathway

Pterostilbene-Isothiocyanate Conjugate Suppresses Growth of Prostate Cancer Cells Irrespective of Androgen Receptor Status

<div><p>Chemotherapy and anti-hormonal therapies are the most common treatments for non-organ-confined prostate cancer (PCa). However, the effectiveness of these therapies is limited, thus necessitating the development of alternative approaches. The present study focused on analyzing the role of pterostilbene (PTER)-isothiocyanate (ITC) conjugate – a novel class of hybrid compound synthesized by appending an ITC moiety on PTER backbone – in regulating the functions of androgen receptor (AR), thereby causing apoptosis of PCa cells. The conjugate molecule caused 50% growth inhibition (IC₅₀) at 40±1.12 and 45±1.50 μM in AR positive (LNCaP) and negative (PC-3) cells, respectively. The reduced proliferation of PC-3 as well as LNCaP cells by conjugate correlated with accumulation of cells in G2/M phase and induction of caspase dependent apoptosis. Both PI3K/Akt and MAPK/ERK pathways played an important and differential role in conjugate-induced apoptosis of these PCa cells. While the inhibitor of Akt (A6730) or Akt-specific small interference RNA (siRNA) greatly sensitized PC-3 cells to conjugate-induced apoptosis, on the contrary, apoptosis was accelerated by inhibition of ERK (by PD98059 or ERK siRNA) in case of LNCaP cells, both ultimately culminating in the expression of cleaved caspase-3 protein. Moreover, anti-androgenic activity of the conjugate was mediated by decreased expression of AR and its co-activators (SRC-1, GRIP-1), thus interfering in their interactions with AR. All these data suggests that conjugate-induced inhibition of cell proliferation and induction of apoptosis are partly mediated by the down regulation of AR, Akt, and ERK signaling. These observations provide a rationale for devising novel therapeutic approaches for treating PCa by using conjugate alone or in combination with other therapeutics.</p></div