bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a TAC-based TDC in 130 nm CMOS technology
Authors: Firlej Mirosław , Fiutowski Tomasz , Idzik Marek , Molenda Aleksandra , Moroń Jakub , Świentek Krzysztof
Published: January 2025

The design and measurement results of a prototype Time-to-Digital Converter (TDC) fabricated in 130 nm CMOS
technology are presented. The TDC architecture with analog interpolators was chosen, which
was motivated by previous experience in Analog-to-Digital Converter (ADC) design [1]. The measured time
difference between the event and the trigger signal is converted to the amplitude and then
digitised by a 10-bit ADC. The TDC prototype is functional and achieved good Differential Non-Linearity (DNL)
and jitter (below 1 LSB), slightly dependent of the selected time precision. The obtained
Integral Non-Linearity (INL) is significantly higher than simulated and should be still improved. The prototype
Application-Specific Integrated Circuit (ASIC) has configurable time resolution from 15 ps to 140 ps, which gives the total possible
time measure range from ±9.5 ns to ±70 ns. In this paper the architecture of the developed
TDC is described, comprising the implementation of the Time-to-Analog Converter (TAC) and 10-bit ADC. The
measurements of the prototype 8 channel TDC ASIC, showing its linearity and timing
resolution are also shown.
Cell viability assessment by using GelRed/SYTO 9-based double staining
Authors: Zheng Yueping , Sun Jian , Li Xiaocui , Qiu Honxin , Liao Lifang , He Shengbin
Published: January 2025

Cell viability assessment plays a crucial role in biological research, pharmaceutical development, and toxicological identification. Here, we used GelRed, a sensitive and safer nucleic acid dye, to selectively label dead cells with red fluorescence (FL) thus distinguishing dead cells from live ones. Further more, the combined use of GelRed and SYTO 9 (another nucleic acid dye) enabled the clear differentiation in FL spectra between the two physiological statuses. The GelRed and SYTO 9 concentrations were optimized to obtain the highest FL ratio of dead to live cells. The GelRed/SYTO 9-based double staining could quantify the cell viability through flow cytometry analysis, with a good correlation between the detected and theoretical dead cell ratios. Compared with traditional prodium iodide (PI) staining, the GelRed/SYTO 9-based double staining showed high accuracy in quantifying dead cell of low levels. The as-developed staining method could be used in biomedical research to accurately measure the cytotoxic effect of various substances in living cells.
Cataland: Why the Fuß?
Authors: Stump Christian , Thomas Hugh , Williams Nathan
Published: January 2025

The three main objects in noncrossing Catalan combinatorics associated to a finite Coxeter system are noncrossing partitions, clusters, and sortable elements. The first two of these have known Fuß-Catalan generalizations. We provide new viewpoints for both and introduce the missing generalization of sortable elements by lifting the theory from the Coxeter system to the associated positive Artin monoid. We show how this new perspective ties together all three generalizations, providing a uniform framework for noncrossing Fuß-Catalan combinatorics. Having developed the combinatorial theory, we provide an interpretation of our generalizations in the language of the representation theory of hereditary Artin algebras.
Primes as Sums of Fibonacci Numbers
Authors: Drmota Michael , Müllner Clemens , Spiegelhofer Lukas
Published: January 2025

The purpose of this paper is to discuss the relationship between prime numbers and sums of Fibonacci numbers. One of our main results says that for every sufficiently large integer

k
k

there exists a prime number that can be represented as the sum of

k
k

different and non-consecutive Fibonacci numbers. This property is closely related to, and based on, a prime number theorem for certain morphic sequences. In our case, these morphic sequences are based on the Zeckendorf expansion of a positive integer

n
n

— we write

n
n

as the sum of non-consecutive Fibonacci numbers. More precisely, we are concerned with the Zeckendorf sum-of-digits function

z

\mathsf {z}

, which returns the minimal number of Fibonacci numbers needed to write a positive integer as their sum. The proof of such a prime number theorem for

z

\mathsf {z}

, combined with a corresponding local result, constitutes the central contribution of this paper, from which the result stated in the beginning follows.

Problems of this type have been discussed intensively in the context of the base-

q
q

expansion of integers. The driving forces of this development were the Gelfond problems (1968/1969), more specifically the behavior of the sum-of-digits function in base

q
q

along the sequence of primes and along integer-valued polynomials, and the Sarnak conjecture. Mauduit and Rivat resolved the question on the sum of digits of prime numbers (2010) and the sum of digits of squares (2009). Later the second author (2017) proved Sarnak’s conjecture for the class of automatic sequences, which are based on the

q
q

-ary expansion of integers, and which generalize the sum-of-digits function in base

q
q

considerably.

For the (partial) solution of the Gelfond problems (1967/1968), Mauduit and Rivat have developed a powerful method that is based on techniques for “cutting off digits”, on sophisticated estimates for Fourier terms, and on estimates for exponential sums. These techniques — together with a new decomposition of finite automata — were also the basis for the second author’s result on automatic sequences.

