bluuebunny/crossref_metadata_2025 huggingface dataset:
Embers of autoregression show how large language models are shaped by the problem they are trained to solve
Authors: McCoy R. Thomas , Yao Shunyu , Friedman Dan , Hardy Mathew D. , Griffiths Thomas L.
Published: October 2024

The widespread adoption of large language models (LLMs) makes it important to recognize their strengths and limitations. We argue that to develop a holistic understanding of these systems, we must consider the problem that they were trained to solve: next-word prediction over Internet text. By recognizing the pressures that this task exerts, we can make predictions about the strategies that LLMs will adopt, allowing us to reason about when they will succeed or fail. Using this approach—which we call the teleological approach—we identify three factors that we hypothesize will influence LLM accuracy: the probability of the task to be performed, the probability of the target output, and the probability of the provided input. To test our predictions, we evaluate five LLMs (GPT-3.5, GPT-4, Claude 3, Llama 3, and Gemini 1.0) on 11 tasks, and we find robust evidence that LLMs are influenced by probability in the hypothesized ways. Many of the experiments reveal surprising failure modes. For instance, GPT-4’s accuracy at decoding a simple cipher is 51% when the output is a high-probability sentence but only 13% when it is low-probability, even though this task is a deterministic one for which probability should not matter. These results show that AI practitioners should be careful about using LLMs in low-probability situations. More broadly, we conclude that we should not evaluate LLMs as if they are humans but should instead treat them as a distinct type of system—one that has been shaped by its own particular set of pressures.
Dysregulated miR-124-3p in endometrial epithelial cells reduces endometrial receptivity by altering polarity and adhesion
Authors: Zhou Wei , Van Sinderen Michelle , Rainczuk Katarzyna , Menkhorst Ellen , Sorby Kelli , Osianlis Tiki , Pangestu Mulyoto , Santos Leilani , Rombauts Luk , Rosello-Diez Alberto , Dimitriadis Evdokia
Published: October 2024

The endometrium undergoes substantial remodeling in each menstrual cycle to become receptive to an implanting embryo. Abnormal endometrial receptivity is one of the major causes of embryo implantation failure and infertility. MicroRNA-124-3p is elevated in both the serum and endometrial tissue of women with chronic endometritis, a condition associated with infertility. MicroRNA-124-3p also has a role in cell adhesion, a key function during receptivity to allow blastocysts to adhere and implant. In this study, we aimed to determine the function of microRNA-124-3p on endometrial epithelial adhesive capacity during receptivity and effect on embryo implantation. Using a unique inducible, uterine epithelial-specific microRNA overexpression mouse model, we demonstrated that elevated uterine epithelial microRNA-124-3p impaired endometrial receptivity by altering genes associated with cell adhesion and polarity. This resulted in embryo implantation failure. Similarly in a second mouse model, increasing microRNA-124-3p expression only in mouse uterine surface (luminal) epithelium impaired receptivity and led to implantation failure. In humans, we demonstrated that microRNA-124-3p was abnormally increased in the endometrial epithelium of women with unexplained infertility during the receptive window. MicroRNA-124-3p overexpression in primary human endometrial epithelial cells (HEECs) impaired primary human embryo trophectoderm attachment in a 3-dimensional culture model of endometrium. Reduction of microRNA-124-3p in HEECs from infertile women normalized HEEC adhesive capacity. Overexpression of microRNA-124-3p or knockdown of its direct target
IQGAP1
reduced fertile HEEC adhesion and its ability to lose polarity. Collectively, our data highlight that microRNA-124-3p and its protein targets contribute to endometrial receptivity by altering cell polarity and adhesion.
Engineering substrate channeling in a bifunctional terpene synthase
Authors: Wenger Eliott S. , Schultz Kollin , Marmorstein Ronen , Christianson David W.
Published: October 2024

