Common Point Of Origin Research Articles

A Rare Cell State Underpins Diverse Mechanisms of Adaptive Resistance to CAR T-Cell Therapy in B-Cell Acute Lymphoblastic Leukemia

The most common pattern of treatment failure of B-cell acute lymphoblastic leukemia (B-ALL) following CD19-targeting chimeric antigen receptor T cell therapy (CAR T), is a measurable residual disease (MRD) negative response followed by relapse. Whilst in a fraction of patients relapse is associated with loss of function mutations &/or deletions of the CD19 locus, a significant proportion of patients relapse with CD19+ disease. We hypothesised that this arises from a rare CAR T tolerant persister population that is able to survive the strong therapeutic pressure and seed relapse. To address this, we investigated the clonal origin and transcriptional dynamics of “CAR T tolerant persister cells” via time resolved clonal tracing of the progeny of individual B-ALL clones, using expressed molecular barcodes in an immunocompetent mouse model of CD19 targeting CAR T. We demonstrate that relapse is a pre-determined fate of rare B-ALL clones, which each adopt diverse, yet clone-specific, transcriptional phenotypes at relapse. Moreover, each diverse relapse phenotype appears to be underpinned by a shared, rare “origin of relapse” cell state that is common to all relapse-fated clones. Our immunocompetent mouse model of murine CAR T cells targeting CD19 (ID3-h41bb-3z) on a syngeneic, BCR::ABL1(p190) driven B-ALL recapitulates the clinical scenario of MRD-negative remission followed by CD19+ relapse. We labelled B-ALL cells with SPLINTR (Fennell & Vassiliadis et al. Nature 2022), a lentiviral lineage tracing reagent comprising expressed molecular barcodes that are read out by single cell RNA sequencing (scRNAseq), to allow dynamic profiling of the clonal origin and transcriptome of individual B-ALL clones over time, across multiple therapeutic timepoints including pre-treatment, remission and relapse. Tumour initiating frequency in this model of B-ALL is high with 23% of transplanted clones able to establish fulminant B-ALL. Only 0.7% of clones, however, were able to persist following CAR-T pressure and seed relapse. In fact, >99% of post-CAR T relapsed disease was comprised by just 3 (0.3%) individual clones and in one mouse disease relapse was driven entirely a single clone. Remarkably, we found that the same clones were able to drive relapse in multiple mice, consistent with a the presence of pre-determined, heritable cell-intrinsic properties capable of causing relapse following CAR T. To further study this phenomenon, we performed scRNAseq on these murine B-ALL samples to examine the transcriptional profiles of these rare, relapse fated clones prior to and following CAR T. Whilst prior to therapy, relapse fated clones were transcriptionally identical to the CAR T sensitive clones, following CAR T we observed that relapse fated clones adopted distinct transcriptional profiles compared to their transcriptome in the absence of therapeutic pressure, suggesting transcriptional adaptation underpins their ability to survive therapy. We noted that each resistant clone had a unique adaptive response and consequent transcriptional signature. Remarkably however, the adaptive response of each clone in different mice was essentially identical, indicative of strong, conserved clone-intrinsic mechanisms of adaptation. Although each CAR T resistant clone adopted disparate transcriptional states in the bulk ALL, we identified a single rare cell state (~1% of the bulk B-ALL) that was shared between all clones, highly suggestive of a common point of origin from which transcriptional adaptation arises. This rare cell state demonstrates metabolic hallmarks of therapy resistance and a distinct developmental transcriptional profile most analogous to the recently characterised preBCR-dependant stage of normal B cell development, raising the prospect that these cells represent an “origin of relapse” cell state. Preliminary data suggests that this rare cell state may also be conserved in human Ph+ B-ALL. In summary, by modelling CD19+ B-ALL relapse following MRD negative remission after CAR T, we have identified a rare cell state that our analysis suggests serves as a common and necessary point from which a transcriptionally diverse range of B-ALL phenotypes can arise and be maintained. We have demonstrated that relapse following CAR T emerges due to clone-specific transcriptional differences from this rare cell state, a phenomenon which may extend to a diverse range of therapies in B-ALL.

Mehmed the Conqueror between Sulh-i Kull and Prisca Theologia

AbstractThis article presents a new interpretation of the reign of the Ottoman sultan Mehmed the Conqueror (r. 1444–46, 1451–81) as refracted through the twin historical lenses of Mughal South Asia and the Renaissance Mediterranean. On the one hand, it argues that Mehmed, despite his current reputation as a conquering hero of Islam, in fact aspired to a model of sovereignty analogous to Akbar's Sulh-i Kull, and with a common point of origin in the conceptual worlds of post-Mongol Iran and Timurid central Asia. On the other hand, it also draws from the historiography of the Italian Renaissance to interpret Mehmed's cultural politics as being simultaneously inspired by a particular thread of Renaissance philosophy, the Prisca Theologia, which in many ways served as the Ottoman equivalent of Akbar's Sulh-i Kull.

