bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cells
Authors: Zikry Tarek M. , Wolff Samuel C. , Ranek Jolene S. , Davis Harris M. , Naugle Ander , Luthra Namit , Whitman Austin A. , Kedziora Katarzyna M. , Stallaert Wayne , Kosorok Michael R. , Spanheimer Philip M. , Purvis Jeremy E.
Published: February 2024

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor–positive, human epidermal growth factor 2 receptor–negative (ER+/HER2−) breast tumor cells. Despite the drug’s success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib—a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle “paths” that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.
Filament structure and subcellular organization of the bacterial intermediate filament–like protein crescentin
Authors: Liu Yue , van den Ent Fusinita , Löwe Jan
Published: February 2024

The protein crescentin is required for the crescent shape of the freshwater bacterium
Caulobacter crescentus
(
vibrioides
). Crescentin forms a filamentous structure on the inner, concave side of the curved cells. It shares features with eukaryotic intermediate filament (IF) proteins, including the formation of static filaments based on long and parallel coiled coils, the protein’s length, structural roles in cell and organelle shape determination and the presence of a coiled coil discontinuity called the “stutter.” Here, we have used electron cryomicroscopy (cryo-EM) to determine the structure of the full-length protein and its filament, exploiting a crescentin-specific nanobody. The filament is formed by two strands, related by twofold symmetry, that each consist of two dimers, resulting in an octameric assembly. Crescentin subunits form longitudinal contacts head-to-head and tail-to-tail, making the entire filament non-polar. Using in vivo site-directed cysteine cross-linking, we demonstrated that contacts observed in the in vitro filament structure exist in cells. Electron cryotomography (cryo-ET) of cells expressing crescentin showed filaments on the concave side of the curved cells, close to the inner membrane, where they form a band. When comparing with current models of IF proteins and their filaments, which are also built from parallel coiled coil dimers and lack overall polarity, it emerges that IF proteins form head-to-tail longitudinal contacts in contrast to crescentin and hence several inter-dimer contacts in IFs have no equivalents in crescentin filaments. Our work supports the idea that intermediate filament-like proteins achieve their shared polymerization and mechanical properties through a variety of filament architectures.
A biochemical description of postsynaptic plasticity—with timescales ranging from milliseconds to seconds
Authors: Li Guanchun , McLaughlin David W. , Peskin Charles S.
Published: February 2024

Synaptic plasticity [long-term potentiation/depression (LTP/D)], is a cellular mechanism underlying learning. Two distinct types of early LTP/D (E-LTP/D), acting on very different time scales, have been observed experimentally—spike timing dependent plasticity (STDP), on time scales of tens of ms; and behavioral time scale synaptic plasticity (BTSP), on time scales of seconds. BTSP is a candidate for a mechanism underlying rapid learning of spatial location by place cells. Here, a computational model of the induction of E-LTP/D at a spine head of a synapse of a hippocampal pyramidal neuron is developed. The single-compartment model represents two interacting biochemical pathways for the activation (phosphorylation) of the kinase (CaMKII) with a phosphatase, with ion inflow through channels (NMDAR, CaV1,Na). The biochemical reactions are represented by a deterministic system of differential equations, with a detailed description of the activation of CaMKII that includes the opening of the compact state of CaMKII. This single model captures realistic responses (temporal profiles with the differing timescales) of STDP and BTSP and their asymmetries. The simulations distinguish several mechanisms underlying STDP vs. BTSP, including i) the flow of

Ca

2
+

through NMDAR vs. CaV1 channels, and ii) the origin of several time scales in the activation of CaMKII. The model also realizes a priming mechanism for E-LTP that is induced by

Ca

2
+

flow through CaV1.3 channels. Once in the spine head, this small additional

Ca

2
+

opens the compact state of CaMKII, placing CaMKII ready for subsequent induction of LTP.
CURTAIN—A unique web-based tool for exploration and sharing of MS-based proteomics data
Authors: Phung Toan K. , Berndsen Kerryn , Shastry Rosamund , Phan Tran L. C. H. B. , Muqit Miratul M. K. , Alessi Dario R. , Nirujogi Raja S.
Published: February 2024

To facilitate analysis and sharing of mass spectrometry (MS)-based proteomics data, we created online tools called CURTAIN (
https://curtain.proteo.info
) and CURTAIN-PTM (
https://curtainptm.proteo.info
) with an accompanying series of video tutorials (
https://www.youtube.com/@CURTAIN-me6hl
). These are designed to enable non-MS experts to interactively peruse volcano plots and deconvolute primary experimental data so that replicates can be visualized in bar charts or violin plots and exported in publication-ready format. They also allow assessment of overall experimental quality by correlation matrix and profile plot analysis. After making a selection of protein "hits", the user can analyze known domain structure, AlphaFold predicted structure, reported interactors, relative expression as well as disease links. CURTAIN-PTM permits analysis of all identified PTM sites on protein(s) of interest with selected databases. CURTAIN-PTM also links with the Kinase Library to predict upstream kinases that may phosphorylate sites of interest. We provide examples of the utility of CURTAIN and CURTAIN-PTM in analyzing how targeted degradation of the PPM1H Rab phosphatase that counteracts the Parkinson’s LRRK2 kinase impacts cellular protein levels and phosphorylation sites. We also reanalyzed a ubiquitylation dataset, characterizing the PINK1-Parkin pathway activation in primary neurons, revealing data of interest not highlighted previously. CURTAIN and CURTAIN-PTM are free to use and open source, enabling researchers to share and maximize the impact of their proteomics data. We advocate that MS data published in volcano plot format be reported containing a shareable CURTAIN weblink, thereby allowing readers to better analyze and exploit the data.
The excitation of high-order localized waves in (3+1)-dimensional Kudryashov-Sinelshchikov equation
Authors: Li Longxing , Cheng Bitao , Dai Zhengde
Published: February 2024

