Role of WASP and N-WASP in B Cell Receptor Signaling.

After the elimination of infection, termination of immune response is necessary. This process can occur only when B-cell activation is shut down otherwise autoimmunity can occur. Recently researchers from University of Maryland and Harvard Medical School USA tried to analyze the process involved in inactivation of B-cells after infection has been cleared from the body. The main focus was on Wiskott-Aldrich syndrome protein (WASP) and neural WASP (N-WASP). Wiskott-Aldrich syndrome is X-linked disorder and results in immune dysregulation. WASP is entirely expressed in hematopoietic cells and N-WASP in neuronal cells.

Which molecules are involved in activation or inhibition of N-WSAP and how the latter affects B-cell activation were some key areas of enquiry and research in this study. The role of N-WASP in BCR (B-cell receptor) activation was analyzed by devising an experiment that activates human B cells and mouse BCR in a similar way. Results of this experiment revealed that at places where BCRs interact with antigen similar to WASP, transient activation of N-WASP occurs. In other words BCR stimulation causes N-WASP activation following WASP activation. Earlier studies lead this team to hypothesize that N-WASP has a compensatory role in WASP KO B-cells. For investigating this hypothesis KO mice were used. Results revealed that for antigen-induced BCR clustering both N-WASP and WASP are critical. Also B-cell morphology and B-cell spreading are affected.  However N-WASP in the absence of WASP, supports B-cell spreading and in presence of WASP, B-cell contraction.

The effects of N-WASP and WASP KO on B-cell morphology led the team of researchers to dig into the BCR signaling.  Experiments revealed that attenuation as well as stimulation of BCR signaling involves N-WASP. Earlier study from the same authors had shown that BCR signaling and clustering are in a two-phase relationship. Since cNKO had effects on both B-cell contraction and clustering, the researchers thought of N-WASP regulating signaling via cluster modulation of surface BCRs. Data from experiments showed role of N-WASP in promoting growth of BCR micro-clusters into the central cluster by down-regulating the BCR signaling system. Infact authors of this paper have clearly demonstrated that N-WASP has role in both positive and negative regulation of BCR signaling. However negative regulation suggested that B-cell self tolerance could also be affected by N-WASP. For clarification serum levels of anti- dsDNA and anti-nuclear DNA antibody were measured in cKNO (N-WASP deleted) mice and were found to be elevated, suggesting a clear role in self-tolerance. Moreover activation of BCR induces receptor internalization which in turn involves reorganization of actin. To elaborate the role of N-WASP and WASP in internalization and co-localization and immmunoflorescence studies were done with a marker named as LAMP-1 and surface-labeled BCRs respectively.

WASP and N-WASP involvement in activation of BCR led to understanding of their relationship. The experimental data suggests that both of them regulate each other negatively during activation of B-cells. However, BCR signaling inversely regulates both WASP and N-WASP activation.

On the whole the results have shown that B cells lacking N-WASP protein are activated for extended periods of time than the normal B-cells. Also mice with B-cells deficient in making N-WASP show increase in number of self-reactive B cells.

Open Access Article Under Creative Commons Attribution License.

References:

Chaohong Liu, Xiaoming Bai, Junfeng Wu, Shruti Sharma, Arpita Upadhyaya, Carin I. M. Dahlberg, Lisa S. Westerberg, Scott B. Snapper, Xiaodong Zhao, and Wenxia Song. N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling. PLoS Biol. doi:  10.1371/journal.pbio.1001704.

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Chromotherapy: Cure by Colors and Quran

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Great gift by God, colors are involved in daily life of ours. Colors are so universal in our daily life that we often take them for-granted. Has any one of you imagined life without colors? It would be in-fact all black and white. But wait, black and white are also colors, isn’t?

Our emotions, feelings and frame of mind are all associated with colors. Upon passing through a prism white light (polychromatic light) splits or disperses into seven colors of light, each having its own characteristic frequency and behavior. Difference in frequencies or vibrations means diverse magnetic effects by each color. Have you ever felt charmed because of any color? Have you ever thought that why some colors are your comforting partners?

Our body contains all the colors in perfect equilibrium as are minerals and vitamins. Disturbance of this balance can cause malfunctions and lead to onset of anxiety and other diseases. Hence colors are pillars of healthiness and happiness; they are healers and nourishers that create and stimulate varied responses in us. You might have listened about other miracles, but the miracles of light are mightier than anything listened or observed. Being at peace is the most desired thing by any person existing on the earth and colors are peacekeepers. They create calmness and rest in your soul. Why a person becomes happy upon seeing a rainbow? You know the answer.