Editors' Selections from Relevant Scientific Publications.

Editors' Selections from Relevant Scientific Publications.

On the stem diameter under positive impulses in long air gaps

The diameter of a stem, a common origin point for streamers where the transition from the streamer to the leader takes place, has a significant effect on the simulation of streamer-to-leader transition. To measure the diameter of the stem, a schlieren system was established with the temporal and spatial resolutions of 5 μs and 70 μm, respectively. Experiments were conducted under positive lightning and switching impulses; the applied voltage, discharge current, and schlieren images were recorded synchronously. A method was proposed to measure the diameter of the stem based on the schlieren images, with which the stem diameter as a function of time was obtained. Moreover, the initial diameters of the stem under different conditions were obtained through the linear fitting. At last, a relation between the initial cross-sectional area of the stem and the discharge current was given within a certain range.

An anomalous band originating from the fabella causing semimembranosus impingement presenting as knee pain: a case report

BackgroundThe presentation of patients with knee injuries which can have a significant impact on their ability to work and perform activities of daily living is constantly rising. The posterolateral corner of the knee has a complex anatomy of muscles, tendons, and ligaments, with huge variation in the population. The fabella is one such structure, found in the posterolateral corner of the knee, which can serve as a common origin point of various ligaments.Case reportWe present a case report of a 53-year-old white man who presented with atraumatic, posterior knee pain and was found to have a congenital, anomalous band originating from the fabella, causing semimembranosus impingement. This was diagnosed with magnetic resonance imaging; he underwent division of the anomalous band, which resulted in complete resolution of his symptoms.ConclusionWe propose that patients who present with posterior knee pain, without any history of trauma, and have no abnormalities on plain radiographs, should undergo magnetic resonance imaging of their knees. This will help in assessing the ligament complex in the posterior compartment of the knee, and exclude impingement of the semimembranosus as an, albeit rare, cause of posteromedial knee pain.

Gordon Tullock's Scholarly Legacy: Extracting It from Buchanan's Shadow

Thinking was Gordon Tullock’s primary interest in life. He let his thinking roam widely and creatively over his many fields of interest; moreover, Tullock is widely recognized for the robust and creative quality of this thought. He left a valuable legacy. All the same, I think the value of that legacy is underappreciated. Too much is Tullock perceived as residing within the shadow of James Buchanan’s constitutional thinking, with Tullock supplying the homo economicus to complement Buchanan’s constitutional concerns. To the contrary, I explain that Tullock and Buchanan resemble divergent parabolas who point analytically in opposing directions despite their common point of origin in the high value they place on individual liberty. Tullock and Buchanan reflected divergent research programs. Unlike Buchanan, however, Tullock left his research program mostly implicit amid his many writings, and in this essay I seek to extract it from Buchanan’s shadow.

Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction.

A recent article by Farrell etal. characterizes the phenomenon, mechanisms, and treatment of a local and severe hypoperfusion/hypoxia event that occurs in brain regions following a focal seizure. Given the well-established role of cerebral ischemia/hypoxia in brain damage and behavioral dysfunction in other clinical settings (e.g., stroke, cerebral vasospasm), we put forward a new theory: postictal hypoperfusion/hypoxia is responsible for the negative consequences associated with seizures. Fortunately, inhibition of two separate molecular targets, cyclooxygenase-2 (COX-2) and l-type calcium channels, can prevent the expression of postictal hypoperfusion/hypoxia. These inhibitors are important experimental tools used to separate the seizure from the resulting hypoperfusion/hypoxia and can allow researchers to address the contribution of this phenomenon to negative outcomes associated with seizures. Herein we address the implications of this postictal stroke-like event in acute behavioral dysfunction (e.g., Todd's paresis) and sudden unexpected death in epilepsy (SUDEP). Moreover, anatomic alterations such as increased blood-brain barrier permeability, glial activation, central inflammation, and neuronal loss could also be a consequence of repeated hypoperfusion/hypoxic events and, in turn, underlie chronic interictal cognitive and behavioral comorbidities (e.g., memory deficits, anxiety, depression, and psychosis) and exacerbate epileptogenesis. Thus these seemingly disparate and clinically important observations may share a common point of origin: postictal hypoperfusion/hypoxia.