The aim of this work is to explore the excitation of high-order localized waves in the (3+1)-dimensional Kudryashov-Sinelshchikov equation, which is used to describe the dynamic of liquid with gas bubble. First of all, classical N-soliton solutions are constructed by means of Hirota bilinear form and symbolic calculation. What’s more, the high-order breather waves are derived through the degeneration process of the N-soliton solutions with conjugate parameter. Then, high-order lump waves are constructed by taking long wave limit technique on N-soliton solutions. Finally, the high-order mixed localized waves involving resonant Y-type solitons, high-order breather waves and high-order lump waves are obtained by utilizing some comprehensive methods. Abundant dynamical and evolutionary behaviors of these results are investigated specifically, some figures are presented to shed light on the nonlinear phenomena hidden in the high-order localized waves vividly.
Reflection and scattering of long-range surface plasmon-polaritons on boundary of free half-space
Authors: Morozov Yuri A
Published: February 2024

We study the long-range surface plasmon-polariton (LRSPP) propagating along a thin metal film embedded in a homogeneous semi-infinite medium. The reflection and scattering of the LRSPP by the end face of the film at the boundary of free half-space are discussed. We apply the self-consistent electromagnetic approach using the expansion of the plasmon and scattered fields by the eigenfunctions of the structure. The Fredholm integral equation of the first kind appearing in the model has been solved with using the variational Ritz-Galerkin procedure. It is shown that the LRSPP reflection coefficient can be approximated by the Fresnel formula of reflection for normal incidence of a plane TEM wave. The power of the back-scattered radiation is predicted to be a considerable part (tens of percents) of the reflected LRSPP power. We discuss the far-field patterns of both the back- and forward-scattered radiation. It is shown that the back-scattered radiation form two narrow lobes directed symmetrically with regard to the metal film plane. The radiation scattered in the forward direction is presented by the one-lobe far-field pattern; decreasing the metal layer thickness results in the narrower lobe of the forward-scattered radiation.
Transport and diffusion of active Brownian particles in a new asymmetric bistable system driven by two Gaussian colored noises
Authors: Zhuo Xiao-Jing , Guo Yong-Feng
Published: February 2024

The transport phenomena (drift and diffusion) of active Brownian particles in a new asymmetric bistable system with a linear bias force and a nonlinear bias force subjected to two colored noises are investigated. Two different biases break the symmetry of the potential to generate motion of the particle with a net velocity. Theoretical analysis of the system is given by virtue of the Langevin equation and the Fokker-Planck methods, which is verified by numerical simulation. The results show that: (i) coexistence of the linear bias and nonlinear bias is capable of tuning the transport of the particle, including current reversal, absolute negative mobility, directional transport; (ii) in the absence of linear bias F, the mean velocity is negative for positive nonlinear bias r but positive for negative r, that is, the nonlinear bias leads to absolute negative mobility. In the absence of nonlinear bias r, the mean velocity is positive for positive linear bias F and negative for negative F; (iii) as the absolute values of the linear bias and nonlinear bias increase, the mean velocity is promoted but the effective diffusion is suppressed; (iv) the enhancement of the multiplicative and additive noise intensities can suppress the transport and effective diffusion; and (v) the transport velocity and diffusion are facilitated with increasing the auto-correlation times of two colored noises. Furthermore, the physical mechanism for the particle’s transport is derived from the velocity distributions and the effective velocity potential gap of the above results.
Error analysis of second-order local time integration methods for discontinuous Galerkin discretizations of linear wave equations
Authors: Carle Constantin , Hochbruck Marlis
Published: February 2024

This paper is dedicated to the full discretization of linear wave equations, where the space discretization is carried out with a discontinuous Galerkin method on spatial meshes which are locally refined or have a large wave speed on only a small part of the mesh. Such small local structures lead to a strong Courant–Friedrichs–Lewy (CFL) condition in explicit time integration schemes causing a severe loss in efficiency. For these problems, various local time-stepping schemes have been proposed in the literature in the last years and have been shown to be very efficient. Here, we construct a quite general class of local time integration methods preserving a perturbed energy and containing local time-stepping and locally implicit methods as special cases. For these two variants we prove stability and optimal convergence rates in space and time. Numerical results confirm the stability behavior and show the proved convergence rates.
A representation of sup-completion
Authors: Polavarapu Achintya , Troitsky Vladimir
Published: February 2024

It was showed by Donner in [Extension of positive operators and Korovkin theorems, Lecture Notes in Mathematics, vol. 904, Springer-Verlag, Berlin-New York, 1982] that every order complete vector lattice

X
X

may be embedded into a cone 

X
s

X^s

, called the sup-completion of 

X
X

. We show that if one represents the universal completion of

X
X

as

C
∞

(
K
)

C^\infty (K)

, then

X
s

X^s

is the set of all continuous functions from

K
K

to

[
−
∞
,
∞
]