In order to obtain corresponding results for Fibonacci numbers, we have to extend Mauduit and Rivat’s method considerably. In fact, we are departing significantly from this method, proving the statement that

exp
⁡
(
2
π
i
ϑ

z

(
n
)
)

\exp (2\pi i \vartheta \hspace {0.5pt}\mathsf {z}(n))

has level of distribution

1
1

. This latter result forms an essential part of our treatment of the occurring sums of type

I

\mathrm {I}

and

I
I

\mathrm {II}

and uses Gowers norms related to the Zeckendorf sum-of-digits function as a central technical tool. Gowers norms are a higher order generalization of the above-mentioned Fourier terms, and their appearance in our method is intimately tied to the iterated application of a new generalization of van der Corput’s inequality.
Equivariant Infinite Loop Space Theory: The Space Level Story
Authors: May J. , Merling Mona , Osorno Angélica
Published: January 2025

We rework and generalize equivariant infinite loop space theory, which shows how to construct

G
G

-spectra from

G
G

-spaces with suitable structure. There is a classical version which gives classical

Ω
\Omega

-

G
G

-spectra for any topological group

G
G

, but our focus is on the construction of genuine

Ω
\Omega

-

G
G

-spectra when

G
G

is finite. We also show what is and is not true when

G
G

is a compact Lie group.

We give new information about the Segal and operadic equivariant infinite loop space machines, supplying many details that are missing from the literature, and we prove by direct comparison that the two machines give equivalent output when fed equivalent input. The proof of the corresponding nonequivariant uniqueness theorem, due to May and Thomason, works for classical

G
G

-spectra for general

G
G

but fails for genuine

G
G

-spectra. Even in the nonequivariant case, our comparison theorem is considerably more precise, giving an illuminating direct point-set level comparison.

We have taken the opportunity to update this general area, equivariant and nonequivariant, giving many new proofs, filling in some gaps, and giving a number of corrections to results and proofs in the literature.
From Allies to Rivals: Portuguese Maritime Espionage in England, 1551–1559
Authors: Vila-Santa Nuno
Published: January 2025

Using an unstudied set of diplomatic instructions given by the Portuguese kings to their ambassadors, spies and agents sent to Tudor England between 1553 and 1559, this article seeks to re-examine the emergence of Anglo-Portuguese maritime rivalry in West Africa. By carefully detailing the contents of these instructions, and matching them with other sources, this study also highlights the role of Mary I (1553–1558) in English maritime expansion. Analysing the contents of each mission in connection to the first English voyages to West Africa, I suggest that Portugal already envisaged Mary Tudor’s England as a serious maritime competitor and provide possible reasons for this conviction. Contextualising this rivalry with Philip II’s reign as king consort of England and the related Portuguese diplomatic strategies aimed at maintaining a mare clausum, this article argues that Portuguese maritime espionage in sixteenth-century England is inextricably linked to the development of a maritime and scientific milieu under Queen Mary. Additionally, I propose that such endeavours are intimately connected with the well-known English maritime achievements of the Elizabethan era, highlighting the importance of Mary’s reign in this process. Although the existence of intensive Portuguese maritime espionage in Mary Tudor’s England may (given the existing historiography) be surprising, I suggest that it should not be read as such, by showing that previous Portuguese maritime rivalries with Spain and France provide a relevant precedent, and stressing the globalisation of nautical knowledge unfolding in the sixteenth century.
Case report of the successful treatment of pemphigus vulgaris using ovine forestomach matrix graft
Authors: Kokal William A , Simon Jessica
Published: January 2025

Pemphigus vulgaris (PV) is a subtype of pemphigus and life-altering disorder that results in the formation of intraepithelial blisters in mucosa and skin. Though the etiology is not well understood, it is an autoimmune disorder resulting in acantholytic blisters due to auto-antibodies targeting proteins of keratinocyte adhesion. Rapid diagnosis and restoration of the epidermal layer is imperative for patients with PV as widespread epidermal damage can lead to high morbidity and mortality rates. This case report presents the treatment of PV in a 53-year-old female who presented after 9 months of worsening symptoms and 30% total body surface area blistering. Most of the lesion was re-epithelialized in 1 week, with complete healing in 4 weeks following a single application of ovine forestomach matrix (OFM) graft. This case represents the first report of the use of OFM to aid regeneration of epithelial lesions resulting from an autoimmune bullous disease.
Staged surgery for the treatment of carotid aneurysm
Authors: Zhao Shiyi , Chen Dejie
Published: January 2025

Extracranial carotid artery aneurysm (ECAA) is a relatively rare vascular lesion of the neck, and is usually found incidentally and is usually asymptomatic. Surgery is currently the first choice for symptomatic or growing ECAA, including open resection of the entire aneurysm, with or without arterial replacement and insertion of grafts. Ischemic stroke is the most serious complication after resection of ECAA. The preoperative Matas test facilitates the collateral circulation through the circle of Willis， which allows the brain to adapt to the hypoxic situation and effectively reduces ischemic stroke. We report a case of a young patient who underwent a staged surgery to treat it (the first stage was prophylactic carotid artery blockade, so called open Matas test), and achieved good results.
R2DT: a comprehensive platform for visualizing RNA secondary structure
Authors: McCann Holly , Meade Caeden D , Williams Loren Dean , Petrov Anton S , Johnson Philip Z , Simon Anne E , Hoksza David , Nawrocki Eric P , Chan Patricia P , Lowe Todd M , Ribas Carlos Eduardo , Sweeney Blake A , Madeira Fábio , Anyango Stephen , Appasamy Sri Devan , Deshpande Mandar , Varadi Mihaly , Velankar Sameer , Zirbel Craig L , Naiden Aleksei , Jossinet Fabrice , Petrov Anton I
Published: January 2025

