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Forces are produced, supported and transmitted by molecular elements such as cytoskeletal and adhesion components. FRET can be used to measure the amplitude of tension that these molecules experience in tissues. A FRET tension sensor module consists of two fluorophores: a donor and an acceptor ( Miyawaki, 2011 ; Gayrard and Borghi, 2015 ; Fig.3 Aa). FRET efficiency ( E ) decreases sharply with the distance R between fluorophores according to the equation E=R 0 6 /( R 6 + R 0 6 ), where R 0 is the distance at which FRET efficiency is 50% ( Fig.3 Ab). A spring of known stiffness, such as a defined polypeptide sequence, is genetically inserted between donor and acceptor ( Mens Air Vrtx Gymnastics Shoes Grey Light Carbonanthracitesailb 005 6 UK Nike yxpNvGE0W
; Grashoff et al., 2010 ). A force pulling on the molecule increases the spring length, thus reducing FRET efficiency. The FRET efficiency-force relationship is calibrated in vitro ; typically, it probes from one to several pN ( Grashoff et al., 2010 ; Fig.3 Ac). This technique relies on the assumption that molecular tension is the only cause of FRET change, which has to be tested using tensionless control constructs, e.g. lacking the N- or C-termini of the encoded proteins, under the same perturbations as their tension-sensing counterpart. In principle, this allows non-tension contributions to FRET changes, regardless of their origin, to be corrected for.

Fig. 3.

Visual sensors. (A) FRET. (Aa) FRET tension sensor module consists of two fluorophores, a donor (blue) and an acceptor (green), linked with a spring of known stiffness, the length of which increases with pulling forces (arrows) acting on it. (Ab) Energy transfer efficiency (light gray arrows in Aa) sharply decreases with the distance between fluorophores. (Ac) The FRET efficiency-force relationship is experimentally calibrated . Red line indicates a fitting curve. (Ad) FRET tension sensor module inserted into DE-cadherin molecules can measure their tension. FRET efficiency (color bar) in border cells of ovary is shown. (B) Liquid drop. (Ba) A liquid drop made of fluorocarbon oil (light orange) is coated by surfactant molecules, fluorescent molecules and adhesion molecules. The surface tension () of an isolated drop is measured in solution (left panel). When the liquid drop is inserted between cells in a tissue (right panel), it is deformed by cellular forces (arrows). Image analysis determines the local mean curvature of the droplet surface (), from which the anisotropic component of the normal stresses on the droplet (σ) can be determined according to the equation σ 2γ. (Bb) Liquid drops (red) injected between tooth mesenchymal cells (green). Scale bar: 20 µm. The values of the anisotropic stresses (color bar) are mapped onto the three-dimensional shape of the liquid drop (enlarged in inset). Adapted with permission from: (Ad) Cai et al. (2014 ) and (Ba, Bb) Campàs et al. (2014 ).

A major advantage of the method is that it could be applicable to any protein of interest as long as the tagged protein (containing the tension sensor) retains the localization and functions of the native protein. In addition, the method is, in principle, compatible with imaging of other proteins and/or structures, other force measurements, or any mechanical manipulation performed on a microscope stage. Within a very short time period (the time for image acquisition, typically around 100 ms), a map of molecular tensions (for the tagged molecule) in a tissue can be obtained in vivo : each pixel intensity results from the sum of FRET efficiencies of the molecules within this pixel. In cell culture, FRET has also been used to measure uniaxial compression ( Paszek et al., 2014 ). More generally, fluorescent materials exhibit a variety of properties that could be dependent on other mechanical quantities, such as intracellular pressure ( Gomez-Martinez et al., 2013 ; Watanabe et al., 2013 ), and thus could be used to develop new force probes.