[-\infty ,\infty ]

that dominate some element of 

X
X

. This provides a functional representation of 

X
s

X^s

, as well as an easy alternative proof of its existence.
Equality between the Bergman metric and Carathéodory metric
Authors: Chen Bo-Yong , Xiong Yuanpu , Zhang Liyou
Published: February 2024

We present an equality between the Bergman metric and Carathéodry metric.
Simply interpolating sequences in complete Pick spaces
Authors: Chalmoukis Nikolaos , Dayan Alberto , Hartz Michael
Published: February 2024

We characterize simply interpolating sequences (also known as onto interpolating sequences) for complete Pick spaces. We show that a sequence is simply interpolating if and only if it is strongly separated. This answers a question of Agler and McCarthy. Moreover, we show that in many important examples of complete Pick spaces, including weighted Dirichlet spaces on the unit disc and the Drury–Arveson space in finitely many variables, simple interpolation does not imply multiplier interpolation. In fact, in those spaces, we construct simply interpolating sequences that generate infinite measures, and uniformly separated sequences that are not multiplier interpolating.
Managing the Flow of Talk: A Longitudinal Case Study of the Multiword Expression det er sant in L2 Norwegian Interactions
Authors: Horbowicz Paulina , Nordanger Marte
Published: February 2024

Drawing on recent scholarship integrating usage-based linguistics (UBL) and conversation analysis (CA) in the investigation of second language development, this paper reports on a microanalysis tracing one adult learner’s recurring, increasingly frequent, and diverse use of the multiword expression det er sant (it/that is true) (DES) in L2 Norwegian interactions over a time span of four months. While the use of DES did not undergo syntactic changes, the analysis revealed that the functions of the expression diversified as DES became more frequent in use. Initially functioning primarily as a means of expressing agreement, DES was increasingly used to preface disagreement and indicate the closing of self-initiated repair sequences. This functional diversification was accompanied by increasing morphophonological reduction indicating an ongoing process of routinization. We argue that these changes, also when non-linear and not complying with the target norm, allowed the learner to participate more actively in managing the flow of talk. The study provides insight into how interaction shapes L2 development and the role of education in providing access to situations that foster increased membership in the speech community.
493 - Lebrikizumab does not impact vaccine-induced immune responses: results from a phase 3 study in adult patients with moderate-to-severe atopic dermatitis
Authors: Soung Jennifer , Laquer Vivian , Merola Joseph F , Forman Seth , Elmaraghy Hany , Meskimen Eric , Hu Chaoran , Natalie Chitra R , Pierce Evangeline , Torisu-Itakura Hitoe , Gil Esther Garcia , Jarell Abel D
Published: February 2024

Introduction

Lebrikizumab (LEB) is a monoclonal antibody (Ab) that has shown efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) in Phase 2/3 trials. LEB targets IL-13 and inhibits signaling of the IL-4Rα/IL-13Rα1 complex. The potential immunomodulator effect of LEB necessitates investigating its impact on immune responses.

Objectives

To report the seroresponses to the Tdap (Diphtheria/Tetanus Toxoids/Pertussis) and MCV (Meningococcal (Groups A, C, Y, and W-135)) vaccines in LEB-treated and placebo (PBO)-treated adult patients (aged 18-15 years) with moderate-to-severe AD; and to compare the efficacy of LEB vs PBO in the treatment of AD.

Methods

ADopt-VA was a US Phase 3, 16-week (W) randomized, double-blind, placebo-controlled study to assess LEB impact on vaccine immune responses in adult patients with moderate-to-severe AD. The primary endpoint was the immune response to 2 vaccines, the Tdap and MCV . LEB was given as a 500 mg loading dose at baseline and W2, followed by 250 mg LEB Q2W. At W12, both vaccines (Tdap and MCV) were administered to all patients, LEB group N=107, Placebo (PBO) group N=81. Immune responses were determined by Ab level differences between W12 and W16. Secondary efficacy endpoints at W16 were Investigator Global Assessment (IGA) and Eczema Area and Severity Index (EASI 75) scores.

Results

For Tdap, 73.6% of LEB patients had a positive Ab response vs 73.4% for PBO, 90% CI, 0.3 (-10.2, 11.2). For MCV, LEB patients had an 86.9% positive Ab response vs 75.0% for PBO, 90% CI, 12.2 (2.5, 22.0). IGA (0,1) was achieved by 40.6% of LEB patients vs 18.9% receiving PBO (p=<0.001); EASI 75 was achieved by 58.0% and 32.7% (p<0.001), respectively. The safety profile was consistent with previous LEB trials.

Conclusions

These data show that LEB does not negatively impact immune responses for Tdap or MCV vaccines in adults with moderate-to-severe AD.
502 - Efficacy and safety of upadacitinib through 140 weeks in adolescents and adults with moderate-to-severe atopic dermatitis: phase 3 randomized clinical trial results
Authors: Silverberg Jonathan I , Guttman-Yassky Emma , Simpson Eric L , Papp Kim A , Blauvelt Andrew , Chu Chia-Yu , Hong H Chih-ho , Stein Gold Linda F , Bieber Thomas , Kabashima Kenji , Rosmarin David , Gamelli Amy , Calimlim Brian , Vigna Namita , Hu Xiaofei , Yang Yang , Wu Xiaoqiang , Huang Xiaohong , Suravaram Smitha , Teixeira Henrique D , Raymundo Eliza , Irvine Alan D
Published: February 2024

Introduction & Objectives

Upadacitinib (UPA) is an oral Janus kinase 1 (JAK1) inhibitor approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe atopic dermatitis (AD). Here, we present the efficacy and safety of UPA administered over 140 weeks in an ongoing randomized, double-blinded, multicenter phase 3 study (Measure Up 1, NCT03569293).