Variations in the branching pattern of femoral artery in full term human fetuses

Introduction: Femoral vessel catheterization is used in neonatal intensive care units for various neonatal health conditions. The present study is to find out the variations in the branching pattern of femoral artery in new born babies which could increase the risk of complications. Materials and Methods: 10 full term dead embalmed fetuses were collected from the Department of Anatomy. Total 20 lower limbs were dissected. Results: Out of 20 extremities 9 showed variations and 11 were normal. Variations observed were – common truck for superficial circumflex femoral and superficial external pudendal arteries, medial; circumflex femoral artery from femoral artery, common point of origin of medial and lateral circumflex femoral and profunda femoris artery and double femoral artery. Conclusion: The variations found in this study may be helpful to the neonatal and pediatric surgeons while dealing with femoral vessel catheterization. Keywords: Femoral artery, Variations, Catheterization, Profunda femoris, Ischemia

Mathematical modeling of the nonlinear electrodynamics effect of signal delay in the magnetic field of pulsars

The paper is devoted to mathematical modeling of the nonlinear vacuum electrodynamics effect: the action of the strong magnetic field of a pulsar on the propagation of electromagnetic waves. It is shown that, due to the birefringence of the vacuum, for one normal wave, it takes more time to travel from a pulsar to a detector installed on astrophysical satellites than for the other normal wave. The delay of the pulse carried by the second normal wave relative to pulse carried by the first normal wave from the common point of origin to the satellite is calculated.

Computational biophysical, biochemical, and evolutionary signature of human R-spondin family proteins, the member of canonical Wnt/β-catenin signaling pathway.

In human, Wnt/β-catenin signaling pathway plays a significant role in cell growth, cell development, and disease pathogenesis. Four human (Rspo)s are known to activate canonical Wnt/β-catenin signaling pathway. Presently, (Rspo)s serve as therapeutic target for several human diseases. Henceforth, basic understanding about the molecular properties of (Rspo)s is essential. We approached this issue by interpreting the biochemical and biophysical properties along with molecular evolution of (Rspo)s thorough computational algorithm methods. Our analysis shows that signal peptide length is roughly similar in (Rspo)s family along with similarity in aa distribution pattern. In Rspo3, four N-glycosylation sites were noted. All members are hydrophilic in nature and showed alike GRAVY values, approximately. Conversely, Rspo3 contains the maximum positively charged residues while Rspo4 includes the lowest. Four highly aligned blocks were recorded through Gblocks. Phylogenetic analysis shows Rspo4 is being rooted with Rspo2 and similarly Rspo3 and Rspo1 have the common point of origin. Through phylogenomics study, we developed a phylogenetic tree of sixty proteins (n = 60) with the orthologs and paralogs seed sequences. Protein-protein network was also illustrated. Results demonstrated in our study may help the future researchers to unfold significant physiological and therapeutic properties of (Rspo)s in various disease models.

DNA evidence for multiple introductions of barley into Europe following dispersed domestications in Western Asia

It has long been recognised that the Neolithic spread across Europe via two separate routes, one along the Mediterranean coasts, the other following the axis of the major rivers. But did these two streams have a common point of origin in south-west Asia, at least with regard to the principal plant and animals species that were involved? This study of barley DNA shows that the domesticated barley grown in Neolithic Europe falls into three separate types (groups A, B and C), each of which may have had a separate centre of origin in south-west Asia. Barley was relatively rarely cultivated by the early Linearbandkeramik farmers of Central and Northern Europe, but became more common during the fifth and fourth millennia BC. The analysis reported here indicates that a genetic variety of barley more suitable for northern growing conditions was introduced from south-west Asia at this period. It also suggests that the barley grown in south-eastern Europe at the very beginning of the Neolithic may have arrived there by different routes from two separate centres of domestication in south-west Asia. The multiple domestications that this pattern reveals imply that domestication may have been more a co-evolutionary process between plants and people than an intentional human action.

