The present work deals with a review on graph theory that has been utilized to estimate thermodynamic properties of binary and ternary liquid mixtures. Various topological indices have been used to ...describe the topology of the chemical species it presents. Elegance and versatility of connectivity parameters of third degree of molecules,
3
ξ
, of the various components (derived from their topology) of mixtures are used to estimate (i) existence of components in mixture as well as pure state along with the extent and nature of the interaction between the constituent molecules; (ii) excess molar volume, V
E
, excess isentropic compressibility,
κ
S
E
, excess molar enthalpy, H
E
, excess heat capacity, C
P
E
, excess Gibb’s energy, G
E
of binary and ternary liquid mixtures. The present review reports the development of graph theory and its utilization for the determination of V
E
,
κ
S
E
, H
E
, C
P
E
, G
E
of two/three component mixtures (components being non-polar, polar differing in size, shape, polarity and ionic liquids).
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High intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that can thermally ablate tumors. Boiling histotripsy (BH) is a HIFU approach that can emulsify tissue in a few ...milliseconds. Lesion volume and temperature effects for different BH sonication parameters are currently not well characterized. In this work, lesion volume, temperature distribution, and area of lethal thermal dose were characterized for varying BH sonication parameters in tissue-mimicking phantoms (TMP) and demonstrated in ex vivo tissues.
The following BH sonication parameters were varied using a clinical MR-HIFU system (Sonalleve V2, Philips, Vantaa, Finland): acoustic power, number of cycles/pulse, total sonication time, and pulse repetition frequency (PRF). A 3×3×3 pattern was sonicated inside TMP's and ex vivo tissues. Post sonication, lesion volumes were quantified using 3D ultrasonography and temperature and thermal dose distributions were analyzed offline. Ex vivo tissues were sectioned and stained with H&E post sonication to assess tissue damage.
Significant increase in lesion volume was observed while increasing the number of cycles/pulse and PRF. Other sonication parameters had no significant effect on lesion volume. Temperature full width at half maximum at the end of sonication increased significantly with all parameters except total sonication time. Positive correlation was also found between lethal thermal dose and lesion volume for all parameters except number of cycles/pulse. Gross pathology of ex vivo tissues post sonication displayed either completely or partially damaged tissue at the focal region. Surrounding tissues presented sharp boundaries, with little or no structural damage to adjacent critical structures such as bile duct and nerves.
Our characterization of effects of HIFU sonication parameters on the resulting lesion demonstrates the ability to control lesion morphologic and thermal characteristics with a clinical MR-HIFU system in TMP's and ex vivo tissues. We demonstrate that this system can produce spatially precise lesions in both phantoms and ex vivo tissues. The results provide guidance on a preliminary set of BH sonication parameters for this system, with a potential to facilitate BH translation to the clinic.
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Colinear chaining has proven to be a powerful heuristic for finding near-optimal alignments of long DNA sequences (e.g., long reads or a genome assembly) to a reference. It is used as an intermediate ...step in several alignment tools that employ a seed-chain-extend strategy. Despite this popularity, efficient subquadratic time algorithms for the general case where chains support anchor overlaps and gap costs are not currently known. We present algorithms to solve the colinear chaining problem with anchor overlaps and gap costs in
denotes the count of anchors. The degree of the polylogarithmic factor depends on the type of anchors used (e.g., fixed-length anchors) and the type of precedence an optimal anchor chain is required to satisfy. We also establish the first theoretical connection between colinear chaining cost and edit distance. Specifically, we prove that for a fixed set of anchors under a carefully designed chaining cost function, the optimal "anchored" edit distance equals the optimal colinear chaining cost. The anchored edit distance for two sequences and a set of anchors is only a slight generalization of the standard edit distance. It adds an additional cost of one to an alignment of two matching symbols that are not supported by any anchor. Finally, we demonstrate experimentally that optimal colinear chaining cost under the proposed cost function can be computed orders of magnitude faster than edit distance, and achieves correlation coefficient >0.9 with edit distance for closely as well as distantly related sequences.
The AIM-II Trial included patients with nondysplastic Barrett's esophagus (NDBE) treated with radiofrequency ablation (RFA). Complete eradication of NDBE (complete response-intestinal metaplasia ...CR-IM) was achieved in 98.4 % of patients at 2.5 years. We report the proportion of patients demonstrating CR-IM at 5-year follow-up.
Prospective, multicenter US trial (NCT00489268). After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, we obtained four-quadrant biopsies from every 1 cm of the original extent of Barrett's esophagus. All specimens were reviewed by one expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA.
