Cells respond to nutrient deprivation a variety of ways. In addition to global down regulation of cap-dependent protein
synthesis mediated by the GCN2 and mTO RC1 signaling pathways, a catabolic process autophagy is upregulated to
provide internal building blocks and energy needed to sustain viability. It has recently been shown that during nutrient
deprivation tRNAs accumulate in the nucleus, but the functional role of this accumulation remains unknown. This study
investigates whether subcellular localization of tRNAs plays a role in signaling nutritional stress and autophagy. We report
that human fibroblasts that accumulate tRNA in the nucleus due to downregulation of their transportin, Xpo-t, show
reduced mTO RC1 activity and upregulated autophagy. This suggests that sub-cellular localization of tRNAs may regulate
an unicellular response to starvation independently of the cellular nutritional status.
Cells respond to nutrient deprivation a variety of ways. In addition to global down regulation of cap-dependent protein
synthesis mediated by the GCN2 and mTO RC1 signaling pathways, a catabolic process autophagy is upregulated to
provide internal building blocks and energy needed to sustain viability. It has recently been shown that during nutrient
deprivation tRNAs accumulate in the nucleus, but the functional role of this accumulation remains unknown. This study
investigates whether subcellular localization of tRNAs plays a role in signaling nutritional stress and autophagy. We report
that human fibroblasts that accumulate tRNA in the nucleus due to downregulation of their transportin, Xpo-t, show
reduced mTO RC1 activity and upregulated autophagy. This suggests that sub-cellular localization of tRNAs may regulate
an unicellular response to starvation independently of the cellular nutritional status.
Activation of surrogate death receptor signalling triggers peroxynitrite depe...Saurabh Shekhar
includes information about cisplatin resistance cancer cells and their execution through peroxynitrite triggered apoptosis due to death signaling receptors basedon the findings of research article published in cell death and diseases.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
2. Background
• In humans,10 members of the toll-like
receptor(TLR)family of proteins recognize different
pathogen-associated molecular patterns(PAMPs)through
their luminal leucine-rich repeats.
• They localize on cell surface (TLR1, 2, 4, 5,6and11) or in
endosomes (TLR3, 7,8and9)
• TLRs are essential in the early events of innate immunity
as well as in the development of robust adaptive immune
responses.
• Microbial products, such as LPS and DNA, trigger signaling
cascades
3. • The recognition of PAMPs by TLRs ultimately leads to
NF-κ B and AP-1 activation and the production of many
pro-inflammatory cytokines, such as TNF-α and IL -6.
Additionally, type 1 interferon s are induced through the
phosphorylation of IRF3 and IRF7. Thus, TLRs are
important in the early innate immune responses against
pathogens. These initial mediators and the activation of
antigen presenting cells (APCs)will also impact the
ensuing adaptive immunity.
4. Tollip Structure
• TLR signals are regulated by molecules such as the
suppressor of cytokine signaling1 (SOCS1)and Toll-
Interacting protein(Tollip). it is an inhibitory adaptor
protein within Toll-like receptors (TLR). The TLR pathway
is a part of the innate immune system that recognizes
structurally conserved molecular patterns of microbial
pathogens, leading to an inflammatory immune response.
5. Cont.
• A TBD (Tom1-binding domain) and a CUE (coupling of
ubiquitin to endoplasmic reticulum degradation)
domain, located on the N-and C-terminal regions
respectively, confer a potential for multiple protein
interactions Finally, a C2 (internal protein kinase C
conserved region 2) domain binds phosphoinositides
and is responsible for the intracellular trafficking of
the protein to the endocytic pathway.
6. Experimental Evidence for Tollip
function
• While experiments on deficient mice suggested that
Tollip was needed for maximal cytokine production
in response to low doses of TLR agonists, most
studies imply a negative regulatory role for Tollip in
various signaling pathways.
• A high throughput shRNA screen identified Tollip as
a potential regulator of MHC class II (MHC II)
trafficking. Up to now, only two E3 ubiquitin ligases
have been shown to modify MHC class II molecules.
