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Cytotoxic lymphocytes eliminate virus-infected and cancerous cells by immune recognition and killing through the perforin-granzyme pathway. Traditional killing assays measure average target cell lysis at fixed times and high effector:target ratios. Such assays obscure kinetic details that might reveal novel physiology. We engineered target cells to report on granzyme activity, used very low effector:target ratios to observe potential serial killing, and performed low magnification time-lapse imaging to reveal time-dependent statistics of natural killer (NK) killing at the single-cell level. Most kills occurred during serial killing, and a single NK cell killed up to 10 targets over a 6-h assay. The first kill was slower than subsequent kills, especially on poor targets, or when NK signaling pathways were partially inhibited. Spatial analysis showed that sequential kills were usually adjacent. We propose that NK cells integrate signals from the previous and current target, possibly by simultaneous contact. The resulting burst kinetics and spatial coordination may control the activity of NK cells in tissues.
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Morte Celular/imunologia , Granzimas/metabolismo , Células Matadoras Naturais/imunologia , Engenharia Celular , Transferência Ressonante de Energia de Fluorescência , Células HeLa , Humanos , Cinética , Células MCF-7 , Microscopia , Imagem com Lapso de TempoRESUMO
INTRODUCTION: Inferior vena cava (IVC) filters act in preventing pulmonary embolisms (PE). Various complications have been reported with their use. However, a credible urological complication rate, filter characteristics, and clinical presentation has yet to be summarized. Thus, we reported these complications in the form of a systematic review. EVIDENCE ACQUISITION: A search strategy was designed using PubMed, MEDLINE, and EMBASE on February 10th, 2022. The design of this search strategy did not include any language restrictions. The key words (and wildcard terms) used in the search strategy were urolog*, ureter*, bladder, kidney coupled with filter, inferior vena cava, and cava*. Inclusion criteria were: patients older than 18, with previous IVC filter placement, and urologic complication reported. Exclusion criteria were: patients younger than 18, no IVC filter placement, and no urologic complication reported. Other case series and reviews were excluded to avoid patient duplication. EVIDENCE SYNTHESIS: Thirty-five articles were selected for full-text screening. Thirty-seven patient cases were reviewed, and the median age was 53 (range: 21-92 years old). Abdominal and or flank pain was reported in 16 (43%) patients, hematuria was seen in eight (22%) and two (5%) patients died due to acute renal failure resulting from the urologic complications of the IVC filter. Indications for IVC filter placement were recurrent pulmonary embolism (PE), contraindication to or noncompliance with anticoagulant therapy. The IVC filters were infrarenal in 29 (78.4%) patients, suprarenal in five (13.5%) patients, not reported in two patients, and misplaced into the right ovarian vein in one patient. Three or more imaging modalities were obtained in 19 patients (51%) for planning. IVC filter removal was not performed in 17 (45.9%) patients, endovascular retrieval occurred in nine (24.3%) patients, and open removal was performed in seven (18.9%) patients, and tissue interposition was performed in two (5.4%) patients. One patient did not have the management reported. CONCLUSIONS: Urological complications caused by IVC filters although rare, are likely underreported, require extensive workup, and pose surgical challenges. Due to their complex management, filter retrieval should be planned for as soon as feasible, and plans should be made as early as during the IVC filter implant. For those that do develop complications, clinical judgement must be exercised in management, and open surgical, endovascular or even conservative management strategies can be viable options and should be discussed in a multidisciplinary setting.