Of 60 eligible patients, 50 consented to participate. Of 1473 esophageal specimens obtained at 5 years 85 % contained lamina propria or deeper tissue (per patient, mean 30 , standard deviation SD 13). CR-IM was demonstrated in 92 % (46 / 50) of patients, while 8 % (4 / 50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR-IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval CI 0.77 - 0.97) and mean duration of CR-IM was 4.22 years (standard error SE 0.12).
In patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4 / 4, 100 %) were converted to CR-IM with single-session focal RFA.
Abstract
Complex behavior poses challenges in extracting models from experiment. An example is spin liquid formation in frustrated magnets like Dy
2
Ti
2
O
7
. Understanding has been hindered by ...issues including disorder, glass formation, and interpretation of scattering data. Here, we use an automated capability to extract model Hamiltonians from data, and to identify different magnetic regimes. This involves training an autoencoder to learn a compressed representation of three-dimensional diffuse scattering, over a wide range of spin Hamiltonians. The autoencoder finds optimal matches according to scattering and heat capacity data and provides confidence intervals. Validation tests indicate that our optimal Hamiltonian accurately predicts temperature and field dependence of both magnetic structure and magnetization, as well as glass formation and irreversibility in Dy
2
Ti
2
O
7
. The autoencoder can also categorize different magnetic behaviors and eliminate background noise and artifacts in raw data. Our methodology is readily applicable to other materials and types of scattering problems.
The anionic dimyristoyl phosphatidylglycerol (DMPG) membrane in solvents with a low ionic strength is known to exhibit an unusually wide melting regime between the gel and fluid phase characterized ...by various anomalous macroscopic characteristics, such as low turbidity and high electrical conductivity and viscosity. A recent neutron spin echo study Kelley, E. G.
et al.
,
Struct. Dyn.
,
7
(2020) 054704 revealed that during the extended melting phase transition the DMPG membrane becomes softer and exhibits faster collective bending fluctuation compared to the higher temperature fluid phase. In contrast, in the present work, using incoherent quasielastic neutron scattering through the anomalous phase transition regime we find that single-particle lateral and internal lipid motions in the DMPG membrane show regular temperature dependence, with no enhanced dynamics evident in the anomalous melting regime. Further, we find that incorporation of NaCl in DMPG suppresses the anomalous extended melting regime, concurrently enhancing the single-particle lipid dynamics, both the lateral diffusivity and (to a lesser extent) the internal lipid motion. This seems rather counterintuitive and in variance with the dynamic suppression effect exerted by a salt on a zwitterionic membrane. However, since incorporation of a salt in anionic DMPG leads to enhanced cooperativity, the disrupted cooperativity in the salt-free DMPG is associated with the baseline lipid dynamics that is suppressed to begin with, whereas addition of salt partially restores the cooperativity, thus enhancing lipid dynamics compared to the salt-free baseline DMPG membrane state. These results provide new insights into the ion-membrane interaction and divulge a correlation between microscopic dynamics and the structure of the lipid bilayer.
Lateral diffusion coefficient of DMPG membrane across the anomalous melting regime. Presence of NaCl enhances the lateral diffusion of anionic DMPG lipid.
In recent years, several
compressed indexes
based on variants of the Burrows–Wheeler transform have been introduced. Some of these are used to index structures far more complex than a single string, ...as was originally done with the FM-index (Ferragina and Manzini in J. ACM 52(4):552–581, https://doi.org/10.1145/1082036.1082039, 2005). As such, there has been an increasing effort to better understand under which conditions such an indexing scheme is possible. This has led to the introduction of Wheeler graphs (Gagie et al. in Theor Comput Sci 698:67–78, https://doi.org/10.1016/j.tcs.2017.06.016, 2017). Gagie et al. showed that de Bruijn graphs, generalized compressed suffix arrays, and several other BWT related structures can be represented as Wheeler graphs, and that Wheeler graphs can be indexed in a space-efficient way. Hence, being able to recognize whether a given graph is a Wheeler graph, or being able to approximate a given graph by a Wheeler graph, could have numerous applications in indexing. Here we resolve the open question of whether there exists an efficient algorithm for recognizing if a given graph is a Wheeler graph. We show:
The problem of recognizing whether a given graph
G
=
(
V
,
E
)
is a Wheeler graph is NP-complete for any edge label alphabet of size
σ
≥
2
, even when
G
is a DAG. This holds even on a restricted subset of graphs called
d
-NFAs for
d
≥
5
. This is in contrast to recent results demonstrating the problem can be solved in polynomial time for
d
-NFAs where
d
≤
2
. We also show that the recognition problem can be solved in linear time for
σ
=
1
on graphs without self-loops;
There exists an
2
e
log
σ
+
O
(
n
+
e
)
time exact algorithm where
n
=
|
V
|
and
e
=
|
E
|
. This algorithm relies on graph isomorphism being computable in strictly sub-exponential time;
We define an optimization variant of the problem called Wheeler Graph Violation, abbreviated WGV, where the aim is to identify the smallest set of edges that have to be removed from a graph to obtain a Wheeler graph. We show WGV is APX-hard, even when
G
is a DAG, implying there exists a constant
C
>
1
for which there is no
C
-approximation algorithm (unless P = NP). Also, conditioned on the Unique Games Conjecture, for all
C
>
1
, it is NP-hard to find a
C
-approximation, implying WGV is not in APX;
We define the Wheeler Subgraph problem, abbreviated WS, where the aim is to find the largest subgraph which is a Wheeler Graph (the dual of WGV). In contrast to WGV, we give an
O
(
σ
)
-approximation algorithm for the WS problem, implying it is in APX for
σ
=
O
(
1
)
.