RNA secondary (2D) structure visualization is an essential tool for understanding RNA function. R2DT is a software package designed to visualize RNA 2D structures in consistent, recognizable, and reproducible layouts. The latest release, R2DT 2.0, introduces multiple significant features, including the ability to display position-specific information, such as single nucleotide polymorphisms or SHAPE reactivities. It also offers a new template-free mode allowing visualization of RNAs without pre-existing templates, alongside a constrained folding mode and support for animated visualizations. Users can interactively modify R2DT diagrams, either manually or using natural language prompts, to generate new templates or create publication-quality images. Additionally, R2DT features faster performance, an expanded template library, and a growing collection of compatible tools and utilities. Already integrated into multiple biological databases, R2DT has evolved into a comprehensive platform for RNA 2D visualization, accessible at https://r2dt.bio.
Increasing a Quitline’s Reach to Low-Income Tobacco Users Through 211 Agencies
Authors: Zhu Shu-Hong , Aughinbaugh Emily , Pratt Andrea S , Zhuang Yue-Lin , Wang Ding , Mayoral Antonio , Anderson Christopher M , Hagaman Tonia
Published: January 2025

Introduction

Low-income individuals bear a disproportionate share of the burden of tobacco use. This study tested the feasibility of increasing a quitline’s reach to low-income tobacco users by collaborating with 211 information and referral agencies, which primarily serve people experiencing economic hardship.

Aims and Methods

Study participants (N = 114 888) were adult tobacco users referred to the California quitline by 211 agencies, referred by healthcare clinics, or self-referred from April 17, 2021 to December 31, 2023. All were offered telephone counseling. Those referred by 211 received $20 for completing one counseling session. A subset (n = 2021) was followed up at 7 months. Referral outcomes, baseline characteristics, counseling and quitting aid utilization, and quitting outcomes were analyzed by referral source in 2024.

Results

Over a 2.7-year period, 211 agencies referred 55 151 clients to the quitline. Participants referred by 211 were more than twice as likely as healthcare-referred participants to enroll in quitline services (34.0% vs. 15.9%, p < .0001). They were more likely than healthcare- and self-referred participants to be female, lesbian, gay, bisexual, transgender, or queer/questioning, Black or multiracial, younger, less educated, and Medicaid-insured; more likely to complete a first counseling session (64.2% vs. 59.7% and 55.7%; both ps < .0001); and completed a similar number of sessions, 2.4. They were less likely to use quitting aids. Quit rates (ie, 30-day point prevalence abstinence) at 7-month follow-up were similar for all three groups.

Conclusions

A collaboration between a quitline and 211 agencies connected large numbers of underserved, low-income tobacco users to evidence-based cessation treatment.

Implications

The study shows that quitlines and 211 agencies can collaborate effectively to help low-income tobacco users quit. It shows that when offered a modest incentive, 211-referred participants engage in counseling as much as healthcare- and self-referred participants and are as likely to quit. If 211 agencies across the US referred at the same rate as agencies in this study, an estimated 65 000 additional tobacco users annually would receive treatment. Total reach at full implementation would likely be much higher. Quitline and 211 funders and other supporters should find ways to sustain these gains and expand their reach.
Cross-sectional analysis of self-promotional language in texts of grant proposals across gender
Authors: Heyard Rachel , Lim Sandar , Jorstad Anne
Published: January 2025

To investigate whether the use of positive, self-promotional language in grant proposals is associated with the gender of the applicant, we used a cross-sectional analysis on 8,150 grant proposals submitted to the Swiss National Science Foundation in life sciences disciplines across three different funding schemes, targeting applicants at different career stages. Multivariate, logistic, and negative binomial regressions were used to model the count and binary presence of positive words in grant proposal titles and abstracts. We found no evidence of an association between the use of self-promotional language and gender in grant proposals from life sciences disciplines. In the Projects funding scheme, funding bottom-up research, male applicants have used on average slightly more positive words in their proposals than their female peers, but the estimates (Rate Ratio 1.057; 95% CI 0.982–1.139) show no evidence of an effect. Similarly, no evidence of gender differences was found in proposals from the Careers funding schemes (Rate Ratio 1.087, 95% CI 0.973–1.214) which target early career researchers, and in a pilot scheme (Rate Ratio 1.089, 95% CI 0.911–1.302), a double-blind funding scheme supporting unconventional research. It is encouraging that we found no evidence indicating a difference in the use of positive words between male and female grant applicants. Although many factors influence how peer reviewers perceive the content of grant proposals, language usage undoubtedly plays an important role. We urge other funding agencies to conduct similar studies to identify if language usage contributes to biases in grant evaluation.
Use of a blinded hypnotic tapering strategy to promote hypnotic discontinuation
Authors: Edinger Jack D , Wamboldt Frederick , Johnson Rachel L , Hudson Bryan , Tsai Sheila , Morin Charles M , Holm Kristen E
Published: January 2025

Study Objectives

Cognitive behavioral insomnia therapy (CBT-I) combined with supervised open-label tapering is effective for helping hypnotic-dependent patients discontinue their hypnotics. This study tested whether slowing the tapering pace and blinding the tapering process enhance outcomes.