Fusicoccadiene synthase from
Phomopsis amygdala
(PaFS) is a bifunctional terpene synthase. It contains a prenyltransferase (PT) domain that generates geranylgeranyl diphosphate (GGPP) from dimethylallyl diphosphate and three equivalents of isopentenyl diphosphate, and a cyclase domain that converts GGPP into fusicoccadiene, a precursor of the diterpene glycoside Fusicoccin A. The two catalytic domains are connected by a flexible 69-residue linker. The PT domain mediates oligomerization to form predominantly octamers, with cyclase domains randomly splayed out around the PT core. Surprisingly, despite the random positioning of cyclase domains, substrate channeling is operative in catalysis since most of the GGPP generated by the PT remains on the enzyme for cyclization. Here, we demonstrate that covalent linkage of the PT and cyclase domains is not required for GGPP channeling, although covalent linkage may improve channeling efficiency. Moreover, GGPP competition experiments with other diterpene cyclases indicate that the PaFS PT and cyclase domains are preferential partners regardless of whether they are covalently linked or not. The cryoelectron microscopy structure of the 600-kD “linkerless” construct, in which the 69-residue linker is spliced out and replaced with the tripeptide PTQ, reveals that cyclase pairs associate with all four sides of the PT octamer and exhibit fascinating quaternary structural flexibility. These results suggest that optimal substrate channeling is achieved when a cyclase domain associates with the side of the PT octamer, regardless of whether the two domains are covalently linked and regardless of whether this interaction is transient or locked in place.
Teaching cross-cultural pragmatics through AVT
Authors: Papakonstantinou Vasiliki
Published: October 2024

There is fairly little research on using translation to advance pragmatic competence in learners of English and highlight how translation can advance cross-cultural pragmatic awareness in EFL. The study attempts to explore how audio-visual translation (AVT) can introduce cross-cultural pragmatics to Greek learners of English. The data derive from the animated film Inside Out (Pixar 2015). The study takes dubbed dialogues to be a target-oriented data set, with the subtitles as an intermediate, constrained type of transfer where pragmatic shifts may be least visible or not at all. The research uses (a) the positive/negative politeness distinction as manifested through interpersonal proximity/distance (Brown and Levinson 1978; Sifianou 1992; Yule 1996; Horn and Ward 2006), and (b) the un/certainty avoidance communication style (Hofstede, Hofstede, and Minkov 2010). The aim is to familiarize learners with the significance of cross-cultural pragmatic awareness and its use in EFL teaching and learning. Analysis of the data is followed by a questionnaire addressing bilingual participants who confirmed the findings of the study. Results show types of pragmatic variation across English and Greek: for instance, the subtitles showed less signs of positive politeness strategies and more uncertainty features, while dubbing manifested more positive politeness strategies and stronger uncertainty avoidance, i.e., in alignment with features of the target language. Findings allow learners to look beyond grammaticality, at the level of pragmatic preference.
Story-telling perspectives in translating Aesop’s fables
Authors: Kostaragkou Maria
Published: October 2024

Aesop’s fables have been multiply adapted and translated over the years to meet the needs of intended audiences. The study selects two Modern Greek (1993, 2011) and two English (1991, 2013) versions of Aesop’s fable The Woodcutter and Mercury to trace intra- and cross-cultural pragmatic variation in story-telling perspectives. Analysis of the four versions suggests that the Modern Greek versions of the fable seem to be more aware of the power differentials between Mercury and the Woodcutter, whereas the English versions rather focus on the woodcutter, somewhat blurring the figure of the god. A questionnaire addressing 15 respondents confirmed (a) power distance variation cross-culturally (with visuals in two of the versions conforming to intended power distance dynamics), and (b) variation in addressee age group identity. The significance of the research lies in that pragmatic aspects of meaning-making become cross-culturally visible in versions of the fable and draw attention to the potential of translation to advance understanding of what is adjusted in cross-cultural transfer.
Aesop’s fable The Lion and the Mouse
Authors: Marinova Olga
Published: October 2024

Aesopic tradition has been highly adaptive (Lefkowitz 2006) as manifested in multicultural versions of fables. The study explores shifts in Aesop’s fable The Lion and the Mouse to highlight shifts in the representation of characters, in agreement with pragmatic tendencies across cultures, as — for instance — in the power distance between the lion and the mouse. It examines two Modern Greek (2003 and 2012), an English (1996), a Russian (2012) and a Ukrainian (1990) version of the fable to trace local perceptions of it. Analysis shows that translators (as storytellers) transform aspects of the fable in pragmatically meaningful ways: they add up to the adaptation process conforming to locally appreciated values. The significance of research lies in that translation is seen as another layer of adaptation which a source fable may undergo intra- and inter-culturally.
Disillusionment and impoverishment in a Greek version of Waiting for Godot
Authors: Kliafa Aliki
Published: October 2024