These are the membrane-associated RING-CH
(MARCH) 1
7. MARCH function
• MARCH1 is mostly expressed in the spleen and more
specifically in follicular B cells. Comparably to the class II
trans-activator (CIITA), which is the master regulator of
MHC II gene transcription, MARCH1 appears to be the
master regulator of MHC II expression where MARCH
proteins add ubiquitin to target lysines in substrate
proteins, thereby signaling their vesicular transport
between membrane compartments. MARCH1 down-
regulates the surface expression of major
histocompatibility complex (MHC)class II molecules and
other glycoproteins by directing them to the late
endosomal/ lysosomal compartment
8. Hypotheses of the study
• Hypothesized that Tollip has regulatory role
in the trafficking of MHC II molecules.
9. Materials and Methods
• Antibodies
L243(HLA-DR), CerCLIP.1(CLIP/HLA-DR complexes), BU45 (human invariant
chain)
• Reagents
Poly(I:C) Polyinosinic-polycytidylic acid (poly(I:C)) is a synthetic analog of
double-stranded RNA (dsRNA)
• Cell lines and mice
C57BL/6 (B6), M1K-O mice (knock out mice), Xid mice (Btk knockout)
• Plasmids and constructs
• Transfections
• Flow cytometry
• Immunoprecipitation and western-blot analysis
10. Cont.
• Bioluminescence resonance energy transfer (BRET)
experiment
• Microscopy
• Luciferase assay
• siRNA
• Real-time quantitative PCR
11. Results/ Discussion
Fig. 1. The response to poly(I:C) and LPS is impaired in the Ii KO and M1 KO mice. (A) Splenocytes from
C57BL/6, Ii KO and Xid mice were isolated and treated ex vivo for 24 h with LPS prior to RNA extraction
and qPCR analysis of TNFα mRNA expression. (B) Splenocytes from C57BL/6, Ii KO and M1 KO mice were
isolated and treated ex vivo for 24 h with either LPS or poly(I:C) prior to RNA extraction and qPCR analysis
of TNFα mRNA expression. Expression is illustrated as fold level compared to the value of untreated
C57BL/6 cells, which was set at 1. Data is representative of at least two different experiments.
12. Fig. 2. HLA-DR interacts with TLR3 in live cells. (A) HEK 293E CIITA cells were transfected with
TLR3-flag. 48 h post-transfection, cells were lysed and immunoprecipitated with a flag specific
antibody and blotted for HLA-DRα or HLA-DMβ. Asterisks represent the antibodies. (B) HEK 293T
cells were transfected with HLA-DR–Rluc and increasing amounts of TLR3-EYFP. The BRET ratio
was calculated by dividing the fluorescence with substrate, subtracted from the fluorescence
without substrate, by the luminescence. Error bars represent standard deviation obtained for
two different transfections.
13. C) FRET experiment performed in HeLa cells 48 h after transfection with TLR3-EYFP and HLA-DRα–
EGFP2/β. One stack of living cells was observed by confocal microscopy. The dotted square shows the
bleached area. The signal intensity for the bleached region was quantified for pre- and post-bleach. The
signals were normalized for the ones of the corresponding regions prior to the beach and plotted in a bar
chart. (D) Luciferase assay of HeLa or HeLa HLA-DR1 cells transfected or not with TLR3 and the NF-κB-
luciferase reporter plasmid. The cells were stimulated for 5 h with poly(I:C) prior to the addition of
luciferine. Error bars represent standard deviation obtained for two different transfections. Data is
14. Fig. 3. Tollip knockdown increases HLA-DR expression. (A) HeLa-CIITA-DO cells were transfected with control or TOLLIP-specific
siRNAs, and cultured for 48 h at 37 °C. The bar chart represents the mRNA expression of Tollip for cells transfected with specific or
control siRNA. (B) The cells were stained and analyzed by flow cytometry for cell surface and total expression of HLA-DR (L243 Ab).
The mean fluorescence values (MFV) were plotted to account for variations in the levels of HLA-DR. Error bars represent standard
deviation obtained for two different transfections. (C) Cells were stained for cell surface expression of CLIP (CerCLIP) and total
expression of invariant chain (BU45). The mean fluorescence values (MFV) were plotted to account for variations in the levels of
CLIP and invariant chain Error bars represent standard deviation obtained for two different transfections. (D) HeLa-DR1 and HeLa-
DR1 TM/TM cells were transfected with control or Tollip-specific siRNAs, and cultured for 48 h in 37 °C. Cells were stained for cell
surface expression of HLA-DR (L243 Ab). The mean fluorescence values (MFV) were plotted to account for variations in the levels of
HLA-DR expression. Error bars represent standard deviation obtained for two different transfections.