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Embolia Pulmonar , Filtros de Veia Cava , Filtros de Veia Cava/efeitos adversos , Humanos , Idoso , Feminino , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Pessoa de Meia-Idade , Adulto , Idoso de 80 Anos ou mais , Masculino , Hematúria/etiologia , Adulto Jovem , Remoção de Dispositivo , Fatores de Risco , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/cirurgia , Doenças Urológicas/etiologia , Doenças Urológicas/terapiaRESUMO
OBJECTIVE: A broad armamentarium of microsurgical techniques affords flexibility to surgeons when choosing a procedure that is best tailored to fit the anatomy of an individual. Herein, we report on the feasibility of using the deep cervical artery (DCA) to revascularize the vertebral artery (VA) via a DCA-V3 bypass graft. METHODS: Fourteen DCAs from 7 injected cadaveric heads were located and traced. The diameter of the main trunk of the DCA was measured bilaterally at the C3 level. The proximal vertebral branches of each DCA were then severed and the main trunk of the DCA was transposed superiorly onto the V3 segment of the VA, which was also exposed bilaterally. RESULTS: The DCA was identified and traced bilaterally on all specimens. The diameter of the main trunk of the DCA at the C3 level ranged from 1.03 to 2.79 mm. The mean diameter of the main trunk of the DCA at this level was found to be 1.52 ± 0.60 mm for the right side and 1.46 ± 0.54 mm for the left side. After releasing the proximal vertebral branches of the DCA, all arteries were able to be transposed to the ipsilateral VA. CONCLUSIONS: Based on the mean diameter of the DCA reported in extant literature and this study, the blood flow volume of the DCA makes it a viable candidate to bypass the proximal VA.
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Revascularização Cerebral/métodos , Microcirurgia/métodos , Artéria Vertebral/cirurgia , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-IdadeRESUMO
Introduction Lateral ankle sprain caused by forcible plantar flexion and inversion of the foot commonly damages the anterior talofibular ligament and other ligaments. Unfortunately, involvement of the bifurcate ligament (BL) is often overlooked when assessing such injuries in clinical practice and identification of this ligament on magnetic resonance (MR) scans can be challenging. Anatomically, the BL is a Y-shaped structure with two bands: the calcaneonavicular ligament (CNL) and calcaneocuboid ligament (CCL). There are few anatomical studies on the morphometric characteristics of the BL and even fewer biomechanical studies. Therefore, the objective of this anatomico-radiological study was to investigate the morphology of the BL using a multifaceted approach, and classify the fiber characteristics of the CNL and CCL. Materials and methods We measured the length and the width of 53 embalmed cadaveric feet. Meticulous dissection of each foot was performed to expose the BL. Measurements of the length, width, thickness, and shape of the CNL and CCL were taken using a digital caliper. We also documented the fiber orientation of each ligament, and used a goniometer to measure the bifurcation angle between the CNL and CCL via two methods. Confirmatory histologic analysis of the ligaments was performed and digital radiographs of the ligaments with attached radiopaque monofilament were taken. We also included an MR scan of the BL. Using descriptive and inferential statistics, we documented any significant relationships between the variables. Results Mean (range) age at death of cadavers was 76 (42-94) years. The CNL was found in all the feet and the CCL was not present in 9.4% of the feet. Mean (standard deviation) length of the CNL and CCL was 22.7 (4.12) mm and 10.9 (2.53) mm, respectively. Mean (standard deviation) thickness of the CNL and CCL was 3.23 (1.56) mm and 1.48 (0.71) mm, respectively. Related to ligament morphology, the CNL was most frequently cord shaped (67.92%) and the CCL was most frequently flat shaped (83.33%). The mean bifurcation angle measured 32.75o and 29.31o in methods 1 and 2, respectively. The correlation between the two measured angles was very strong (p < 0.001). Discussion We found that 90.6% of feet had both the CNL and CCL, 9.4% had the CNL and no CCL, and none (0%) had the CCL and no CNL. These frequencies are similar to a recent Japanese study. Our sample of donors were American and predominantly white. Whether the difference in frequencies between the studies is related to ethnicity is unknown and requires future investigation. Interestingly, on average the CNLs were twice as long and twice as thick as the CCLs. The CCLs tended to be wider distally and tapered compared to the CNLs. Conclusions Our findings better classify the morphology and fiber orientation of the BL. Coupled with the radiographs and MR scan, our data may be of particular value to radiologists and surgeons. Our BL fiber orientation classification system and angle measurements can pave the way for future biomechanical studies to investigate any relationships between fiber type, angle, and strength of the constituent bands. More accurate descriptions of the BL should lead to improved diagnosis and treatment of ligamentous injuries of the foot.