The study examines how impoverishment and disillusionment in Samuel Beckett’s Waiting for Godot (1949) have been rendered on the Greek stage (transl. Papathanassopoulou 1984). Ιt examines the use of impoliteness which renders the protagonists’ outcast identity and frustration, as Godot is not showing up. Findings show that respondents appreciated both foul language (impoliteness) and humour (low-power distance) in the Greek version of the play. The significance of the study lies in that target audiences may enjoy aspects of characters’ identities perhaps unsuspected in the ST, because local contexts may prioritize codes manifesting intended attitudes.
Handwritten letters and grammatical structures in German
Authors: Reinken Niklas
Published: October 2024

The German writing system reflects a lot of grammatical structures, such as morphological structures or syllables.
Writing shows grammar. This is already true in printed texts, but even more so in handwritten texts, because the potential
for variation is greater in those texts. Writers can more easily deviate from the usual shape of a character and use these deviations to mark
grammatical patterns. This article presents a suggestion for a methodology for the systematic categorisation of such form
deviations in handwritten German texts. Subsequently, it is shown with 〈e〉 and 〈h〉 that form deviations can indeed correlate with
linguistic structures.
Structure and electrical properties of polysilicon films doped with ammonium tetraborate tetrahydrate
Authors: Tang Yehua , Wang Yuchao , Zhou Chunlan , Wang Ke-Fan
Published: October 2024

Here, p-type polysilicon films are fabricated by ex-situ doping method with ammonium tetraborate tetrahydrate (ATT) as the boron source, named ATT-pPoly. The effects of ATT on the properties of polysilicon films are comprehensively analyzed. The Raman spectra reveal that the ATT-pPoly film is composed of grain boundary and crystalline regions. The preferred orientation is the (111) direction. The grain size increases from 16−23 nm to 21−47 nm, by ~70% on average. Comparing with other reported films, Hall measurements reveal that the ATT-pPoly film has a higher carrier concentration (>1020 cm−3) and higher carrier mobility (>30 cm2/(V·s)). The superior properties of the ATT-pPoly film are attributed to the heavy doping and improved grain size. Heavy doping property is proved by the mean sheet resistance (R
sheet,m) and distribution profile. The R
sheet,m decreases by more than 30%, and it can be further decreased by 90% if the annealing temperature or duration is increased. The boron concentration of ATT-pPoly film annealed at 950 °C for 45 min is ~3 × 1020 cm−3, and the distribution is nearly the same, except near the surface. Besides, the standard deviation coefficient (σ) of R
sheet,m is less than 5.0%, which verifies the excellent uniformity of ATT-pPoly film.
A review of ToF-based LiDAR
Authors: Ma Jie , Zhuo Shenglong , Qiu Lei , Gao Yuzhu , Wu Yifan , Zhong Ming , Bai Rui , Sun Miao , Chiang Patrick Yin
Published: October 2024

In recent years, propelled by the rapid iterative advancements in digital imaging technology and the semiconductor industry, encompassing microelectronic design, manufacturing, packaging, and testing, time-of-flight (ToF)-based imaging systems for acquiring depth information have garnered considerable attention from both academia and industry. This technology has emerged as a focal point of research within the realm of 3D imaging. Owing to its relatively straightforward principles and exceptional performance, ToF technology finds extensive applications across various domains including human−computer interaction, autonomous driving, industrial inspection, medical and healthcare, augmented reality, smart homes, and 3D reconstruction, among others. Notably, the increasing maturity of ToF-based LiDAR systems is evident in current developments. This paper comprehensively reviews the fundamental principles of ToF technology and LiDAR systems, alongside recent research advancements. It elucidates the innovative aspects and technical challenges encountered in both transmitter (TX) and receiver (RX), providing detailed discussions on corresponding solutions. Furthermore, the paper explores prospective avenues for future research, offering valuable insights for subsequent investigations.
Single-fundamental-mode cryogenic (3.6 K) 850-nm oxide-confined VCSEL
Authors: Liu Anjin , Hao Chenxi , Huo Jingyu , Han Hailong , Wang Minglu , Tang Bao , Li Lingyun , You Lixing , Zheng Wanhua
Published: October 2024

Cryogenic oxide-confined vertical-cavity surface-emitting laser (VCSEL) has promising application in cryogenic optical interconnect for cryogenic computing. In this paper, we demonstrate a cryogenic 850-nm oxide-confined VCSEL at around 4 K. The cryogenic VCSEL with an optical oxide aperture of 6.5 μm in diameter can operate in single fundamental mode with a side-mode suppression-ratio of 36 dB at 3.6 K, and the fiber-coupled output power reaches 1 mW at 5 mA. The small signal modulation measurements at 298 and 292 K show the fabricated VCSEL has the potential to achieve a high modulation bandwidth at cryogenic temperature.
The space of vectored hyperbolic surfaces is path-connected
Authors: Warakkagun Sangsan
Published: October 2024