Colors exist from the very beginning of the universe and have been utilized for varied purposes from ancient times. In many religious books like Quran there are verses mentioning about colors e.g., Chapter Al-Insan mentions that those who believe in God (Allah) shall wear fine green silk in heaven. Also in Chapter 35 verse 27 (Surat-ul Fatir) Allah says:

quranic 2

meaning

Khwaja Shamsuddin Azeemi in his book Muraqaba defines color meditation and there has been no conflict regarding his theories so far. However with the advancement of science, Photodynamic therapy (PDT) came into existence. This technique employs photosensitive chemicals that area injected intravenously. The injected chemicals accumulate in cancerous cells and help to identify and eliminate them. Chromo-therapy is now used to perk up the performance of athletes. The endocrine system is known to get stimulated by color therapy as the radiations of color interact differently with this system.

White light has seven primary components and each of them is represented by VIBGYOR. Among them the first three (VIB) are soothers and the last three (YOR) are great stimulators. Let us know about the healing powers of VIBGYOR.

VIOLET RAYS:violet

This color has least wavelength and maximum frequency amongst the other colors of VIBGYOR. This color is element of air, transformation, relaxation, compassion, sensitiveness, dignity and spirituality. This color provides immunity boost up, deepens ones appetite, nourishes brain cells to battle against diseases and is useful for the treatment of skin ailments and nervous imbalance.

INDIGO RAYS:indigo

Indigo is called as color of imagination, stabilization and purification. This color is known to create tranquility, awareness, accurate intuition, deep sleep and relaxation. It increases glow on skin and nourishes bones and cartilages. Urinary tract problems are better treated with this color.

BLUE RAYS:blue

Blue is most bounteous color of the universe. This color is called as color of confidence or color of truth. This color is astringent, miraculous, electrical and antiseptic in nature. It increases speaking capabilities, relaxation and vitality. This color can cure throat problems and hearing impairments by providing proper magnetic vibrations. Skin ailments can also be cured by blue color because of its bactericidal nature. Blood circulation improvement, nerve sheath nourishment and weight loss rectification can also be achieved by this color. Anti-stress and anti-inflammatory effects have been achieved by this color. The AAAS scientists in late nineties reported to have used this light for treatment of depressions and addictions. Moreover, neonatal jaundice, rheumatoid arthritis, lung ailments and scars of tissues are also known to be treatable by this magical color.

GREEN RAYS:green

Green is the master color and creates calmness, psychological harmony, hope, rejuvenation, inner peace, healing and sense of love. it represents creative intelligence.  Skin problems, digestive ailments, ulcers, typhoid, fever, kidney problems can be treated with this color. Turquoise-Blue is an amalgamation of blue and green color that can be used to cure skin tanning and wrinkles. Green color is mentioned in Quran also. Chapter 36 verse 80 says (Surat-ul Yaasin) :

quranicWords (لَون) means color and (أخضر) means green

YELLOW RAYS:

yellow

This color is called as the color of wisdom. Mental clarity, cheerfulness, confidence, vitality, communication and quick learning can be achieved by this color. Excretory organ diseases (constipation, gall bladder stones), skin and bone marrow problems are all treatable by this color. This color can speed-up digestive system. Arthritis, unnecessary calcium deposits, mental disorders and night blindness are all curable by this color.

ORANGE RAYS:orange

This color is called as social color, as resourcefulness, social confidence and happiness are all known to be created by this color. This color is associated with encouragement, optimism, opulence, enthusiasm, cheering, innovation, merriment and non-constricting. Hemorrhage, gout, menstrual cramps, anemia, mental ailments, anxiety, hypertension, tuberculosis and hiccups are all treatable by this color. This color is known to increase supply of oxygen to the body tissues and decrease depression. Stimulation of lungs, digestion and relief from spasms and muscle cramps fall also in the lap of this color.

RED RAYS:red

This color has least frequency and longest wavelength amongst all other colors. It has often been called as color of power as it can reach extremities. Pioneering spirit, attentiveness, sexuality, exuberance, dynamism, brazenness is achievable by this color. Tendons and face muscles can be strengthened by this color. This color produces warmth, energy, stimulation, increases blood circulation and sexual desire, releases constriction, stimulates ovulation and cell growth. Strength increase is due to effect of this color on adrenal glands that release adrenalin. Moreover, female disorders, anemia, nerve inactivity, constipation, asthma, goiter, numbness, tiredness, wound healing, cancer and obesity can be treated with this color.