Methods

Seventy-eight benzodiazepines (BZD) or benzodiazepine receptor agonists (BZRA) users completed 4 CBT-I sessions, followed by a randomly assigned blinded tapering protocol wherein hypnotic dosage was: held constant, reduced by 10% every two weeks, or reduced by 25% every two weeks. After 20 weeks those who did not have their medications reduced were offered an open-label tapering protocol. Participants completed assessments 3 months after completing their respective tapering protocols. Outcomes included discontinuation rates, hypnotic withdrawal effects, and responder and remission rates determined by Insomnia Severity Index (ISI) scores.

Results

No differences were observed between the two tapering paces (10% vs. 25%). Blinded tapering had a consistent association with better outcomes that did not reach statistical significance. At 3-month follow-up the number of patients needed to be treated with blinded taper instead of open-label tapering in order for one additional individual to achieve desired endpoints was 7.7 for BZD/BZRA discontinuation, 3.4 for hypnotic withdrawal effects, 4.4 for ISI responder status, and 5.0 for insomnia remission. One-third (32.3%) of the sample was using benzo-related hypnotics at 3-month follow-up. Twice as many individuals (64.6%) were using some type of medication or substance for sleep at this time point.

Conclusions

Blinding tapering may enhance hypnotic discontinuation rates and insomnia treatment response and remission rates.

Trial Registration: Clinicaltrials.gov Identifier: NCT02831894, “The Role of Tapering Pace and Selected Traits on Hypnotic Discontinuation;” URL:https://clinicaltrials.gov/ct2/show/ NCT02831894?term=hypnotics&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&draw=2&rank=2
Minimally Invasive Versus Open Surgery for Thoracolumbar Fractures Treatment
Authors: Daher Mohammad , Aoun Marven , Cottrill Ethan J. , Wang Zhi , Hurley Richard K. , Lavelle William F. , Passias Peter G. , Diebo Bassel G. , Daniels Alan H. , Sebaaly Amer
Published: January 2025

Study Design.

Meta-analysis.

Objective.

The purpose of this systematic review and meta-analysis was to pool the available data comparing MIS to open surgery for thoracolumbar fractures and provide a more comprehensive assessment of this topic.

Background.

There remains a debate over whether minimally invasive surgery (MIS) or open fixation provides superior outcomes for patients with thoracolumbar fractures. While several randomized controlled trials and prospective studies have compared these two approaches, the published studies are limited by sample size.

Methods.

Following PRISMA guidelines, a systematic review of the PubMed, Cochrane, and Google Scholar (pages 1–20) databases was performed on October 1, 2024. The extracted data consisted of complications, surgery-related parameters, early and late postoperative back pain, and postoperative regional kyphosis.

Results.

Five RCTs and five prospective studies were included in the meta-analysis, including 584 patients, with 299 in the MIS group and 285 in the open group. MIS patients were shown to have less EBL (MD=−155.86; 95% CI: −217.97 to −93.76, P<0.001), a shorter LOS (MD=−3.34; 95% CI: −4.62 to −2.06, P<0.001), lower pain scores during the early postoperative period (MD=−1.14; 95% CI: −1.56 to −0.71, P<0.001), and less regional kyphosis (MD=−5.17; 95% CI: −7.17 to −3.16, P<0.001), even when stratifying by study type. In addition, fluoroscopy time was longer in the MIS group (MD=0.60; 95% CI: 0.21–0.98, P=0.003), although this difference was not seen when looking at RCTs only.

Conclusions.

Among patients with thoracolumbar fractures, treatment with MIS was associated with decreased EBL, shorter LOS, earlier pain reduction, and less regional kyphosis compared with treatment with open fixation. In addition, higher radiation exposure was seen among patients treated with MIS. While MIS offers several potential benefits, both MIS and open fixation remain safe and reliable options for the treatment of thoracolumbar fractures.
Comparison of Recruitment Method on Clinical Outcomes Following Cervical Disc Arthroplasty
Authors: Foley David P. , Beutler Graham J. , Robinson Daniel L. , McCarthy Michael H. , Sasso Rick C.
Published: January 2025

Study design:

Retrospective cohort

Objective:

To compare the clinical outcomes of trial versus standard clinical practice (SCP) patients following cervical disc arthroplasty (CDA)

Background:

CDA is hypothesized to reduce the shear strain and related complications resulting from fusion procedures. CDA has gained significant traction in recent decades. The typical non-trial patient undergoing CDA does not undergo the same level of preoperative scrutiny as those treated in formal clinical trials. Concerns exist about diverging clinical outcomes between these groups.

Methods:

This investigation retrospectively reviews prospectively collected data on one and two-level CDA patients from C3-T1. Patients were recruited into randomized, controlled trials or SCP practice beginning in 2002 or 2018, respectively. One-year minimum follow-up was required. Hybrid constructs and prior cervical spine surgical history have been excluded. Clinical assessments included reoperation history and the patient-reported outcome measures of Visual Analog Scale (VAS) neck, VAS arm, and Neck Disability Index (NDI). Data was collected at the preoperative, postoperative, one-year, two-year, three-year, five-year, and ten-year time points.