The above findings suggest that most problems under this theme are computationally difficult. However, we identify a class of graphs for which the recognition problem is polynomial-time solvable, raising the question of which properties determine this problem’s difficulty.
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Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity ...focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors.
We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival.
Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4
Foxp3
, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4
, CD8α
, and CD8α
CD11c
cells, CD11c
in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival,
< 0.0001). This combination treatment significantly also induces CD4
CD44
CD62L
and CD8α
CD44
CD62L
population and is adoptively transferable, imparting immunity, slowing subsequent
tumor engraftment.
Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.
Alignment-free sequence comparison methods are attracting persistent interest, driven by data-intensive applications in genome-wide molecular taxonomy and phylogenetic reconstruction. Among all the ...methods based on substring composition, the average common substring (ACS) measure admits a straightforward linear time sequence comparison algorithm, while yielding impressive results in multiple applications. An important direction of this research is to extend the approach to permit a bounded edit/hamming distance between substrings, so as to reflect more accurately the evolutionary process. To date, however, algorithms designed to incorporate k ≥ 1 mismatches have O(n(2)) worst-case time complexity, where n is the total length of the input sequences. On the other hand, accounting for mismatches has shown to lead to much improved classification, while heuristics can improve practical performance. In this article, we close the gap by presenting the first provably efficient algorithm for the k-mismatch average common string (ACSk) problem that takes O(n) space and O(n log(k) n) time in the worst case for any constant k. Our method extends the generalized suffix tree model to incorporate a carefully selected bounded set of perturbed suffixes, and can be applied to other complex approximate sequence matching problems.
The ATP-gated ionotropic P2X7 receptor (P2X7R) has the unusual ability to function as a small cation channel and a trigger for permeabilization of plasmalemmal membranes. In murine microglia, ...P2X7R-mediated permeabilization is fundamental to microglial activation, proliferation, and IL-1β release. However, the role of the P2X7R in primary adult human microglia is poorly understood.
We used patch-clamp electrophysiology to record ATP-gated current in cultured primary human microglia; confocal microscopy to measure membrane blebbing; fluorescence microscopy to demonstrate membrane permeabilization, caspase-1 activation, phosphatidylserine translocation, and phagocytosis; and kit-based assays to measure cytokine levels.
We found that ATP-gated inward currents facilitated with repetitive applications of ATP as expected for current through P2X7Rs and that P2X7R antagonists inhibited these currents. P2X7R antagonists also prevented the ATP-induced uptake of large cationic fluorescent dyes whereas drugs that target pannexin-1 channels had no effect. In contrast, ATP did not induce uptake of anionic dyes. The uptake of cationic dyes was blocked by drugs that target Cl
channels. Finally, we found that ATP activates caspase-1 and inhibits phagocytosis, and these effects are blocked by both P2X7R and Cl
channel antagonists.
Our results demonstrate that primary human microglia in culture express functional P2X7Rs that stimulate both ATP-gated cationic currents and uptake of large molecular weight cationic dyes. Importantly, our data demonstrate that hypotheses drawn from work on murine immune cells accurately predict the essential role of P2X7Rs in a number of human innate immune functions such as phagocytosis and caspase-1 activation. Therefore, the P2X7R represents an attractive target for therapeutic intervention in human neuroinflammatory disorders.
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