In the space

H

2

\mathcal {H}^2

of hyperbolic surfaces decorated with a base unit vector, the topology induced by the Gromov–Hausdorff convergence coincides with the Chabauty topology on the space of discrete torsion-free subgroups of

P
S
L

2

(

R

)

\mathrm {PSL}_2(\mathbb {R})

. Using paths constructed from changing the Fenchel–Nielsen coordinates and shrinking simple closed curves to cusps, we demonstrate path-connectivity of

H

2

\mathcal {H}^2

and some of its subspaces.
New curvature characterizations for spherical space forms and complex projective spaces
Authors: Yang Xiaokui , Zhang Liangdi
Published: October 2024

In this paper, we introduce a new positivity notion for curvature of Riemannian manifolds and obtain characterizations for spherical space forms and the complex projective space

C

P

n

\mathbb {C}\mathbb {P}^n

.
Group actions on multitrees and the 𝐾-theory of their crossed products
Authors: Brownlowe Nathan , Spielberg Jack , Thomas Anne , Wu Victor
Published: October 2024

We study group actions on multitrees, which are directed graphs in which there is at most one directed path between any two vertices. In our main result we describe a six-term exact sequence in

K
K

-theory for the reduced crossed product

C
0

(
∂
E
)

⋊
r

G

C_0(\partial E)\rtimes _r G

induced from the action of a countable discrete group

G
G

on a row-finite, finitely-aligned multitree

E
E

with no sources. We provide formulas for the

K
K

-theory of

C
0

(
∂
E
)

⋊
r

G

C_0(\partial E) \rtimes _r G

in the case where

G
G

acts freely on

E
E

, and in the case where all vertex stabilisers are infinite cyclic. We study the action

G
↷
∂
E

G\curvearrowright \partial E

in a range of settings, and describe minimality, local contractivity, topological freeness, and amenability in terms of properties of the underlying data. In an application of our main theorem, we describe a six-term exact sequence in

K
K

-theory for the crossed product induced from a group acting on the boundary of an undirected tree.
Dimension constraints in some problems involving intermediate curvature
Authors: Xu Kai
Published: October 2024

In [Comm. Pure Appl. Math. 77 (2024), pp. 441–456] Brendle-Hirsch-Johne proved that

T
m

×

S

n
−
m

T^m\times S^{n-m}

does not admit metrics with positive

m
m

-intermediate curvature when

n
≤
7

n\leq 7

. Chu-Kwong-Lee showed in [Math. Res. Lett., to appear] a corresponding rigidity statement when

n
≤
5

n\leq 5

. In this paper, we show sharpness of the dimension constraints by giving concrete counterexamples in

n
≥
7

n\geq 7

and extending the rigidity result to

n
=
6

n=6

. Concerning uniformly positive intermediate curvature, we show that simply-connected manifolds with dimension

≤
5

\leq 5

and bi-Ricci curvature

≥
1

\geq 1

have finite Urysohn 1-width. Counterexamples are constructed in dimension

≥
6

\geq 6

.
Comprehensive clinical evaluation of indirect and direct bonding techniques in orthodontic treatment: a single-centre, open-label, quasi-randomized controlled clinical trial
Authors: Kono Kana , Murakami Takashi , Tanizaki Saori , Kawanabe Noriaki , Fujisawa Atsuro , Nakamura Masahiro , Hoshijima Mitsuhiro , Izawa Takashi , Kamioka Hiroshi
Published: October 2024

Background

Few prospective investigations have compared direct and indirect techniques through comprehensive and detailed clinical evaluations, considering the impact of all factors.

Objectives

This study aimed to compare and evaluate direct and indirect bonding methods at a single institution and to clarify the selection criteria for the bonding method.

Materials and methods

This single-centre, quasi-randomized controlled clinical trial included 153 patients who required fixed orthodontic treatment. They were randomly divided into indirect and direct binding groups by the project lead (K.K.), who was blinded to all clinical data, and performed the allocation using medical record numbers. The chair time for bracket bonding, discomfort during bracket bonding, oral hygiene after bonding, number of bracket failures, number of intentional bracket reattachments, post-treatment occlusal index, and total treatment time were assessed. Outcomes were compared using a two-sample t-test or Mann–Whitney U test (P < .05).