Materials & Methods

Patients (12–75 years) with moderate-to-severe AD were randomized 1:1:1 to receive UPA 15 mg (UPA15), UPA 30 mg (UPA30), or placebo (PBO) once daily at baseline. At week 16, PBO-treated patients were re-randomized 1:1 to receive UPA15 (PBO/UPA15) or UPA30 (PBO/UPA30) once daily. Co-primary endpoints were the proportion of patients achieving ≥75% reduction in EASI (EASI 75) from baseline and vIGA-AD of clear (0) or almost clear (1) with ≥2 grades of reduction from baseline (vIGA-AD 0/1) at week 16. A meaningful improvement in itch, defined as a ≥4-point reduction in Worst Pruritus Numeric Rating Scale (ΔWP-NRS≥4), was assessed among patients with baseline WP-NRS≥4. All efficacy endpoints were summarized using the Observed Cases (OC) approach, and no missing data imputation was applied. Safety was assessed by monitoring of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and treatment-emergent adverse events of special interest (AESI), which were analysed as exposure-adjusted rates per 100 patient-years (PY).

Results

Efficacy results were sustained up to week 140 since week 16. Proportions of patients in the UPA15 (205), UPA30 (206), PBO/UPA15 (91), and PBO/UPA30 (94) groups achieving EASI 75 at week 140 were 88.8% (182), 90.3% (186), 83.5% (76), and 89.4% (84), respectively, and for vIGA-AD 0/1 was 63.4% (130), 65.5% (135), 60.4% (55), and 75.5% (71), respectively. Proportions of patients achieving an improvement (reduction) in WP-NRS≥4 from baseline at week 140 were 68.0% (136), 70.5% (146), 71.3% (62), and 81.3% (74) respectively. Overall, the rates of AESIs were similar across treatment groups, which aligned with prior reports at earlier time points. Both UPA15 and UPA30 were well-tolerated in all patients, and no new safety signals were observed compared to the known safety profile of UPA. Data from two additional pivotal studies will be available at the time of presentation.

Conclusion

In this interim analysis, sustained skin clearance and itch and a consistent safety profile were observed with UPA 15 mg and UPA 30 mg across 140 weeks in adolescent and adult patients with moderate-to-severe AD.
503 - Visualizing 3-year treatment outcome trajectories of dupilumab in adults with moderate-to-severe atopic dermatitis in real world practice
Authors: Wang Zhixiao , Martins Bruno , Ardeleanu Marius , Yang Min , Bégo-Le-Bagousse Gaëlle , Sierka Debra , Strober Bruce
Published: February 2024

Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease with high global prevalence and profound negative impact on the quality of life of children and adults. RELIEVE-AD, a prospective, longitudinal cohort study, included adults with moderate-to-severe AD who initiated dupilumab in real-world clinical practice. Results from RELIEVE-AD showed significant improvements in patient-reported disease control, quality of life, and treatment satisfaction in the overall study population that were sustained through 3 years of dupilumab treatment.

Objective

To report on response to dupilumab treatment over time at the individual patient-level in adults with moderate-to-­severe AD, using 3-year data from RELIEVE-AD.

Methods

RELIEVE-AD is a single-arm, prospective, observational study of adults with moderate-to-severe AD prescribed dupilumab and enrolled in the US dupilumab patient support program, who agreed to participate in online surveys at baseline and Months 1, 2, 3, 6, 9, 12, and 30–36. Post hoc analysis of the RELIEVE-AD 3yr data, describing changes from baseline through all post-dupilumab initiation time points at individual patient level, using Sankey plots to assess variability of individual patient response over time for the following patient-reported outcomes: Atopic Dermatitis Control Tool (ADCT) total score-based disease control status, AD-related health status, and AD treatment satisfaction.

Results

Of 698 patients who completed the baseline survey, 425 completed the Months 30–36 survey. Disease control (as measured by the ADCT) increased rapidly from 5.9% at baseline to 61.0% at Month 1, further increasing to 80.7% at Months 30–36. Patients reported improved AD-related health status at Month 30–36, with 70.9% reporting “Excellent” or “Very Good”, compared to 2.8% at baseline. At Months 30–36, 86.8% of patients reported being “Extremely Satisfied/Very Satisfied/Somewhat Satisfied” with their AD treatment, compared to 17.7% at baseline. All endpoints were significant vs baseline (P < 0.001). Sankey plots of the three outcomes indicated that the majority of patients maintained response over time after achieving the initial response.