Results:

One hundred and sixty-eight patients underwent CDA at 193 cervical levels, including 104 trial patients and 64 SCP patients. Mean follow-up for the entire cohort was 6.1 years (0.9 – 20.4 years). Eight unique disc designs were utilized. Trial patients had a greater proportion of females and longer follow-up duration (P<0.05). Trial patients had significantly worse preoperative clinical scores with greater improvements at each follow-up time point. SCP patients had significantly higher index-level reoperation rates at five years.

Conclusion:

Trial patients have lower rates of reoperation and improved clinical performance which could be in part due to more stringent selection criteria. This study is limited by long-term SCP response rates. Additional studies with larger cohorts are needed to improve our understanding of disc implant performance.
Identification and validation of mitochondria-related LncRNA signatures as a novel prognostic model for glioma
Authors: Deng Kaihan , Zhao Wei , Dai Lin , Jing Zixuan , Ma Lixin
Published: January 2025

A predictive model for long-term survival is needed, and mitochondrial dysfunction is a key feature of cancer metabolism, though its link to glioma is not well understood. The aim of this study was to identify the molecular characteristics associated with glioma prognosis and explore its potential function. We analyzed RNA-seq data from The Cancer Genome Atlas and identified differentially expressed mitochondrial long noncoding RNAs (lncRNAs) using R’s ‘limma’ package. A prognostic model was developed using 10 selected lncRNAs and validated with Cox regression and least absolute shrinkage and selection operator algorithm. The model’s efficacy was assessed using Kaplan–Meier and receiver operating characteristic curve analyses, and its correlation with immune cell profiles and drug sensitivity was explored. A 10-mitochondria-related LncRNA signature was generated. The median risk score values are used to classify glioma samples into low-risk and high-risk groups. In breast patients, the signature-based risk score demonstrated a more potent ability to predict survival than conventional clinicopathological features. Furthermore, we noted a substantial disparity in the number of immune cells, including B cells, CD8+T cells, and macrophages, between the two groups. In addition, the high-risk group exhibited lower half-maximal inhibitory concentration values for specific chemotherapy medications, including bortezomib, luminespib, rapamycin, and 5-fluorouracil. Our study elucidates the diagnostic and prognostic value of mitochondria-related-lncRNAs in the promotion, suppression, and treatment of glioma.
WDR62 mediates MAPK/ERK pathway to stimulate DNA damage repair and attenuate cisplatin sensitivity in lung adenocarcinoma
Authors: Li Xu , Guo Yingwei , Qi Zecheng , Zheng Yi
Published: January 2025

Chemotherapy resistance has long stood in the way of therapeutic advancement for lung cancer patients, the malignant tumor with the highest incidence and fatality rate in the world. Patients with lung adenocarcinoma (LUAD) now have a dismal prognosis due to the development of cisplatin (DDP) resistance, forcing them to use more costly second-line therapies. Therefore, overcoming resistance and enhancing patient outcomes can be achieved by comprehending the regulatory mechanisms of DDP resistance in LUAD. WD repeat domain 62 (WDR62) expression in LUAD tissues and in DDP-resistant or sensitive LUAD patients was analyzed bioinformatically, and a K-M plot was utilized to assess survival status. Real-time quantitative PCR was employed for WDR62 expression detection, cell-counting kit-8 assay for half maximal inhibitory concentration determination, flow cytometry for cell apoptosis detection, immunofluorescence for γ-H2AX expression analysis, and western blot for nonhomologous end joining repair and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway-related protein expression analysis. Poor prognosis was linked to WDR62, which was overexpressed in LUAD tissues and cells. Compared to sensitive cells, DDP-resistant cells had increased WDR62 expression. WDR62 knockdown may enhance DDP-induced cell apoptosis while reducing cell proliferation and DNA damage repair. Functional investigations verified that overexpressed WDR62’s encouraging impact on DNA damage repair in A549/DDP cells could be reversed by MAPK inhibitors, increasing the cells’ susceptibility to DDP. LUAD cells became less sensitive to DDP when WDR62 activated the MAPK/ERK pathway, which promoted DNA damage repair, indicating that DDP resistance might be reversed by treating LUAD with inhibitors of the MAPK pathway.
Intense Pulsed Light in the Treatment of Dry Eye and Meibomian Gland Dysfunction in Patients With Chronic Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis
Authors: de Alcântara Rafael Jorge Alves , Wakamatsu Tais Hitomi , Hirai Flávio Eduardo , Demeda Vanessa Favero , Frizon Luciana , Pereira Gomes José Álvaro
Published: January 2025

Purpose:

To evaluate the efficacy and safety of intense pulsed light (IPL) combined with meibomian gland expression (MGX) for the treatment of dry eye disease and meibomian gland dysfunction associated with chronic Stevens–Johnson syndrome and toxic epidermal necrolysis.

Methods:

This prospective noncomparative interventional study included 29 patients (58 eyes) who underwent 3 sessions of IPL and MGX at 2-week intervals. Subjective symptoms (ocular surface disease index score) and objective dry eye tests: matrix metalloproteinase 9, tear meniscus height, bulbar redness score, tear film lipid layer thickness (LLT), Schirmer I test, conjunctival and corneal staining, meibomian gland loss, MGX score [meibomian gland score (MGS)], and tear break-up time were assessed at the baseline and after 4, 8, and 12 weeks.