Results

Fifty-eight patients were included in the indirect bonding group (20 male, 38 female; mean age: 20.63 ± 5.69 years) and 66 (14 male, 52 female; mean age: 23.17 ± 8.83 years) in the direct bonding group. Compared to the direct bonding group, the indirect bonding group had shorter chair time (P < .001), a shorter total treatment period (P < .01), and a better final occlusal relationship (P < .001). The number of bracket detachments was higher (P < .001) in the indirect bonding group, but the number of intentional reattachments was lower (P < .001).

Conclusion

Indirect bonding may improve the efficiency of orthodontic treatment.

Harms

No harm was observed during the study.

Trial registration number

This trial was approved by the Ethics Review Committee of Okayama University (approval number: d10001), UMIN registration number 000022182.
Diplopia: When Seeing Double is Worrisome
Authors: Jaiswal Sanjana , Hur Minjun , Chen John J.
Published: October 2024

Diplopia can result from a benign or a life-threatening cause, and therefore it is important to identify and assess diplopia. This review discusses how to approach diplopia in a stepwise manner to identify the underlying etiology and recognize potentially dangerous diplopia, such as a third cranial nerve palsy that could be a harbinger of an aneurysm. The review also highlights the targeted neuroimaging that is required for various clinical scenarios of diplopia.
The effects of the ketogenic diet on cancer treatment: a narrative review
Authors: Deng Qingxuan , Lv Ruyue , Zou Tangbin
Published: October 2024

Despite significant advances in therapy, cancer remains the top cause of death in parts of the globe. For many types of cancer, the typical treatment is a combination of surgery, chemotherapy, and radiotherapy. However, this conventional treatment is not successful on its own. As a consequence, innovative approaches that improve treatment efficacy are urgently needed. The ketogenic diet is a high-fat, moderate protein, and low-carbohydrate diet that appears to sensitize most cancers to conventional therapies by exploiting cancer cells’ altered metabolism, making it an effective adjuvant cancer treatment alternative. This diet could decrease glucose metabolism while enhancing lipid metabolism, interfering with the Warburg effect, and inhibiting tumor cell proliferation. The anticancer impact of ketogenic diet has been established in numerous animal trials and clinical investigations on a wide range of tumor types, including glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, invasive rectal cancer, ovarian cancer, and endometrial cancer. In this review, we discussed the various types of ketogenic diets, the mechanism of action for ketogenic diet as a cancer therapy, and the data gathered from continuing preclinical and clinical studies, intending to establish a solid theoretical foundation for future research.
Dietary mineral intake and risk of bladder cancer: a systematic review and meta-analysis
Authors: Zhong Xin , Li Guanyi , Zhu Liusheng
Published: October 2024

This meta-analysis aimed to investigate the association between dietary mineral intake and the risk of bladder cancer. Relevant studies on bladder cancer and dietary mineral intake, including sodium, calcium, iron, magnesium, phosphorus, potassium, and zinc, were systematically identified through searches in Scopus and PubMed up to July 2024. Data from 12 studies were pooled using odds ratios (OR) and 95% confidence intervals (CI) with a random-effects model. The meta-analysis of 12 studies indicated a positive association between higher dietary sodium intake and bladder cancer risk (OR = 1.62, 95% CI: 1.04–2.55), with significant heterogeneity observed. No clear linear or nonlinear dose–response relationship was found for sodium intake. However, no significant associations were found between the intake of other minerals and the risk of bladder cancer. This study suggests that a high intake of sodium is significantly associated with an increased risk of bladder cancer. Further research is needed to explore the potential mechanisms underlying this relationship.
Enhanced interactions within microenvironment accelerates dismal prognosis in HBV-related HCC after TACE
Authors: Wang Libo , Cao Jiahui , Liu Zaoqu , Wu Shitao , Liu Yin , Liang Ruopeng , Zhu Rongtao , Wang Weijie , Li Jian , Sun Yuling
Published: October 2024

Background:

Transarterial chemoembolization (TACE) is the first-line treatment for patients with advanced HCC, but there are limited studies on the microenvironment alterations caused by TACE.