Conclusion

The majority of patients who completed the survey reported benefits of dupilumab, such as AD control, treatment satisfaction, and health status, which remained stable or significantly improved during long-term treatment up to 36 months.
552 - Improvement of the head and neck regions with continuous tralokinumab treatment for up to 4 years in adults with moderate-to-severe atopic dermatitis
Authors: Chovatiya Raj , Wollenberg Andreas , Ribero Simone , Saeki Hidehisa , Øland Christian B , Steffensen Louise A , Tindberg Ann-Marie , Thyssen Jacob P , Blauvelt Andrew
Published: February 2024

Introduction

Atopic dermatitis (AD) is a chronic, inflammatory disease that can affect multiple regions of the body, but can be particularly burdensome on exposed areas of skin, such as the head and neck (H&N).Tralokinumab, a high-affinity monoclonal antibody that specifically neutralizes interleukin-13, is approved in multiple countries for adults with moderate-to-severe AD. Phase 3 trials showed tralokinumab provided significant improvements in AD severity and was well-tolerated up to 52 weeks of treatment. The ongoing open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses the safety and efficacy of tralokinumab after the completion of parent trials (PT).

Objective

To assess tralokinumab efficacy in the head and neck region.

Methods

This post hoc analysis included adult patients with moderate-to-severe AD initially randomized to tralokinumab 300mg Q2W in the phase 3 PTs ECZTRA 1 (NCT03131648) or ECZTRA 2 (NCT03160885). Patients on active tralokinumab treatment were followed for up to 52 weeks in PTs and for up to 152 weeks in ECZTEND as of data cutoff April 30, 2022. Patients re-randomized to placebo at Week (Wk) 16 were not included beyond that timepoint. For this analysis, overall EASI and H&N regional EASI (H&N EASI) were evaluated. H&N EASI (0-7.2) was calculated based on the severity of erythema, induration/papulation, excoriation, lichenification and area of involvement. All data were analyzed and presented as observed.

Results

At baseline, 87.8% (1047/1192) of patients had H&N involvement (H&N EASI>1), and 49.9% (591/1192) of patients exhibited severe AD (IGA 4). Baseline median H&N EASI for the pooled PTs was 3.0 (IQR 1.8; 4.5). In the pooled PTs, 48.2% (542/1125) and 71.2% (558/784) of patients achieved H&N EASI≤1, at Wk16 and Wk52, respectively. After 3 years additional treatment (Wk152 in ECZTEND), the proportion of patients with H&N EASI≤1 was 87.2% (232/266) and the median H&N EASI was 0.2 (IQR 0.0; 0.5). In the subgroup of patients (n=301) with severe AD (IGA 4) and high H&N involvement (H&N EASI≥4), median H&N EASI improved from 5.4 at baseline to 2.4 and 0.8 at Wk16 and Wk52, respectively, and 0.4 at Wk152. Improvements in H&N region were comparable to overall EASI improvement.

Conclusions

Tralokinumab provided sustained improvements in the H&N regions in patients with moderate-to-severe AD for up to 4 years. Sustained improvements were also seen in patients with severe disease and substantial H&N involvement at baseline.
543 - Early repigmentation of stable vitiligo through point-of-care melanocyte transfer using non-cultured autologous skin cell suspension
Authors: Girish Munavalli
Published: February 2024

Introduction

Vitiligo is an acquired depigmenting skin condition characterized by the loss of skin pigmentation, impacting 0.5% to 2% of the global population.1–3 Vitiligo presents as distinct depigmented patches resulting from autoimmune melanocyte destruction. Individuals with visual vitiligo lesions often experience negative body image, diminished self-confidence, discomfort, and overall lower quality of life (QoL).4 While there are medical treatment options available, these can be associated with poor efficacy and low medication compliance.4 Residual lesions after treatment may require surgical intervention which allows for melanocyte transplantation from an area that is pigmented to one that is lacking functional melanocytes. Through a point-of-care device, a non-cultured autologous skin cell suspension (ACSC) can be prepared using a small skin sample; the ASCS contains healthy melanocytes and is immediately applied onto skin treated with ablative laser to aid in the repigmentation of affected areas.

Objective

The objective of this study was to evaluate the one-time application of ASCS, with a 1:20 donor to treatment site expansion ratio, for the safe and effective repigmentation of stable vitiligo lesions.

Methods

A randomized, within-subject controlled, central observer-blinded study was conducted to compare the clinical performance of laser ablation, ASCS, and NB-UVB to NB-UVB alone for repigmentation of stable vitiligo lesions in adults. Subjects received NB-UVB phototherapy on both ASCS-treated and controlled lesions as per recommended by the Vitiligo Working Group. Repigmentation of ASCS-treated and control lesions were categorized by a Central Review Committee (CRC) of blinded dermatologists as one of the following: 0%-25%, 26%-50%, 51%-79%, or 80-100%. The primary effectiveness endpoint was defined as the proportion of lesions achieving ≥80% repigmentation for ASCS-treated versus control areas at Week 24. Early regimentation was assessed at Weeks 4 and 12 as a post hoc analysis.

Results

A significantly higher proportion of the ASCS-treated areas (36.0%, n = 9) compared to control-treated areas (0.0%) attained ≥80% repigmentation at Week 24 (P = 0.012). At Week 4, 30.4% (n = 7/23) of ASCS-treated areas had ≥26% repigmentation compared to 4.3% (n = 1/23) in the control areas. At Week 12, 56.5% (n = 13/23) of ASCS-treated areas had ≥26% repigmentation compared to 21.7% (n = 5/23) in the control areas. At Week 24, 64% (n = 16/25) of ASCS-treated areas had ≥26% repigmentation compared to 28% (n = 7/25) in the control areas.