English

The renal vasculature was always a subject of variations both in the number and pattern of portal of entry into kidney and Perihilar placement of the artery, vein and pelvis. Good anatomical insight is an essential prerequisite besides the surgical expertise. The cadaveric dissection at Shadan Institute of Medical Sciences, Teaching Hospital and Research Centre, revealed superior / upper polar artery arising from the lateral aspect of the aorta just proximal to the origin of Main Renal Artery (MRA). The main renal artery and the accessory renal artery had almost a common point of origin. The peri-hilar segmentation of the main renal artery was a fork like pattern. One of the segmental arteries was long and had its portal of entry into the kidney by perforating the capsule of the anterior substance of the kidney. The remaining segmental branches had their portal of entry through the hilum. The lower two segmental branches were placed anterior to the main renal vein causing altered hilar anatomy. A thorough knowledge of the frequently to the rarely occurring wide range of variations of renal vasculature has significance in exploration and treatment of renal trauma, renal transplantation, renal artery embolization, surgery for abdominal aortic aneurysm and conservative or radical renal surgery. Such a rare variation including the combination of extra renal peri-hilar segmentation of MRA with superior polar artery is worthy of concern to the urologists harvesting kidneys from the live donors for performing transplantation procedures, partial nephrectomies for the hilar tumors and for Radiologists during interpretation of the

English

The present case report describes one of the rare unilateral variations in the formation of median nerve by the union of three roots, twin (two) roots given off by the lateral cord and one root given off by the medial cord encountered in the right upper arm of an adult male cadaver during the pro-section hours. From the lateral cord which was seen lateral to the third part of axillary artery the musculocutaneous nerve and the twin lateral roots were seen arising very close to each other. The musculocutaneous nerve coursed laterally to innervate the coracobrachialis muscle. The origin of twin lateral roots was just medial to the origin of musculocutaneous nerve. The first lateral root which emerged proximal to the shoulder and united with the medial root and formed the median nerve was labeled as LR - 1, the second lateral root which fused with the already formed median nerve was labeled as LR - 2, In fact the second lateral root LR - 2, and the musculocutaneous nerve had a common point of origin seen as small bulge. The second lateral root LR - 2, was slightly thicker in its diameter and longer in course than the first root LR - 1 and it maintained its individual identity for about 3.5 cm before merging with the median nerve lying antero-lateral to it. The median nerve was seen forming anterior to the third part of axillary artery which continued as brachial artery. The knowledge of the formation, course and distribution with all the possible variations is an essential pre- requisite for traumatologists, neurologists, surgeons performing shoulder arthroscopy by anterior gleno-humeral portal and shoulder reconstructive surgeries, neuro-surgeons

A hypothetical relationship between the nuclear reprogramming factors for induced pluripotent stem (iPS) cells generation – bioinformatic and algorithmic approach

A hypothetical evolutionary relationship was generated between the nuclear reprogramming factors for induced pluripotent stem (iPS) cells generation. Utilizing bioinformatics techniques, sequence analyses and phylogenetic tree algorithms, a comparative study has been performed to understand the evolutionary relationship of human nuclear reprogramming factors of induced pluripotent stem cells (iPSCs) generation. Among the total six nuclear reprogramming factors, the four reprogramming factors (SOX2, C-MYC, KLF4, and LIN28) have significant evolutionary origin. Our study shows SOX2 and C-MYC have evolutionary relationship and common point of origin. Likewise, KLF4 and LIN28 are having evolutionary relationship and have common point of origin. Based on these evidences, we propose that our study may be a great help to the future researchers to understand the mechanism(s) as well as pathway of nuclear reprogramming process.

Aethiopissae: the classical tradition, Neo-Latin verse and images of race in George Herbert and Vincent Bourne

This article examines two Latin poems, one by the well-known writer of English as well as Latin poetry, George Herbert (1593–1633), and the other by Vincent Bourne (c. 1695–1747), probably the most widely read British writer of Latin verse in the eighteenth century. Each of these poems is written in the voice of a black woman, and, at least on the surface, appears to seek the reader’s sympathy for her position in a white world. A common point of origin is suggested, in the figure of the AEthiopissa in Terence’s Eunuch, and the popularity of Terence in education in the period. The poems are analysed in relation to classical antecedents and to the position of Latin verse in seventeenth and eighteenth century British culture, as well as to contemporary attitudes to race, and it is suggested that they reinforce, rather than challenge, negative stereotypes.

On the Sociological Significance of the American Jewish Experience: Boundary Blurring, Assimilation, and Pluralism