Apart from the above mentioned, there are many other varieties of colors like pink, magenta etc.  These colors are also known to have health benefits. Pink is known to suppress revenge, tranquilize veins, balance sex and mitigate stress. Magenta color is known to promote physical healing and is excellent for children.

Viral Fusion, Stability and Infectivity Affected by a Single Amino Acid Mutation in H1N1 Influenza Virus.

Flu or Influenza is a seasonal infectious disease caused by an RNA virus that belongs to Orthomyxoviridae family. A seasonal epidemic of this disease causes millions of deaths. Influenza virus mutates to produce a new strain every time. This process occurs by blending of genes of humans and birds mostly. In the year 2009 a novel strain appeared and was named as swine flu or A/H1N1. This strain also caused Spanish flu of 1918. Strain A is most virulent and has many identified serotypes like H1N1, H2N2 (Asian Flu), H3N2, H5N1 (Bird Flu), H7N7, H1N2, H9N2, H7N9 etc.

RNA genome is segmented into seven to eight pieces of RNA and encodes proteins like neuraminidase(NA), hemagglutinin (HA), nucleoprotein(NP), nuclear export protein (NS1 and 2) etc. HA is indispensable for target binding and NA for release of progeny virus. HA has a stalk region and a head region. It specifically binds sialic acid residues on host cell surfaces and is known to be major determinant of viral host tropism and pathogenicity. After viral fusion and endocytosis, the low pH inside endosome is known to be encouraging for irreversible structural changes for HA subunits viz., HA1 and HA2. Scrutiny of data suggests that in the HA2 stalk there is a mutation (E47K). This mutation of H1N1 isolates has been exploited by the authors to contrast two H1N1 viruses that differ at HA2 position 47 of their HA proteins.

Original strain of H1N1 A/California/7/2009 (Cal/09) and a later strain A/Brisbane/10/2010 (Bris/10) were used in this study. Cal/09-like strains contain E47 in the HA2 stalk. However since 2009, an E47K mutation emerged and became dominant globally. Membrane fusion activity as determined by transient expression assay and viral fusion assay revealed that the HA2-47 in H1N1 HA stalk region affects the threshold pH for membrane fusion. Cal/09 HA fusion triggers at pH 5.4 and that of Bris/10 at pH 5, indicating a difference of 0.4 units. Moreover HA2-E47K substitution (glutamic acid to lysine substitution) lowered threshold pH of Cal/09 HA fusion, indicating HA2 47th residues regulatory role. It is to note that higher threshold pH for fusion means a lower viral thermal stability.

Since it is known both for balance of viral acidic stability in invaded tissues and for fusion activation, optimal pH is required. Hence pH affects host-specific replication and pathogenicity even in narrow pH range differences. Thus for transmission and virus host tropism, pH of HA fusion activation could be an important factor. In order to account for such statements vero cells (Verda Reno Cells) were used. Vero cells are known to have higher endosomal pH than MDCK cells; they were exploited for comparing pH and viral replication support. Experiments revealed that replication support for viruses with a fusion pH threshold of 5.4 is more as compared to those with pH 5. Moreover it has been demonstrated that Cal/09 HA2-E47 virus that has low acid stability (high threshold pH for fusion) also displays lower thermal stability compared to HA2-K47 virus. Compared to Cal/09, the H1N1pdm strain of 2012 has lower fusion pH, indicating that lower fusion pH might be coupled with adapting to human environment.

Most effective approach to prevent influenza is vaccination. Vaccinations against flu usually contains antigens from three viral strains (two A strains and one B strain) that are inactivated and is called as trivalent influenza vaccine(TIV). Each year a new vaccine has to be formulated as the virus is mutating rapidly to render previously formulated vaccines as ineffective. For the 2009 pandemic, a monovalent live attenuated vaccine (LAIV) was produced. In this study it has been found that E47 mutation of HA2 in Cal/09 vaccine awards more stability from 4°C to about 57.5°C.

In summary, this study adds to the better understanding of influenza infection and might aid in speedy reaction to future epidemics. In-fact genetic signature identified in the HA stalk has noteworthy implication for production of vaccines for future pandemics.

Chromosomally integrated human herpes virus 6 (Cl-HHV6) disrupts telomere stability and favors release of functional viruses.