Results:

Twenty-nine individuals (57 eyes) were included in this analysis. The ocular surface disease index score decreased significantly from 60.07 ± 23.34 (baseline) to 38.36 ± 22.39 (after 90 days) (P < 0.01). The fluorescein and lissamine green staining scores, MGS, and LLT improved significantly (P < 0.01). In contrast, there were no significant changes in the tear meniscus height values, matrix metalloproteinase 9 positivity, bulbar redness score, Schirmer test, meibography of the superior and inferior eyelids, and tear break-up time. Ocular or skin complications were not observed.

Conclusions:

Three IPL therapy sessions followed by MGX seemed to be safe and effective in treating dry eye disease and meibomian gland dysfunction, improving vision-related quality of life, dry eye symptoms, and ocular surface signs, such as corneal and conjunctival staining scores, MGS, and LLT after 90 days in patients with chronic Stevens–Johnson syndrome and toxic epidermal necrolysis.
Human Immunodeficiency Virus
Authors: Das Pankaj , Singh Neelam , Kharayat Veena , Vasudevan Biju , Priya Krishnan Lekshmi , Mukhida Sahjid , Das Nikunja Kumar , Sutar Anupama
Published: January 2025

Often overlooked or misdiagnosed, cutaneous symptoms are common in chronic human immunodeficiency virus (HIV) disease and can serve as early signs of the disease. These cutaneous signs prompted to test for HIV on the three patients, which all were found to be positive. In this article, we are attempting to highlight the importance of recognizing cutaneous manifestations of HIV for early diagnosis and timely initiation of antiretroviral therapy. Three cases of cutaneous symptoms are presented: (a) generalized hyperpigmentation; (b) generalized hyperpigmentation with oral hairy leukoplakia; and (c) seborrheic dermatitis, xerosis, oral hairy leukoplakia, multiple foci of furuncles, and linear gingival erythema. Studies have shown that various cutaneous symptoms are common in chronic HIV disease. The most common are seborrheic dermatitis, xerosis, oral candidiasis, and folliculitis. Recognition of these skin findings is crucial, as it can lead to early diagnosis and treatment of HIV infection, thereby reducing morbidity and mortality associated with HIV infection and improving quality of life for patients.
Dermoscopy 101
Authors: Davis Kyleen E.
Published: January 2025

Dermoscopy is a noninvasive diagnostic technique that allows dermatology clinicians to evaluate suspicious skin lesions and determine the need for biopsy. Basal cell carcinomas (BCCs) exhibit distinct dermoscopic features that when accurately identified help aid in diagnosis. This article focuses on the most pathognomonic dermoscopic feature of BCC—arborizing vessels.
Cerebellar infarction due to atlantoaxial subluxation in spondyloepimetaphyseal dysplasia-joint laxity type 1 case
Authors: Bilgeç Nagehan , Çalişkan Burcu , Eravci Saliha Yavuz , Güven Ahmet Sami , Çaksen Hüseyin
Published: January 2025

Introduction

Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1) is an extremely rare skeletal dysplasia belonging to a group of disorders called linkeropathies. It is characterized by skeletal and connective tissue abnormalities. Biallelic variants in genes encoding enzymes that synthesize the tetrasaccharide linker region of glycosaminoglycans lead to linkeropathies, which exhibit clinical and phenotypic features that overlap with each other. SEMD-JL1 results in impaired growth and short stature, along with increased joint flexibility leading to limb joint dislocations and progressive spinal deformity.

Methods and Result

Whole exome sequencing was performed on the patient’s genomic DNA. A novel variant in the B3GALT6 gene was detected as homozygous. During the patient’s follow-up, signs of cerebellar infarction was observed due to atlantoaxial subluxation. Posterior circulation ischemic strokes have not been described with SEMD-JL1 and it was the second case in the skeletal dysplasia group to develop posterior circulation ischemic stroke due to atlantoaxial luxation.

Conclusion

Linkeropathies present with varying clinical manifestations and necessitate comprehensive genetic testing for accurate diagnosis of this complex patient group. Skeletal dysplasias, such as spondyloepimetaphyseal dysplasia, may be accompanied by atlantoaxial instability that can lead to serious spinal symptoms and even sudden death.
Biallelic variants in AGRN with recurrent pregnancy losses in a family with a fetal akinesia deformation sequence
Authors: Shravya Mangalore S. , Chaurasia Ankur , Girisha Katta M. , Nayak Shalini S.
Published: January 2025

Introduction

Agrin, encoded by AGRN, plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS.

Methods

We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants.

Results

Perinatal phenotyping revealed an FADS in the family, and genomic testing identified novel null variants in AGRN. First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1_952+3del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN.