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The translational research paradigm is a process of discovering basic science concepts and applying the knowledge in clinical practice, aiming to improve patient care. The stages involved in the paradigm form a complex network of shared knowledge amongst research collaborators, including patients. This nature of the paradigm allows those involved to work together effectively. However, the translational research paradigm is often overlooked by many scientists, educators, and research institutions. Hence, a large amount of comprehensive and hugely invested research projects fail to make a scientific impact. We aim to outline and describe this paradigm in order to aid in the successful translation of effective research.
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Glioblastoma multiforme (GBM) is the most common type of malignant primary brain cancer in adults. It is composed of highly malignant cells that display metastatic and angiogenic characteristics, making it resistant to current first-line chemotherapy with temozolomide, an alkylating agent. Despite many years of research, GBM remains poorly responsive to multiple available therapies, giving GBM patients, who receive the conventional combination of chemoradiotherapies and surgical resection, a dismal prognosis. There is growing evidence that the conventional systemic chemotherapeutic agents for GBM are ineffective in improving the disease progression. We aim to explore the emerging cellular therapies which may play a significant role in treating GBM.
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Chordomas are primary low-grade bone tumors derived from the embryonic notochord that make up less than 5% of all osseous malignancies and commonly affect the spine at its vertebral body and at its two ends i.e., skull base and the sacrum. Although histologically defined to be low-grade, chordoma is locally destructive, metastatic, and has a serious recurrence rate, which all contribute to the dismal median survival rate of six years. Its locally destructive nature places the adjacent vital neurovascular structures at risk, making an en-bloc resection a challenge. This tumor is also known to show high resistance to currently available chemoradiotherapy, although the benefit of proton beam therapy for skull base chordoma has been demonstrated. There is an additional need to focus our attention on investigating the molecular biology of this chemoradiotherapy-resistant tumor to develop a more targeted therapy, which has additional diagnostic and prognostic values. In this paper, we discuss the therapeutic, diagnostic, and prognostic role of microRNAs (miRNAs) in chordomas.
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Telesurgery uses wireless networking and robotic technology to allow surgeons to operate on patients who are distantly located. This technology not only benefits today's shortage of surgeons, but it also eliminates geographical barriers that prevent timely and high-quality surgical intervention, financial burden, complications, and often risky long-distance travel. The system also provides improved surgical accuracy and ensures the safety of surgeons. In this paper, we describe the current trend of telesurgery's innovative developments and its future.
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OBJECTIVE: Anatomy of the posterior ascending artery (PAA) has been well documented. The PAA forms an apical arcade, which supplies the small branches to the tip of the dens. However, morphometrics of this artery such as diameter and distance from the midline, which could be applied to the diagnosis and surgical procedure, are scant. We aimed to investigate the anatomy of the PAA in order to apply our findings to surgical procedures such as C2 pedicle screw placement. METHODS: Ten sides from 5 Caucasian cadaveric heads in which red latex was injected were used. The origin of the PAA, diameter of the PAA and apical arcade, and the distance from midline were recorded. RESULTS: Diameters of the PAA and apical arcade were approximately 1 mm and 0.7 mm, respectively. Distance from the midline to the PAA was approximately 7 mm. In 1 specimen, the os odontoideum was observed on top of the dens. CONCLUSIONS: The result of this study could provide anatomic knowledge, which is important for C2 pedicle screw placement to the spine surgeon.
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Vértebras Cervicais/cirurgia , Parafusos Pediculares , Fusão Vertebral/métodos , Artéria Vertebral/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Vertebral/cirurgiaRESUMO
Owing to its rarity, rhabdomyosarcoma of the head and neck (HNRMS) has seldom been discussed in the literature. As most of the data is based only on the retrospective experiences of tertiary healthcare centers, there are difficulties in formulating a standard treatment protocol. Moreover, the disease is poorly understood at its pathological, genetic, and molecular levels. For instance, 20% of all histological assessment is inaccurate; even an experienced pathologist can confuse rhabdomyosarcoma (RMS) with neuroblastoma, Ewing's sarcoma, and lymphoma. RMS can occur sporadically or in association with genetic syndromes associated with predisposition to other cancers such as Li-Fraumeni syndrome and neurofibromatosis type 1 (von Recklinghausen disease). Such associations have a potential role in future gene therapies but are yet to be fully confirmed. Currently, chemotherapies are ineffective in advanced or metastatic disease and there is lack of targeted chemotherapy or biological therapy against RMS. Also, reported uses of chemotherapy for RMS have not produced reasonable responses in all cases. Despite numerous molecular and biological studies during the past three decades, the chemotherapeutic regimen remains unchanged. This vincristine, actinomycin, cyclophosphamide (VAC) regime, described in Kilman, et al. (1973) and Koop, et al. (1963), has achieved limited success in controlling the progression of RMS. Thus, the pathogenesis of RMS remains poorly understood despite extensive modern trials and more than 30 years of studies exploring the chemotherapeutic options. This suggests a need to explore surgical options for managing the disease. Surgery is the single most critical therapy for pediatric HNRMS. However, very few studies have explored the surgical management of pediatric HNRMS and there is no standard surgical protocol. The aim of this review is to explore and address such issues in the hope of maximizing the number of options available for young patients with HNRMS.