Each end of chromatid contains a region of repetitive nucleotide sequences that guard deterioration of chromosomes. This region is known as telomere and aids in prevention of shortening of chromosomes during the process of replication. A protein complex termed as Shelterin binds via TRF1/2 and POT 1 to telomeric DNA to prevent inappropriate recombination repair events. The length of telomeres is varied among different species and is generally composed of guanine rich residue repeats. Telomere loops or T-loops are formed at the ends due to ss-DNA curls stabilized by proteins. Telomeres are shortened in almost all cancers and tumors.

Human Herpes Virus 6 (HHV6), which is a collective name for two sub families HHV 6A and HHV 6B, is one of the most common cause of “sixth disease” or “roseola infantum”, that occurs in infants. An important feature of HHV6 is that it can integrate into human telomeric DNA. This process is achieved by right direct repeat (DRr) of the virus. Once integrated, this virus can inherit itself into the germline of an organism. About 1% of population inherits a chromosomally integrated human herpes virus 6 (Cl-HHV6) and less is known regarding the effects of this integration on the telomere length and function.

Recently a research team at the Department of Genetics, University of Leicester, UK, tried to determine whether integration of HHV6 is a biological form of latency or not and how does its association affect the telomere or telomere length in carriers of HHV6? While looking for the answers the researchers of this study have established that T1 region has a role in erosion process that aids in the loss of PAC1 and DRl-T1 region until telomere repeats are added in the germline. The virus associated telomere is readily lengthened by telomerase in the germline. Cl-HHV6 associated telomere is one of the shortest in somatic cells. It is more prone to deletions and truncations that cause manufacture of short telomere at the new spot in the viral genome.

About 1178 samples from HapMap Phase I, the CEPH-HGDP and the CEPH family panels, 528 samples from the People of the British Isles panel, 2153 samples from the Orkney Complex Disease Study and 92 sperm DNA samples were analyzed in this study for identification of CL-HHV6 carriers.

In case of 92 sperm DNA samples that were tested to scrutinize virus-associated telomere lengths in the germline, it was found that proportion of outlier molecules was considerably shorter than the mean length and this shortening outcome was likely due to t-loop erasure. Single telomere length analysis (STELA) was used for measuring the telomere lengths. Moreover, telomere capping is affected by HHV6 via t-loop formation. The integrated copies of HHV6B can be excised via t-loop formation and it could be one of the preliminary steps towards reactivation of virus for spread to new locations in the cell. In-fact the authors have detected that within Cl-HHV6 genome extra-chromosomal and truncated CL-HHV6 molecules are present that are responsible for disruption of telomere stability. Thus, Instability and replicative senescence, due to fusion events, are more likely to occur in cells carrying short telomerase associated with Cl-HHV6.

Overall in wrapping up, this study has proved it that HHV6 latency is as a result of telomeric integration.

Reference:

Yan Huang, Alberto Hidalgo-Bravo, Enjie Zhang, Victoria E. Cotton, Aaron Mendez-Bermudez, Gunjan Wig, Zahara Medina-Calzada, Rita Neumann, Alec J. Jeffreys, Bruce Winney, James F. Wilson, Duncan A. Clark, Martin J. Dyer, and Nicola J. Royle. Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Res. 2014 January; 42(1): 315–327. doi:  10.1093/nar/gkt840

This is an OA article under creativecommons.org/licenses/by/3.0/

Spindle pole orientation is not dependent on LGN, but rotation is dependent.

During the process of cell division, the distribution of chromosomes to daughter cells is affected by a particular cell organelle namely spindle apparatus. This apparatus is composed of hundreds of proteins and its orientation during the process of cell division is responsible for the determination of cell-division plane. The proteins that come to aid the process include LGN, STIL and motor proteins like dyenins etc.

Recently a publication was updated in Cell Cycle journal were in authors have tried to elucidate that how orientation process and spindle apparatus positioning are correlated during cell division. While trying to find an answer to the query, they have developed a method of live microscopy that could be used to monitor orientations and movements of spindle in a cell. Software capable of achieving tracking such happenings in an automated manner came into existence because of this effort by researchers. It has been named as Spindle3D.

It has been found that spindles are rotated and then maintained along the interphase long axis. Quantification of spindle movements has revealed that the rotational movements require LGN while as spindle orientation does not require LGN. However the mechanisms that maintain the orientation along the long-axis are disrupted or are sensitive to 2ME2 (2-Methoxy Estradiol).

Reference:

Cell Cycle. 2013 August 15; 12(16): 2643–2655. doi:  10.4161/cc.25671