Methods:

Six fresh HBV-related HCC specimens with or without TACE intervention were used to perform single-cell RNA sequencing. The 757 bulk samples from 3 large-scale multicenter cohorts were applied for comprehensive analysis. The biological functions of the biomarkers were further validated by phenotypic experiments.

Results:

Using single-cell RNA sequencing analysis, we delineated the global cell atlas of post-TACE and demonstrated elevated tumor heterogeneity and an enhanced proinflammatory microenvironment induced by TACE. Cell-cell communication analysis revealed that markedly elevated interactions between NABP1+ malignant hepatocytes, neutrophils, and CD8+ T cells after TACE might accelerate the shift from CD8+ effector memory T cells to CD8+ effector T cells. This result was substantiated by the developmental trajectory between the 2 and dramatically decreased resident scores along the pseudotemporal trajectory. Integrating bulk data, we further found that the increased estimated proportion of NABP1+ malignant hepatocytes was related to poor TACE response and dismal prognosis, and its biomarker role could be replaced by NABP1. In vitro, multiple biological experiments consistently verified that NABP1 knockdown significantly inhibited the proliferation and migration of HCC cells.

Conclusions:

Based on our depicted global map of post-TACE, we confirmed that the enhanced interactions within the microenvironment after TACE may be the culprits for postoperative progression. NABP1 may become an attractive tool for the early identification of patients sensitive to first-line TACE in clinical practice.
Motion Restriction Caused by Thoracic-Lumbar-Sacral Orthoses During Activities of Daily Living
Authors: Vania Natasha , Jacofsky Marc , McCamley John
Published: October 2024

Introduction

Lower back pain is a common musculoskeletal disability affecting individuals of every income and age. The main cause of lower back pain is still not fully understood, with some theories suggesting that it is related to posture and placement of the spine in compromising positions. This study investigated the ability of two styles of thoracic-lumbar-sacral orthoses to restrict range of motion during activities of daily living.

Materials and Methods

Fourteen able-bodied adults were recruited. Two styles of TLSOs from two companies were chosen for the comparison with the no-brace condition. Two brands of each brace style were selected for comparison. Subjects were first asked to perform motion in three planes, then asked to complete seven motions to simulate daily living.

Results

There were no significant differences between the no-brace and brace conditions for motion in the sagittal and coronal plane ranges of motion. There were significant reductions in transverse plane range of motion detected between the no-brace condition and both styles of brace. During bending, reaching, walking, and stair ascent differences between the brands of brace were observed.

Conclusions

The chosen brands were equivalent across most movements. All braces were able to restrict motion, though the level of restriction varied between brace during some tasks for some planes of motion. Understanding the differing restrictions will assist health care providers and consumers choose the best TLSO to provide the motion restriction they require.

Clinical Relevance

Health care providers and consumers can have options when choosing a TLSO depending on which planes of motion need to be restricted.
Effect of occlusion site on the effectiveness and safety of endovascular thrombectomy for large ischemic cores: A cohort study
Authors: Yang Shihai , Wu Lele , Shi Xiaolei , Guo Changwei , Yue Chengsong , Fan Shitao , Yang Jie , Song Jiaxing , Ye Dongsheng , Xu Xu , Peng Zhouzhou , Li Linyu , Huang Jiandi , Liu Chang , Huang Jiacheng , Yu Nizhen , Tian Yan , Ma Jinfu , Yang Dahong , Kong Weilin , Wang Zhixi , Sun Wenzhe , Yang Qingwu , Chen Boyu , Zi Wenjie
Published: October 2024

Background:

Recent clinical trials have shown that patients with large ischemic cores have better outcomes with endovascular thrombectomy (EVT) compared with standard medical treatment (SMT) alone.We aim to assess whether the relationship between EVT and improvements in clinical outcomes varies depending on the location of the occlusive sites.

Methods:

This study is a subgroup analysis conducted within a prospective, nationwide, multi-center registry. The cohort included patients with acute large vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 0 to 5 within 24 hours from last known well. We utilized the adjusted common odds ratio for a shift toward better outcome on the modified Rankin Scale after EVT compared with SMT alone as the primary outcome. Safety outcomes included symptomatic intracranial hemorrhage (sICH).