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The inferior alveolar nerve block (IANB) procedure delivers anesthetics to the pterygomandibular space through which the lingual nerve (LN) and inferior alveolar nerve (IAN) travel. Injury to the LN has been reported more often than injury to the IAN. However, the number of anatomical studies of LN injury is limited. We aimed to establish evidence by investigating LN and IAN anatomy at the level of the mandibular foramen (MF). Forty-four sides from 22 Caucasian cadaveric heads (16 fresh-frozen and six formalin-fixed cadavers) were used in this study. The LN and IAN were laterally dissected, and the diameter and the distance between the two nerves were measured at the level of the MF. The mean diameters of the LN and IAN were 2.57 mm and 2.53 mm in fresh-frozen specimens and 2.97 mm and 2.93 mm in formalin-fixed specimens, respectively. The mean diameters of the LN and IAN in all the specimens were 2.65 mm and 2.64 mm. The distance between the posterior edge of the LN and anterior edge of the IAN at the level of the MF ranged from 1.62 to 8.36 mm with a mean of 5.33 ± 1.88 mm. These findings could elucidate the risk of LN injury during the IANB procedure.
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Vein of Galen aneurysmal malformation (VGAM) is a rare angiopathy, which most commonly presents in infancy. Although very rare, it is associated with high morbidity and mortality rates. In order to minimize such morbid rates, a prompt diagnosis followed by a timely initiation of management is crucial. Multiple antenatal and postnatal imaging techniques for the diagnosis have been described and discussed in the literature. However, to our knowledge, a comprehensive review exploring such a list of imaging options for VGAM has never been established. We aim to review the diagnostic tools to aid in better understanding of the investigative modalities physicians may choose from when treating patients with a VGAM.
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Introduction A reoperation for a cubital tunnel syndrome is not uncommon. Patients often complain of sensorimotor symptoms in the ulnar nerve distribution after their primary surgery. The documented etiologies for such a phenomenon include a "new" kinking of the distal ulnar nerve and a "new" compression of the ulnar nerve by the fascial septum in between or tendinous bands over the muscles of the forearm. The deep fascial plane along which the ulnar nerve travels in the forearm has had scant attention. We present an anatomical study to provide a better understanding of such etiologies to aid physicians in performing successful primary ulnar nerve release that does not lead to risky reoperations and ultimately yields improved patient satisfaction. Materials and methods The forearms of 12 fresh frozen cadavers (24 arms) underwent dissection, during which the fascial relationships between the ulnar nerve and muscles of the anterior compartment were explored with a blunt technique. The relationship between the fascial planes and the ulnar nerve was quantitatively and qualitatively documented. The ranges of motion of the elbow were also observed for any potential compression points on the nerve during the movement. Results In all specimens (n = 24), the ulnar nerve entered the forearm between the humeral and ulnar heads of the flexor carpi ulnaris, after which it routed deep to a deep fascia between the anterior surface of the flexor carpi ulnaris and the posterior surface of the flexor digitorum superficialis. Ulnar nerve branches to the flexor carpi ulnaris pierced this fascial septum while en route to the posterior surface of the muscle. Medially, the branches to the flexor digitorum profundus also pierced this fascial plane. In most arms, the fascia became thinner near the junction between the proximal two-thirds and distal one-third of the forearm. On no side was the ulnar nerve found to be grossly compressed by this deep fascia. However, with the extension of the elbow, a degree of angulation of the proximal ulnar nerve was observed due to its compact connection with the deep fascia. Conclusion Our study revealed that there is an intimate relationship between the ulnar nerve and the deep fascia of the forearm. Since the ulnar branches to the overlying flexor carpi ulnaris pierce this deep structure, a care should be given to its anatomical course during surgery in this region to prevent denervation of the muscle.