In thinking about the results reported here from the 2000/01 NJPS, it is crit ical to have a clear-eyed view of how the social landscape in which American Jews find themselves has changed in the post-World War II period. Some of the papers (Phillips and Fishman; Phillips and Keiner) argue that a soft version of rational choice can help to shed light on such key indicators of the contempo rary Jewish situation as intermarriage, and I agree that it can. But a choice-based framework is useful only insofar as one has a firm conceptual grip on the range of options faced by minority individuals, along with their perceived benefits, risks, and costs. If that configuration has changed substantially over time, past research may not give useful guidance, indeed may be fundamentally incom mensurate with the findings from new data. The applicability of past models is, quite appropriately, called into question by some of the papers, most notably, Phillips and Keiner. The concept of a social boundary provides a useful way of specifying some of the major changes that have taken place in the last six decades or so, as well as of identifying the value of the American Jewish case for comparative studies. By a boundary, I mean a social distinction that individuals make in their everyday lives and that shapes their actions and mental orientations towards others; it is typically embedded in a variety of social and cultural differences between groups that give a boundary concrete significance (so that those on one side think of those on the other, are not like us because ...). When we discuss ethnici ty, the kinds of boundaries we invoke have the character that Weber attributed to the ethnic group: namely, that they are rooted in a belief in com mon descent?i.e., in a shared history based on a common point of origin in the past, which may be real or putative. Admittedly, this subjective belief in a shared history may be felt more by one side of a boundary than the other and thus, to a greater or lesser extent, the boundary may be imposed, as is typically the case with race-like distinctions.

Vertex reconstruction using a single layer silicon detector

Typical vertex finding algorithms use reconstructed tracks, registered in a multi-layer detector, which directly point to the common point of origin. A detector with a single layer of silicon sensors registers the passage of primary particles only in one place. Nevertheless, the information available from these hits can also be used to estimate the vertex position, when the geometrical properties of silicon sensors and the measured ionization energy losses of the particles are fully exploited. In this paper, the algorithm used for this purpose in the PHOBOS experiment is described. The vertex reconstruction performance is studied using simulations and compared with results obtained from real data. The very large acceptance of a single-layered multiplicity detector permits vertex reconstruction for low multiplicity events where other methods, using small acceptance subdetectors, fail because of insufficient number of registered primary tracks.

Network Topology and the Efficiency of Equilibrium

Different kinds of networks, such as transportation, communication, computer, and supply networks, are susceptible to similar kinds of inefficiencies. These arise when congestion externalities make the cost for each user depend on the other users' choice of routes. If each user chooses the least expensive (e.g., the fastest) route from the users' common point of origin to the common destination, the result may be Pareto inefficient in that an alternative choice of routes would reduce the costs for all users. Braess's paradox represents an extreme kind of nefficiency, in which the equilibrium costs may be reduced by raising the cost curves. As this paper shows, this paradox occurs in an (undirected) two-terminal network if and only if it is not series-parallel. More generally, Pareto inefficient equilibria occur in a network if and only if one of three simple networks is embedded in it.

Network topology and the efficiency of equilibrium

Different kinds of networks, such as transportation, communication, computer, and supply networks, are susceptible to similar kinds of inefficiencies. These arise when congestion externalities make the cost for each user depend on the other users' choice of routes. If each user chooses the least expensive (e.g., the fastest) route from the users' common point of origin to the common destination, the result may be Pareto inefficient in that an alternative choice of routes would reduce the costs for all users. Braess's paradox represents an extreme kind of inefficiency, in which the equilibrium costs may be reduced by raising the cost curves. As this paper shows, this paradox occurs in an (undirected) two-terminal network if and only if it is not series-parallel. More generally, Pareto inefficient equilibria occur in a network if and only if one of three simple networks is embedded in it.

Dialectic and Enlightenment: The Concept of Enlightenment in Hegel and Horkheimer- Adorno

The opening line of Horkheimer-Adorno's Dialectic of reads, Enlightenment has always aimed at liberating men from fear and establishing their sovereignty. Yet the fully enlightened earth radiates disaster triumphant. This path of enlightenment is what the interpretations found in Hegel's Phenomenology of Spirit and Horkheimer-Adorno's Dialectic of have in common. Considered in terms of their broad outlines, these interpretations are the same. They differentiate themselves from one another only in the details. The conceptions of the enlightenment process in Hegel's Phenomenology of Spirit and Horkheimer-Adorno's Dialectic of are like perpendicular lines; they begin at the same point and then proceed to move further and further apart. However, even as they move apart, both conceptions still point back to their common origin, and no matter how far from that original point they move, one can still draw two parallel lines that relate them, one connecting the perpendicular lines, the other bisecting their point of origin. What I propose to do in this paper is draw a series of such parallel lines in the hopes of reaching the common point of origin: the concept of enlightenment. I will begin at the limit of enlightenment, the border where enlightenment crosses over into barbarism, and work my way back, step by step, line by line, from the limits of enlightenment to its public face, to its positive aspect, to its negative aspect, and finally to the very heart of enlightenment as conceived by Hegel and Horkheimer-Adorno. In the end, I believe, it will be shown that, while Hegel and Horkheimer-Adorno have different interpretations of how enlightenment plays itself out, they start