Results:

A total of 745 patients with large ischemic cores were included: 272(36.5%) with internal carotid artery occlusion, 392(52.6%) with M1 segment of the middle cerebral artery occlusion, and 81(11.0%) with M2 segment of the middle cerebral artery occlusion. The adjusted common odds ratios were as follows: 1.98 (95% CI, 1.01-3.89) for ICA occlusions, 2.09 (95% CI, 1.35-3.23) for M1 occlusions, and 1.13 (95% CI, 0.43-2.94) for M2 occlusions. There was no significant treatment-by-occlusion site interaction observed (P=0.69). However, the incidence of sICH was significantly greater in all groups receiving EVT than in those receiving SMT alone. Additionally, we observed that the secondary outcomes and subgroup analyses were generally consistent with the main outcomes.

Conclusions:

In this study, we found that patients with internal carotid artery and M1 occlusion demonstrated a better outcome with EVT, while the benefit for patients with M2 occlusion remains uncertain.
An evolutionarily conserved role for VEGF signaling in the expansion of non-vascular tissue during regeneration
Authors: Savage Aaron M. , Wagner Alexandra C. , Kim Ryan T. , Gilbert Paul , Singer Hani D. , Chen Erica , Kim Elane M. , Lopez Noah , Dooling Kelly E. , Paoli Julia C. , Wu S.Y. Celeste , Bohm Sebastian , Chilambi Rachna , Froitzheim Tim , Blair Steven J. , Powell Connor , Abouelela Adnan , Luong Anna G. , Thornton Kara N. , Tajer Benjamin , Payzin-Dogru Duygu , Whited Jessica L.
Published: October 2024

Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched within tetrapods. Limb regeneration is dependent upon the formation of a blastema, which contains undifferentiated cells capable of giving rise to most cells of the regenerated limb. Innervation is required for regeneration, along with many signaling pathways, including FGF, BMP and Wnt, but the role of VEGF signaling during salamander limb regeneration is not well understood. Here we show that VEGF signaling is essential for limb regeneration and that blastema cells and limb fibroblasts display impaired proliferation in the absence of VEGF signaling. By performing analogous experiments in planaria, which lack vasculature, we show a potential evolutionarily conserved role for VEGF in the expansion of blastema tissues that is separable from angiogenesis. Moreover, loss of VEGF signaling reduces induction of EMT-like processes, suggesting VEGF signaling functions upstream of the expression of EMT transcription factors, includingSnai2. These findings highlight potential roles for VEGF signaling during regeneration which may extend beyond typical findings related to angiogenesis.
Maturity Onset Diabetes of the Young (MODY) is not always monogenic: candidate genes involved in a Latino Population
Authors: Moscona-Nissan Alberto , Marrero-Rodríguez Daniel , Andonegui-Elguera Sergio , Luna-Ávila Eduardo Salif , Martínez-Mendoza Florencia , Vela-Patiño Sandra , Ramírez-Ramos Itzel , Hinojosa-Alvarez Silvia , Hernandez-Perez Jesus , Chavez-Santoscoy Rocio A , Mercado-Medrez Sophia , León-Wu Kapy S , De Miguel-Ibáñez Regina , Mercado Moisés , Taniguchi-Ponciano Keiko , Ferreira-Hermosillo Aldo
Published: October 2024

Introduction

MODY misdiagnosis remains widespread, existing remarkable variability within genetic variants across populations. While diagnostic tools are based on Caucasian cohorts, Whole Exome Sequencing (WES) studies are needed to identify new genes in non-Caucasians, as up to 77% of patients do not harbor variants of significance in MODY-known genes. In Latino populations, no WES studies have addressed MODY genomic landscape beyond its canonical genes.

Methods

We carried out WES in 17 patients with MODY, 17 patients with type 2 diabetes (T2DM) and 17 healthy controls (HC). MODY diagnosis was established according to Exeter criteria (score ≥36%) in subjects with no or minimal insulin requirements. We compared the single nucleotide variant (SNV) landscape across groups.

Results

Patients with MODY present a polygenic landscape with allelic variants in canonical and non-canonical genes. Canonical MODY genes used for routine genetic diagnosis showed low discrimination utility, having similar frequencies between MODY, T2DM and HC in the Mexican population. We propose 14 genes with variants that distinguish MODY from T2DM and HC, as we detected variants in genes asMAP2K3, SYT15, TPTE, KCNJ12, PEX5,andOR2A1in 75-100% of MODY cases while were absent in T2DM and HC. Enrichment analysis revealed involvement in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase kinase/MAPK cascade, and insulin/IGF pathway-protein kinase B/AKT signaling cascade.