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BACKGROUND: A few options of extracranial donor vessels exist for use in intracranial vascular bypass procedures. To our knowledge, the use of an internal thoracic artery for cerebral revascularization has not been studied previously. Hence, this cadaveric feasibility study was performed. METHODS: The internal thoracic artery was dissected in 5 adult cadaveric specimens. The proximal diameter, distal diameter, and length of the vessel were measured and recorded. The artery was then transected distally at the seventh intercostal space and transposed cranially, through a pterional craniotomy opening to reach the middle cerebral artery at the skull base. RESULTS: The mean diameter of the internal thoracic artery at its proximal end was 3.5 mm and at its distal end was 2 mm. The average length of the vessel was 31 cm. There was no statistical difference between the measurements recorded from different sides or sexes. In each specimen, an internal thoracic artery was dissected, rotated superiorly, and advanced subcutaneously behind the ear to reach the middle cerebral artery at the skull base without difficulty and remained tensionless at the site of anastomosis. CONCLUSIONS: In this cadaveric study, we demonstrated the suitability of the internal thoracic artery in use as a donor vessel for a single site anastomosis in a high-flow cerebral bypass procedure.
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Revascularização Cerebral/métodos , Artéria Torácica Interna , Artéria Cerebral Média , Idoso , Idoso de 80 Anos ou mais , Cadáver , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Enxerto Vascular/métodosRESUMO
Pterygopalatine ganglion block (sphenopalatine ganglion block) is a well-known procedure for treating cluster headache and for relieving cancer pain. In this review, the history and anatomy of the pterygopalatine ganglion are discussed, and images, including computed tomography and endoscopy, are presented to improve understanding of the clinical anatomy of the ganglion regarding the block procedure.
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Anestésicos Locais/administração & dosagem , Gânglios Parassimpáticos/anatomia & histologia , Bloqueio do Gânglio Esfenopalatino/métodos , Pontos de Referência Anatômicos , Cadáver , Endoscopia , Gânglios Parassimpáticos/diagnóstico por imagem , Humanos , Injeções , Tomografia Computadorizada por Raios XRESUMO
A variant of the columellar artery (CoA), also known as the nasal septal branch of the superior labial artery of the facial artery, and its unusual direct anastomosis with the right infraorbital artery were identified in a cadaveric dissection. Numerous variants and distribution patterns of the CoA have been described in the literature. However, an oblique and a third CoA variant that anastomoses with the contralateral infraorbital artery has never been reported or depicted. We highlight the significance of a preprocedural vascular examination of the perioral region for optimal functional and esthetic outcome by presenting this unique case. This CoA variant should be known by surgeons performing invasive surgical techniques in the columellar region.
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A sternal foramen (SF), which arises from the incomplete fusion of the cartilaginous neonatal sternum, is a relatively common anatomical variation found in 2.5% to 13.8 % of all individuals. SFs are usually located at the lower third of the sternal body and their average diameter is 6.5 mm. An SF is subclinical; however, its close proximity to the thoracic organs, i.e., the heart and lungs, entails a risk of serious complications from blinded sternal interventions. Moreover, its presence can lead to misinterpretation of radiological and postmortem findings. The SF is ignored by many physicians and non-physician healthcare providers who must understand its clinical significance in order to optimize patient care. Our aim in this review is to highlight the potential clinical consequences for SF patients, discuss recommendations for performing sternal procedures safely when this anatomical variation is present, and preclude radiological and pathological misinterpretations so that patient care can be improved.