15. Fig. 4. Tollip blocks MARCH1-mediated down-
regulation of HLA-DR. (A) HEK 293E CIITA cells
were transfected with GFP-Tollip, EYFP and
MARCH1 or GFP-Tollip and MARCH1. Cells
were stained for cell surface expression of HLA-
DR and Tfr. Bar charts represent the mean
fluorescence intensity of EYFP or GFP positive
cells. (B) HeLa CIITA cells were transfected with
GFP-Tollip, EYFP and MARCH1 or GFP-Tollip
and MARCH1. Cells were stained for cell surface
expression of HLA-DR. The bar chart represents
the mean fluorescence intensity of EYFP or GFP
positive cells. (C) Cells were lysed and blotted
for HLA-DRα and HLA-DRβ. The intensity of the
bands was quantified and divided by the one of
cells transfected with the YFP control. Results
are represented as a bar chart. Data is
representative of at least two different
experiments.
16. Fig. 5. Tollip reduces the expression of
MARCH1. (A) HeLa CIITA and HEK 293E CIITA
cells were transfected with EYFP-
MARCH1, GFP-Tollip or an empty vector
(mock). Cell lysates were blotted for actin
(asterisk) and MARCH1. The intensity of the
bands was quantified, normalized to actin and
divided by the one of cells transfected with
MARCH1. Results are represented as a bar
chart. (B) HeLa CIITA cells were transfected
with EYFP-MARCH1, GFP-Tollip or an empty
vector (mock). Cell lysates were blotted for
Tollip. The intensity of the bands was quantified
and the value obtained for cells expressing
Tollip alone was set to 1. Results are
represented as a bar chart. (C) HeLa CIITA or
HEK 293E CIITA cells were transfected with
EYFP-MARCH1 (left panel) of EYFP-
MARCH1K-0 (right panel) with or without GFP-
Tollip, GFP-SOCS1 and EYFP. Cells were
stained for cell surface MHC II and analysed by
flow cytometry. The mean fluorescence values
for MHC II in cells expressing Tollip and EYFP
was set to 1. Data is representative of a least
two different experiments.
17. Figure(6)
Fig. 6. Tollip interacts with MHC II. HeLa cells were transfected with MARCH1
and/or GFP-Tollip and/or empty vector. Samples were immunoprecipitated
with a HLA-DR-specific antibody and blotted for (A) Tollip and (B) DRα. The
asterisk indicates the position of the immunoprecipitating mouse antibody light
chain recognized by the goat secondary antibody. Data is representative of at
least two different experiments.
18. Summery
• Results showed that Ii-deficiency impairs TLR
responses are in line with a functional role of MHC II
molecules in innate immunity. More
specifically, given the well-described endosomal
sorting signals of Ii, this data supports the assertion
that the intracellular pool of MHC II molecules is
needed for efficient LPS response However, they
were not able to rule out that the effect of Ii may be
due to the lower trafficking of MHC II molecules
from the ER in the C57BL/6 background.
19. Recommendation and Conclusion
• The preliminary observations in this study presented
an interplay between MARCH1 and Tollip warrant a
more in-depth mechanistic characterization of the
molecular interactions taking place between
TLRs, MHC II, Tollip, MARCH1 and the endocytic
machinery. Also, future studies should address more
in depth the effect of Tollip on MHC II trafficking in
the absence of MARCH1 as It will be extremely
interesting to test the impact of Ii deficiency on
other mice backgrounds where surface MHC II, at
least quantitatively, appears normal.
20. Reference
• M.-C. Bourgeois-Daigneault, A. M.Pezeshki, T. Galbas, M. Houde, M.
Baril, K. Früh, A. Amrani, S. Ishido, D. Lamarre, J. Thibodeau, Tollip-
induced down-regulation of MARCH1, Results in Immunology, Volume
3, 2013, Pages 17-25