Conclusion

This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN.
Peribacillus simplex and Klebsiella pneumoniae responsible for pyonephrosis with secondary psoas abscess: a case report
Authors: Malihy Zakaria , Abassor Tilila , Ben Lahlou Yassine , Benaissa Elmostafa , Chadli Mariama
Published: January 2025

Bacterial urinary tract infections (UTIs) are common, ranging from benign cystitis to complicated pyelonephritis, which can lead to severe complications such as pyonephrosis and sepsis. Pyonephrosis, characterized by the presence of pus in the renal cavities, often requires urgent urological intervention. We report a unique case of pyonephrosis with a psoas abscess caused by Klebsiella pneumoniae and Peribacillus simplex in a 64-year-old diabetic female patient. This is the first case of pyonephrosis caused by P. simplex. The patient presented with acute right lumbar pain, fever and altered consciousness. Imaging revealed severe right hydronephrosis, pyonephrosis and a perirenal phlegmon infiltrating the psoas with abscesses. Surgical drainage and nephrectomy were performed. Microbiological and proteomic analyses identified K. pneumoniae and P. simplex. This case highlights the importance of considering environmental bacteria like P. simplex in severe infections and ensuring rigorous protocols to avoid contamination. Successful management of pyonephrosis relies on prompt surgical drainage and appropriate antibiotic therapy based on culture results.
Developing ERAF-AI: An Early-stage Research Assessment Framework for Artificial Intelligence
Authors: Falvo David , Weidener Lukas , Karlsson Martin
Published: January 2025

Today, most research evaluation frameworks are designed to assess mature projects with well-defined data and clearly articulated outcomes. Yet, few, if any, are equipped to evaluate the promise of early-stage research, which is inherently characterized by limited evidence, high uncertainty, and evolving objectives. These early-stage projects require nuanced assessments that can adapt to incomplete information, project maturity, and shifting research questions. Compounding these challenges is the difficulty of systematically scaling evaluations with the increasing volume of research projects. As a step toward addressing this gap, we introduce the Early-Stage Research Assessment Framework for Artificial Intelligence (ERAF-AI), a systematic approach to evaluate research at Technology Readiness Levels (TRLs) 1 to 3 – maturity levels where ideas are more conceptual and only preliminary evidence exists to indicate potential viability. By leveraging AI-driven methodologies and platforms such as Lateral’s Coordination.Network, ERAF-AI ensures transparent, scalable, and context-sensitive evaluations that integrate research maturity classification, adaptive scoring, and strategic decision-making. Importantly, ERAF-AI aligns criteria with the unique demands of early-stage research, guiding evaluation through the 4P framework (Promote, Pause, Pivot, Perish) to inform next steps. As an initial demonstration of its potential, we apply ERAF-AI to a high-impact early-stage project, providing actionable insights and measurable improvement over conventional practices. Although ERAF-AI shows significant promise in improving the prioritization of early-stage research, further refinement and validation across a wider range of disciplines and datasets is required to refine its scalability and adaptability. Overall, we expect this framework to serve as a valuable tool for empowering researchers to make informed decisions and to prioritize high-potential initiatives in the face of uncertainty and limited data.
Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Hackel Alexander , Sotzny Franziska , Mennenga Elise , Heidecke Harald , Schulze-Foster Kai , Fourlakis Konstantinos , Lüders Susanne , Grasshoff Hanna , Rubarth Kerstin , Konietschke Frank , Lange Tanja , Scheibenbogen Carmen , Akbarzadeh Reza , Riemekasten Gabriela
Published: January 2025

Post-COVID syndrome (PCS) has emerged as a significant health concern with persisting symptoms. A subset of PCS patients develops severe myalgic encephalomyelitis/chronic fatigue syndrome (pcME/CFS). Dysregulated autoantibodies (AABs) have been implicated in PCS, contributing to immune dysregulation, impairment of autonomous nerve and vascular function. As recently shown in autoimmune diseases, IgG fractions translate disease-specific pathways into various cells. Therefore, we asked whether IgG fractions from PCS patients could be applied in-vitro to identify specific cytokine responses for PCS patients without (nPCS) and with pcME/CSF. To assess this, we have stimulated monocyte cell lines with IgG fractions from PCS patients. Our findings reveal distinct cytokine responses induced by patient derived AABs which are suggested in vascular and immune dysfunction. In contrast to nPCS, pcME/CSF AABs induced enhanced neurotrophic responses, characterized by significant cytokine correlations involving brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and tumor necrosis factor superfamily member 14(LIGHT). Further, AAB-induced cytokine levels correlate with clinical symptoms. This study emphasizes a contribution of AABs in PCS, in mitigating long-term immune dysregulation, and a need for therapies modulating IgG-induced signaling pathways.
Characterizing Oligodendrocyte-Lineage Cells and Myelination in the Basolateral Amygdala: Insights from a Novel Methodology in Postmortem Human Brain
Authors: Perlman Kelly , Curto Emanuel , Barnett-Burns Sarah , Davoli Maria-Antonietta , Yerko Volodymyr , Merza Reem , Papadakis Andreas I , Spatz Alan , Pryce Christopher R , Turecki Gustavo , Mechawar Naguib
Published: January 2025