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Evolutionary traces of thermophilic adaptation are manifest, on the whole-genome level, in compositional biases toward certain types of amino acids. However, it is sometimes difficult to discern their causes without a clear understanding of underlying physical mechanisms of thermal stabilization of proteins. For example, it is well-known that hyperthermophiles feature a greater proportion of charged residues, but, surprisingly, the excess of positively charged residues is almost entirely due to lysines but not arginines in the majority of hyperthermophilic genomes. All-atom simulations show that lysines have a much greater number of accessible rotamers than arginines of similar degree of burial in folded states of proteins. This finding suggests that lysines would preferentially entropically stabilize the native state. Indeed, we show in computational experiments that arginine-to-lysine amino acid substitutions result in noticeable stabilization of proteins. We then hypothesize that if evolution uses this physical mechanism as a complement to electrostatic stabilization in its strategies of thermophilic adaptation, then hyperthermostable organisms would have much greater content of lysines in their proteomes than comparably sized and similarly charged arginines. Consistent with that, high-throughput comparative analysis of complete proteomes shows extremely strong bias toward arginine-to-lysine replacement in hyperthermophilic organisms and overall much greater content of lysines than arginines in hyperthermophiles. This finding cannot be explained by genomic GC compositional biases or by the universal trend of amino acid gain and loss in protein evolution. We discovered here a novel entropic mechanism of protein thermostability due to residual dynamics of rotamer isomerization in native state and demonstrated its immediate proteomic implications. Our study provides an example of how analysis of a fundamental physical mechanism of thermostability helps to resolve a puzzle in comparative genomics as to why amino acid compositions of hyperthermophilic proteomes are significantly biased toward lysines but not similarly charged arginines.
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Entropia , Proteoma/química , Proteoma/metabolismo , Aminopeptidases/metabolismo , Arginina/metabolismo , Biologia Computacional , Simulação por Computador , Citocromos c/metabolismo , Endopeptidases/metabolismo , Estabilidade Enzimática , Escherichia coli/enzimologia , Genoma/genética , Lisina/metabolismo , Método de Monte Carlo , Mutação/genética , Dobramento de Proteína , Proteômica , Temperatura , Thermus thermophilus/enzimologiaRESUMO
Molecular mechanisms can protect cancer cells from immune attacks. At the level of bulk tissue, these survival mechanisms are often indistinguishable and simply appear as reduced cell death. However, by tracking individual cell survival and death times, we found broad variation in the kinetics of immune evasion. In response to attacks by natural killer cells, we observed that some cancer lines exhibited exponential survival time distributions. Slowly killed cancer lines had reduced exponential rate constants. In contrast, a line engineered to express the serpin protein PI-9, which is known to promote resistance to immune killing, exhibited a markedly nonexponential survival time distribution. By following the histories of individual cancer cells with multiplexed reporters, we obtained evidence that two or more immune attacks are likely required to kill serpin-expressing cells. Thus, resistance is a finite and measurable quantity, with a distinct kinetic signature. A quantitative model based on independently measured parameters is consistent with our conclusions.
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Apoptose/imunologia , Comunicação Celular/imunologia , Sobrevivência Celular/imunologia , Imunidade Celular/imunologia , Células Matadoras Naturais/imunologia , Modelos Imunológicos , Serpinas/imunologia , Simulação por Computador , Células HeLa , Humanos , Cinética , Modelos Estatísticos , Serpinas/genéticaRESUMO
Due to regulatory feedback, biological networks can exist stably in multiple states, leading to heterogeneous phenotypes among genetically identical cells. Random fluctuations in protein numbers, tuned by specific molecular mechanisms, have been hypothesized to drive transitions between these different states. We develop a minimal theoretical framework to analyze the limits of switching in terms of simple experimental parameters. Our model identifies and distinguishes between two distinct molecular mechanisms for generating stochastic switches. In one class of switches, the stochasticity of a single-molecule event, a specific and rare molecular reaction, directly controls the macroscopic change in a cell's state. In the second class, no individual molecular event is significant, and stochasticity arises from the propagation of biochemical noise through many molecular pathways and steps. As an example, we explore switches based on protein-DNA binding fluctuations and predict relations between transcription factor kinetics, absolute switching rate, robustness, and efficiency that differentiate between switching by single-molecule events or many molecular steps. Finally, we apply our methods to recent experimental data on switching in Escherichia coli lactose metabolism, providing quantitative interpretations of a single-molecule switching mechanism.