Conclusion

A one-time treatment of ASCS, with the addition of NB-UVB, can result in excellent repigmentation results by 24 weeks, with most subjects seeing ≥26% repigmentation as early as 4 to 12 weeks.
Synthesis and optical properties of dithieno-1,4-thiaborins bearing electron-donating amino groups
Authors: Agou Tomohiro , Hayama Shota , Takano Naoya , Yamada Shigeyuki , Konno Tsutomu , Oshiki Toshiyuki , Komatsuzaki Hidehito , Fukumoto Hiroki
Published: February 2024

Dibenzo-1,4-heteraborins and their π-extended derivatives have been paid increased attention to because of their potential as optical and electronic functional materials such as organic electroluminescence emitters. However, 1,4-heteraborin compounds with heteroaromatic ring systems remain scarce, even though Liu et al. recently reported the synthesis, properties, and functionalization of dithieno-1,4-thiaborins (DTTBs). In this work, DTTBs with 10H-phenothiazine-10-yl (Pz), 9H-carbazol-9-yl (Cz), and p-(Ph2N)C6H4 groups as electron-donating amino groups at the α-positions of their thiophene moieties were synthesized using palladium-catalyzed coupling reactions. X-ray crystallographic analysis revealed the molecular structure of a DTTB substituted with Pz groups. This analysis showed that the 2 Pz moieties adopted extra (quasi-axial) conformations. The Cz- and p-(Ph2N)C6H4-substituted DTTBs showed red-shifted absorption and emission when compared to the original DTTBs. This shift is due to donor–acceptor interactions between the amino groups and the DTTB cores. The Pz-substituted DTTB exhibited dual fluorescence emissions, originating from the locally excited (LE) and twisted intramolecular charge transfer (TICT) states. The intensity and nature of these emissions varied based on solvent polarity, temperature, and viscosity, suggesting the potential of the Pz-substituted DTTB to act as a fluorescent environment sensor.
Activating autophagy promotes skin regeneration induced by mechanical stretch during tissue expansion
Authors: Du Jing , Liu Wei , Song Yajuan , Zhang Yu , Dong Chen , Xiong Shaoheng , Huang Zhaosong , Wang Tong , Ding Jianke , He Qiang , Yu Zhou , Ma Xianjie
Published: February 2024

Background

Tissue expansion, a technique in which skin regeneration is induced by mechanical stretch stimuli, is commonly used for tissue repair and reconstruction. In this study, we aimed to monitor the autophagy levels of expanded skin after the application of expansion stimuli and explore the effect of autophagy modulation on skin regeneration.

Methods

A rat scalp expansion model was established to provide a stable expanded skin response to mechanical stretch. Autophagy levels at different time points (6, 12, 24, 48 and 72 h after the last expansion) were detected via western blotting. The effect of autophagy regulation on skin regeneration during tissue expansion was evaluated via skin expansion efficiency assessment, western blotting, immunofluorescence staining, TUNEL staining and laser Doppler blood flow imaging.

Results

The autophagic flux reached its highest level 48 h after tissue expansion. Activating autophagy by rapamycin increased the area of expanded skin as well as the thicknesses of epidermis and dermis. Furthermore, activating autophagy accelerated skin regeneration during tissue expansion by enhancing the proliferation of cells and the number of epidermal basal and hair follicle stem cells, reducing apoptosis, improving angiogenesis, and promoting collagen synthesis and growth factor secretion. Conversely, the regenerative effects were reversed when autophagy was blocked.

Conclusions

Autophagy modulation may be a promising therapeutic strategy for improving the efficiency of tissue expansion and preventing the incidence of the complication of skin necrosis.
Link Residual Closeness of Graphs with Fixed Parameters
Authors: Xu Leyou , Li Chengli , Zhou Bo
Published: February 2024

Link residual closeness is a newly proposed measure for network vulnerability. In this model, vertices are perfectly reliable and the links fail independently of each other. It measures the vulnerability even when the removal of links does not disconnect the graph. In this paper, we characterize those graphs that maximize the link residual closeness over the connected graphs with fixed order and one additional parameter such as connectivity, edge connectivity, bipartiteness, independence number, matching number, chromatic number, number of cut vertices and number of cut edges.
Behind the curve: technology challenges facing the homeland intelligence and counterterrorism workforce
Authors: Black Michelle , Obradovic Lana , House Deanna
Published: February 2024

Those charged with protecting the homeland through intelligence analysis, particularly in counterterrorism, must be capable of rapidly adopting innovative technologies to detect and prevent exploitation and disruption of vulnerable critical infrastructures. However, implementing these responses requires a highly skilled technical workforce that is continually provided with timely educational and training programs. Yet, questions remain regarding the technical aptitude necessary to respond to today’s terrorism threats and the Department of Homeland Security’s ability to provide consistent and rigorous standards for technology training and education. By surveying analysts, we examine what, if any, educational and training programs have been provided to adapt and remain technologically competitive and effectively utilize emerging technologies. We find a distinct need to focus on improvements that involve clarifying terms, building a technology and cybersecurity roadmap for analysts, allocating additional training time for employees, and building partnerships with private industry.
A systematic review of lethal means safety counseling interventions: impacts on safety behaviors and self-directed violence
Authors: Spitzer Elizabeth G , Stearns-Yoder Kelly A , Hoffberg Adam S , Bailey Hannah M , Miller Christopher J , Simonetti Joseph A
Published: February 2024