The basolateral amygdala (BLA) plays a key role in the pathophysiology of depressive disorders and trauma, yet oligodendrocyte-lineage cells and myelin in this brain region remain understudied in humans. This might be due, at least in part, to the lack of a cost-effective, antibody-based method to isolate oligodendrocytes (OL) and OL precursor cells (OPC) from postmortem brain tissue that is compatible with molecular biology applications. This study aimed to: 1) create and validate a method for isolating OPC and OL nuclei from frozen postmortem grey matter; 2) compare OPC and OL gene expression in the BLA between subjects having died with depression and matched controls; and 3) provide histological characterizations of OPC, OL, and myelin in the BLA. Frozen left-hemisphere BLA samples were obtained from brain donors with well-characterized phenotypic information. Immunolabeled nuclei were sorted into OPC (SOX10+/CRYAB-) and OL (SOX10+/CRYAB+) populations, and RNA was measured using a custom Nanostring codeset. Fluorescence in situ hybridization was used to determine OPC (PDGFRα+) and OL (MYRF+) densities, and immunofluorescence was used to label axons (NF-H) and myelin (MBP) for myelin area fraction. The method successfully isolated OPC and OL nuclei with correct transcriptomic profiles. While no significant group differences were observed in gene expression, cell densities, or myelin coverage, we did observe significant age-related patterns. Moreover, a strong significant correlation between OL density and myelin area fraction was identified. This study provides a novel sorting method and a comprehensive characterization of OL-lineage gene expression, cell densities, and myelin in the human BLA.
Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects
Authors: Vigneron Seth F. , Ohno Shohei , Braz Joao , Kim Joseph Y. , Kweon Oh Sang , Webb Chase , Billesbølle Christian , Bhardwaj Karnika , Irwin John , Manglik Aashish , Basbaum Allan I. , Ellman Jonathan A. , Shoichet Brian K.
Published: January 2025

Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines. These “natural-product-like” molecules are rare in the current libraries and are functionally congested, making them interesting as receptor probes. Using a modular, four-component reaction scheme, we built and docked a virtual library of over 14.6 million isoquinuclidines against both the µ- andκ-opioid receptors (MOR and KOR, respectively). Synthesis and experimental testing of 18 prioritized compounds found nine ligands with low µM affinities. Structure-based optimization revealed low- and sub- nM antagonists and inverse agonists targeting both receptors. Cryo-electron microscopy (cryoEM) structures illuminate the origins of activity on each target. In mouse behavioral studies, a potent member of the series with joint MOR-antagonist and KOR-inverse-agonist activity reversed morphine-induced analgesia, phenocopying the MOR-selective anti-overdose agent naloxone. Encouragingly, the new molecule induced less severe opioid-induced withdrawal symptoms compared to naloxone during withdrawal precipitation, and did not induce conditioned-place aversion, likely reflecting a reduction of dysphoria due to the compound’s KOR-inverse agonism. The strengths and weaknesses of bespoke library docking, and of docking for opioid receptor polypharmacology, will be considered.
A Vascularized Liver Microphysiological System Captures Key Features of Hepatic Insulin Resistance and Monocyte Infiltration
Authors: Tevonian Erin N. , Kan Ellen L. , Maniar Kairav K. , Wang Alex J. , Datta Anisha , Kamm Roger D. , Lauffenburger Douglas A. , Griffith Linda G.
Published: January 2025

Three-dimensionalin vitroliver models are a promising means to recapitulate key aspects of human liver disease pathologies, thereby aiding therapeutic development. Spheroidal aggregates of hepatocytes, sometimes including non-parenchymal cells, are an established approach for modeling facets of metabolism and drug responses, yet these models often lack dynamic interactions with vascular and immune cells that also contribute to disease development and progression. To address this, we developed a microphysiological system (MPS) that integrates multicellular human hepatic spheroids with self-organized microvascular networks. We show extensive interaction between primary human spheroids and functional vasculature while maintaining key hepatic functions. We demonstrate the utility of this MPS by modeling an insulin resistance state through chronic exposure to disease-mimetic media conditions. This disease model displays altered hepatocyte metabolism, dysregulated vascular features, and increased inflammation state. Enabled by the functional vasculature, we further extend this disease model to capture changes in immune cell recruitment. When culturing CD14+ monocytes in our liver MPS, a subset of monocytes extravasate, localize to hepatic spheroids, and begin differentiating into CD163+ macrophages. These cells infiltrate with greater frequency in insulin resistant samples, consistent with known clinical findings. All together, this vascularized MPS model captures disease-relevant liver biology including inflammatory features.
Noise Correlations in Balanced Networks with Unreliable Synapses
Authors: Leone Michael J. , Huang Chengcheng , Doiron Brent
Published: January 2025

Synaptic physiology is highly stochastic in the neocortex: immediately following an action potential, individual synapses release neurotransmitter unreliably, sometimes even failing to release any vesicles. However, theoretical models of neuronal networks typically neglect this well-established feature of biology, especially recurrent networks. In this work, to better understand the effects of synaptic unreliability in recurrent networks, we describe neuronal variability in a balanced network model of non-leaky integrate-and-fire neurons incorporating a Bernoulli model of synaptic release. For arbitrary network size, synaptic unreliability contributes non-negligibly to spike count variability. Most notably, this additional noise is overshadowed by effects on noise correlations. In particular, we find that feedforward and recurrent synaptic reliability have opposite influences on noise correlations: while increased reliability of synaptic input from neurons outside of the network increase correlations, reliability of recurrent synapses de-correlates population activity. We explain this dichotomy by examining the average input currents to cell pairs, and verify this effect with simulations of exponential integrate-and-fire neurons with adaptation and conductance-based synapses. Overall, our results emphasize the importance of synaptic unreliability in the study of noise correlations.