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An arm type in which a group of participants receives the intervention/treatment that is the focus of the clinical trial.
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A type of intervention model describing a clinical trial in which groups of participants receive one of several combinations of interventions. For example, two-by-two factorial assignment involves four groups of participants. Each group receives one of the following pairs of interventions: (1) drug A and drug B, (2) drug A and a placebo, (3) a placebo and drug B, or (4) a placebo and a placebo. So during the trial, all possible combinations of the two drugs (A and B) and the placebos are given to different groups of participants.
The date on which the study record was first available on There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
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U.S. Public Law 110-85, which was enacted on September 27, 2007. Section 801 of FDAAA amends Section 402 of the U.S. Public Health Service Act to expand and create a clinical study results database . For more information on FDAAA 801, see the History, Policies, and Laws page on this site.
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A type of eligibility criteria . These are the reasons that a person is allowed to participate in a clinical study.
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The general design of the strategy for assigning interventions to participants in a clinical study. Types of intervention models include: single group assignment , parallel assignment , cross-over assignment , and factorial assignment .
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A type of clinical study in which participants are assigned to groups that receive one or more intervention/treatment (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. The assignments are determined by the study's protocol . Participants may receive diagnostic, therapeutic, or other types of interventions.
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The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown .
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A clinical trial design strategy in which one or more parties involved in the trial, such as the investigator or participants, do not know which participants have been assigned which interventions. Types of masking include: open label, single blind masking, and double-blind masking.
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An arm type in which a group of participants does not receive any intervention/treatment during the clinical trial.
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The general design of the strategy for identifying and following up with participants during an observational study . Types of observational study models include cohort, case-control, case-only, case-cross-over, ecologic or community studies, family-based, and other.
An adverse event that is not a serious adverse event , meaning that it does not result in death, is not life-threatening, does not require inpatient hospitalization or extend a current hospital stay, does not result in an ongoing or significant incapacity or interfere substantially with normal life functions, and does not cause a congenital anomaly or birth defect; it also does not put the participant in danger and does not require medical or surgical intervention to prevent one of the results listed above.
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For clinical trials , a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies , a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure .
A type of intervention model describing a clinical trial in which two or more groups of participants receive different interventions. For example, a two-arm parallel assignment involves two groups of participants. One group receives drug A, and the other group receives drug B. So during the trial, participants in one group receive drug A "in parallel" to participants in the other group, who receive drug B.
A summary of the progress of participants through each stage of a clinical study, by study arm or group/cohort . This includes the number of participants who started, completed, and dropped out of the study.
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA) . The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0) , Phase 1 , Phase 2 , Phase 3 , and Phase 4 . Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to determine the drug's most frequent and serious adverse events and, often, how the drug is broken down and excreted by the body. These trials usually involve a small number of participants.
A phase of research to describe clinical trials that gather preliminary data on whether a drug works in people who have a certain condition/disease (that is, the drug's effectiveness). For example, participants receiving the drug may be compared to similar participants receiving a different treatment, usually an inactive substance (called a placebo ) or a different drug. Safety continues to be evaluated, and short-term adverse events are studied.
A phase of research to describe clinical trials that gather more information about a drug's safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. These studies typically involve more participants.
A phase of research to describe clinical trials occurring after FDA has approved a drug for marketing. They include postmarket requirement and commitment studies that are required of or agreed to by the study sponsor. These trials gather additional information about a drug's safety, efficacy, or optimal use.
Describes trials without FDA-defined phases , including trials of devices or behavioral interventions.
An inactive substance or treatment that looks the same as, and is given in the same way as, an active drug or intervention/treatment being studied.
An arm type in which a group of participants receives a placebo during a clinical trial.
The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure . Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "estimated" primary completion date is the date that the researchers think will be the primary completion date for the study.
In a clinical study's protocol , the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment . Most clinical studies have one primary outcome measure, but some have more than one.
The main reason for the clinical trial . The types of primary purpose are: treatment, prevention, diagnostic, supportive care, screening, health services research, basic science, and other.
The person who is responsible for the scientific and technical direction of the entire clinical study.
The written description of a clinical study. It includes the study's objectives, design, and methods. It may also include relevant scientific background and statistical information.
National Library of Medicine (NLM) staff perform a limited review of submitted study records for apparent errors, deficiencies, or inconsistencies. NLM staff identify potential major and advisory issues and provide comments directly to the study sponsor or investigator. Major issues identified in QC review must be addressed or corrected (see First submitted that met QC criteria and Results first submitted that met QC criteria ). Advisory issues are suggestions to help improve the clarity of the record. NLM staff do not verify the scientific validity or relevance of the submitted information. The study sponsor or investigator is responsible for ensuring that the studies follow all applicable laws and regulations.
A type of allocation strategy in which participants are assigned to the arms of a clinical trial by chance.
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Hope, I had a very similar experience and felt like I had more energy and muscle strength after starting B12 shots. I had to increase my intake of Potassium to about 2400 mg a day as my body was using more potassium because it was no longer starved for B12. I still have problems but the B12 shots helped a lot.


Gregory says

Dear Hope, I am not at all surprised at the difference between the shots and the sublingual. The sublingual is not really a very good mode of delivery, and there is no conclusive evidence that shows it is better than high dose tablets. It is based upon an incorrect premise that there are blood vessels near the surface of the underside of the tongue and so the material should go into them. Well that is the problem, it doesn’t, and I don’t know of any study that has shown it does. In the intestine you have a massive area for uptake of vitamin B12, much, much bigger than under the tongue. Best estimates for 1 mg sublingual tablet, 1 mg sublingual spray or 1 mg oral tablet is that up to 10 ug gets in. If you are deficient, you are down somewhere between 10-50 mg, or around 1,000 to 50,000 times more than you can aborb by either of the 3 methods. That is why the shots are so much better. It is also why we are working on a transdermal oil that gets around the same amount as the shots.


I started to get excellent results from sublingual B12 when I began to put the tablet between my cheek and gum and hold it there for 1-2 hours. It is absorbed slowly, chewing it up doesn’t work. If you continue with B12 shots, make sure you are getting the active form, methylcobalamin, not the cheap imitation stuff. I also use adenosylcobalamin, the other active form of b12, marketed as dibencozide, with great results.


sue says

HI, everyone. Just wanted to say how we underestimate Vitamin B12. My son has ASpergers syndrome. Last winter, out of the blue, he had Total Bell’s Palsy. It took him 6 months for the cheek to move, and 12 months for the nerve totally recuperate, even though his left side of face is still drooping. Everyone(including my son’s father, who is a doctor) were saying that Bell’s palsy comes only once. Well, guess what? 4 weeks ago, my son ‘s right side of the face was affected with nasty Bell’s palsy again!! His neurologist gave him anti viral and steroid. When my son came back(he is 21 years old, he was visiting his father during 2nd Bell’s occurrence) , I read so much about B12 methylcobalamine. I immediately gave him injections every other day. BELIEVE ME, AFTER 1ST INJECTION, HIS LIP STARTED MOVING. AFTER ONE WEEK, HIS FACE HAS COMPLETELY HEALED, MOVING, SMILING!!!!! MY SON’S FATHER, WHO IS A DOCTOR, SAID THAT THIS WAS JUST A COINCIDENCE . i give my son injections 1mg every other day. Hi stopped having twitches(he always had them), he is smiling and moving his lips.


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