For lethal means safety counseling (LMSC) interventions to reduce population-level suicide rates, interventions must be deployed across many settings and populations. We conducted a systematic search in 6 databases to review the current state of LMSC interventions across study designs, settings, intervention providers, populations, and injury prevention levels (eg, universal). Eligibility criteria were as follows: any individual or group receiving an LMSC intervention involving a human-to-human component aiming to influence adult behaviors related to lethal suicide methods, and outcome assessment of storage behaviors and/or suicidal self-directed violence (SDV). Risk of bias was assessed using the Effective Public Health Practice Project quality assessment tool. A descriptive synthesis approach was used for analysis. Twenty-two studies were included that reported medication- and/or firearm-storage behaviors and/or SDV after LMSC. Of the 19 studies assessing behavioral change, 14 reported a significant improvement in safe storage behaviors, and all studies measuring acceptability reported that participants found the interventions favorable. The quality of evidence was limited. No studies were rated low risk of bias, and 77% were rated high risk of bias. There was substantial heterogeneity in the settings, populations, injury prevention levels, delivery methods, and intervention elements. Many included studies focused on caregivers of pediatric populations, and few studies assessed SDV outcomes. Higher-quality trials conducted across a variety of settings, particularly those focusing on adults at risk of suicide, are needed. This review was preregistered with the International Prospective Register of Systematic Reviews (no. CRD42021230668).
ATR-FTIR spectroscopy and LDA: a rapid, non-destructive and cost effective strategy to trace the geographical origin of Cannabis sativa L
Authors: Ramos Mariana Fernandes , Kinney Chad A , Coblinski João A , Fett Mauro Sander , Dick Deborah Pinheiro , de Oliveira Camargo Flávio A
Published: February 2024

Cannabis recreational and/or medicinal use have been legalized in the past years in many states and countries. As a consequence, many Cannabis growers and product developers have emerged in a new market throughout the world; at the same time, issues regarding questionable quality control have also risen, as several reports on Cannabis users’ health-related problems caused by inaccurate labeling content in Cannabis-based medicines, edibles or other derivatives are being published and brought out to the public’s attention. These facts make traceability methodologies crucial whether for forensic use, such as drug trafficking eradication, or for quality control purposes of legal Cannabis and of products derived from it. Hence, the objective of this study was to analyze Cannabis by means of Attenuated Total Reflection Spectroscopy (ATR-FTIR) in order to assess the capability of this technique to trace the geographical origin of Cannabis cultivated in Brazil and in Colorado, United States of America. Forty-seven samples from Brazil and 18 samples from Colorado were analyzed by ATR-FTIR. Linear Discriminant Analysis (LDA) was employed to source the samples. The combination of ATR-FTIR and LDA achieved up to 95.23% accuracy in assigning Cannabis samples to their geographical locations of origin in Brazil and up to 100% in Colorado.
The probability of edge existence due to node degree: a baseline for network-based predictions
Authors: Zietz Michael , Himmelstein Daniel S , Kloster Kyle , Williams Christopher , Nagle Michael W , Greene Casey S
Published: February 2024

Important tasks in biomedical discovery such as predicting gene functions, gene–disease associations, and drug repurposing opportunities are often framed as network edge prediction. The number of edges connecting to a node, termed degree, can vary greatly across nodes in real biomedical networks, and the distribution of degrees varies between networks. If degree strongly influences edge prediction, then imbalance or bias in the distribution of degrees could lead to nonspecific or misleading predictions. We introduce a network permutation framework to quantify the effects of node degree on edge prediction. Our framework decomposes performance into the proportions attributable to degree and the network’s specific connections using network permutation to generate features that depend only on degree. We discover that performance attributable to factors other than degree is often only a small portion of overall performance. Researchers seeking to predict new or missing edges in biological networks should use our permutation approach to obtain a baseline for performance that may be nonspecific because of degree. We released our methods as an open-source Python package (https://github.com/hetio/xswap/).
Exploring definitions of daily enteric methane emission phenotypes for genetic evaluations using a population of indoor-fed multi-breed growing cattle with feed intake data
Authors: Ryan Clodagh V , Pabiou Thierry , Purfield Deirdre C , Berry Donagh P , Conroy Stephen , Murphy Craig P , Evans Ross D
Published: February 2024

Genetic selection has been identified as a promising approach for reducing enteric methane (CH4) emissions; a prerequisite for genetic evaluations; however, these are estimates of the necessary genetic parameters based on a population representative of where the genetic evaluations will be used. The objective of this study was, therefore, to derive genetic parameters for a series of definitions of CH4, carbon dioxide (CO2), and dry matter intake (DMI) as well as genetic correlations between CH4, CO2, and DMI in a bid to address the paucity of studies involving methane emissions measured in beef cattle using GreenFeed systems. Lastly, estimated breeding values (EBV) were generated for nine alternative definitions of CH4 using the derived genetic parameters; the EBV were validated against both phenotypic performance (adjusted for non-genetic effects) and the Legarra and Reverter method comparing EBV generated for a subset of the dataset compared to EBV generated from the entire dataset. Individual animal CH4 and CO2 records were available from a population of 1,508 multi-breed growing beef cattle using 10 GreenFeed Emission Monitoring systems. Nine trait definitions for CH4 and CO2 were derived: individual spot measures, the average of all spot measures within a 3-h, 6-h, 12-h, 1-d, 5-d, 10-d, and 15-d period and the average of all spot measures across the full test period (20 to 114 d on test). Heritability estimates from 1,155 animals, for CH4, increased as the length of the averaging period increased and ranged from 0.09 ± 0.03 for the individual spot measures trait to 0.43 ± 0.11 for the full test average trait; a similar trend existed for CO2 with the estimated heritability ranging from 0.17 ± 0.04 to 0.50 ± 0.11. Enteric CH4 was moderately to strongly genetically correlated with DMI with a genetic correlation of 0.72 ± 0.02 between the spot measures of CH4 and a 1-d average DMI. Correlations, adjusted for heritability, between the adjusted phenotype and (parental average) EBV ranged from 0.56 to 1.14 across CH4 definitions and the slope between the adjusted phenotype and EBV ranged from 0.92 to 1.16 (expectation = 1). Validation results from the Legarra and Reverter regression method revealed a level bias of between −0.81 and −0.45, a dispersion bias of between 0.93 and 1.17, and ratio accuracy (ratio of the partial evaluation accuracies on whole evaluation accuracies) from 0.28 to 0.38. While EBV validation results yielded no consensus, CH4 is a moderately heritable trait, and selection for reduced CH4 is achievable.
Exploring risk factors and molecular targets in leukemia patients with COVID-19: a bioinformatics analysis of differential gene expression
Authors: Ullah Md Asad , Moin Abu Tayab , Nipa Jannatul Ferdous , Islam Nafisa Nawal , Johora Fatema Tuz , Chowdhury Rahee Hasan , Islam Saiful
Published: February 2024

The molecular mechanism of COVID-19's pathogenic effects in leukemia patients is still poorly known. Our study investigated the possible disease mechanism of COVID-19 and its associated risk factors in patients with leukemia utilizing differential gene expression analysis. We also employed network-based approaches to identify molecular targets that could potentially diagnose and treat COVID-19–infected leukemia patients. Our study demonstrated a shared set of 60 genes that are expressed differentially among patients with leukemia and COVID-19. Most of these genes are expressed in blood and bone marrow tissues and are predominantly implicated in the pathogenesis of different hematologic malignancies, increasingly imperiling COVID-19 morbidity and mortality among the affected patients. Additionally, we also found that COVID-19 may influence the expression of several cancer-associated genes in leukemia patients, such as CCR7, LEF1, and 13 candidate cancer-driver genes. Furthermore, our findings reveal that COVID-19 may predispose leukemia patients to altered blood homeostasis, increase the risk of COVID-19–related liver injury, and deteriorate leukemia-associated injury and patient prognosis. Our findings imply that molecular signatures, like transcription factors, proteins such as TOP21, and 25 different microRNAs, may be potential targets for diagnosing and treating COVID-19–infected leukemia patients. Nevertheless, additional experimental studies will contribute to further validating the study's findings.
Organization of microtubule plus-end dynamics by phase separation in mitosis
Authors: Yang Fengrui , Ding Mingrui , Song Xiaoyu , Chen Fang , Yang Tongtong , Wang Chunyue , Hu Chengcheng , Hu Qing , Yao Yihan , Du Shihao , Yao Phil Y , Xia Peng , Adams Jr Gregory , Fu Chuanhai , Xiang Shengqi , Liu Dan , Wang Zhikai , Yuan Kai , Liu Xing
Published: February 2024

abstract

In eukaryotes, microtubule polymers are essential for cellular plasticity and fate decisions. End-binding (EB) proteins serve as scaffolds for orchestrating microtubule polymer dynamics and are essential for cellular dynamics and chromosome segregation in mitosis. Here, we show that EB1 forms molecular condensates with TIP150 and MCAK through liquid–liquid phase separation to compartmentalize the kinetochore–microtubule plus-end machinery, ensuring accurate kinetochore–microtubule interactions during chromosome segregation in mitosis. Perturbation of EB1–TIP150 polymer formation by a competing peptide prevents phase separation of the EB1-mediated complex and chromosome alignment at the metaphase equator in both cultured cells and Drosophila embryos. Lys220 of EB1 is dynamically acetylated by p300/CBP-associated factor in early mitosis, and persistent acetylation at Lys220 attenuates phase separation of the EB1-mediated complex, dissolves droplets in vitro, and harnesses accurate chromosome segregation. Our data suggest a novel framework for understanding the organization and regulation of eukaryotic spindle for accurate chromosome segregation in mitosis.
Ureterocele as differential diagnosis of hydrosalpinx—an interesting case from the clinical practice
Authors: Psilopatis Iason , Beckmann Matthias W , Emons Julius , Schulmeyer Carla E
Published: February 2024

Hydrosalpinx is a common condition in women of reproductive age that correlates with infertility. A ureterocele is a dilatation of the terminal ureter within the bladder and/or urethra that occurs seldomly in adults, but can sonographically be mistaken for a hydrosalpinx. We report of a 29-year-old patient (G2/P1) who was referred in our department with secondary infertility and suspicion of hydrosalpinx. Intraoperatively, no hydrosalpinx could be visualized. Postoperatively, an intravesical cystic mass was detected, alongside a second-degree urinary retention. Sonographically, a double kidney on the left side and an accentuated calyx system could be diagnosed. Ureteroceles seem to represent a rare but still possible differential diagnosis in suspected hydrosalpinx, given the similar sonographic presentation of both conditions.