Discussion

MODY presents a polygenic landscape. Besides improving our understanding of glycemic regulation pathways, the candidate genes could serve as MODY diagnostic biomarkers in Latino populations.

Funding

Supported by grant R-2019-785-052 from Instituto Mexicano del Seguro Social.
SPECIAL CARE BABY UNIT NEONATAL DISEASE OUTCOMES IN A TERTIARY HOSPITAL IN NIGERIA: 2-YR RETROSPECTIVE CROSS-SECTIONAL ANALYSIS
Authors: Anosike Udochukwu Godswill , Amalahu Ugochukwu Godson , Ezenyeaku Chijioke Amara , Ubajaka Chika Florence , Osmond Anokwulu Ifeanyi , Nsude Chiamaka Sandra , Adeniyi Joseph Moses , Okonkwo Chinemerem , Nwajinka Uzoma Love , DivineFavour Malachy Echezona , Okeke Chukwuemelie Darlington , Akwiwu-Uzoma Chidozie Valentine
Published: October 2024

BACKGROUND

Neonatal diseases contribute significantly to global under-five mortality. The highest neonatal mortality rate in sub-Saharan Africa can be traced to Nigeria. This study aims to evaluate the outcomes of neonatal admissions in a select tertiary hospital in Nigeria.

METHODS

A retrospective analysis of data collected on 656 neonates admitted in the special care baby unit of Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nigeria over a period of 2 years (January 2021and December 2022). Descriptive analysis and inferential statistics were done at p<0.05 using SPSS version 25.

RESULTS

Median age at presentation was 4 hours (interquartile range 0.5,24) hours. The Median duration of hospital stay was 6 days (interquartile range 3,11). The commonest morbidities were perinatal asphyxia (n=295/656; 45.0%) and prematurity (n=158/656; 24%); while congenital anomalies (n=22/47; 46.8%), perinatal asphyxia (n=73/295; 24.7%) and prematurity (n=35/158; 22.2%) had the highest case fatality rates. Gestational age at birth, duration of hospital stay, place of delivery, and mode of delivery were the variables determined to be statistically associated with outcome of care.

CONCLUSION

This study showed a mortality of 22.9% (n=150/656) in our study area with perinatal asphyxia (48.7%; n=73/150), prematurity (24.0%; n=36/150), congenital anomalies (11.3%; n=22/150), and neonatal sepsis (6.7%; n=10/150) as the primary causes. This work highlights the need for emergency care of critically ill newborns through financing transition from special care baby unit to neonatal intensive care unit across tertiary institutions in Nigeria.

KEY MESSAGES

What is already known on this topic

Poor outcome of neonatal disease is associated with lack of quality care at birth or skilled care and treatment immediately after birth and in the first days of life.

Premature birth, birth asphyxia, neonatal infections and congenital anomalies are the prominent causes of neonatal deaths.

What this study adds

Case fatality rate, mortality rate and duration of hospital stay were the primary outcomes assessed in a spectrum of neonatal disease.

Higher mortality was recorded among neonates within the first 7days of hospital stay.

How this study might affect research, practice, or policy (implications)

Our work informs the need for transition from special care baby unit to neonatal intensive care unit across tertiary institutions in Nigeria to enable comprehensive care for critically ill neonates or neonates with severe neonatal morbidities.

Creates awareness on the need for incorporation of processes that enable safeguarding of neonatal hospital records for tracking of trends and research.
The Effect of Sensory Therapy on Upper Extremity Functions and Activities of Daily Living in Patients with Chronic Stroke: A Randomized Controlled Trial
Authors: Yazıcı Muhammed Rohat , Cekmece Cigdem
Published: October 2024

Introduction

The aim of this study was to investigate the effects of intensive sensory therapy on upper extremity functions, daily activity and life quality of stroke survivors.

Methods

This randomized controlled trial included 30 participants aged between 18 and 80 years, who were divided into a sensory-training group (n = 15) and a control group (n = 15). Both groups received 15 sessions of 30 minutes of physical therapy, occupational therapy, and 20 minutes of activity daily living training for three weeks. The ST group also received intensified sensory therapy during each session. Thumb localization, finger shift, and stereognosis tests were performed in both groups only before the start of intervention. The Jebsen Taylor Hand Function Test, Canadian Occupational Performance Measure, Modified Frenchay Scale, and Stroke Specific Quality of Life Scale (SS-QOL) were administered before and after intervention.

Results

Statistically significant differences were observed between the ST group and the control group across all tests, except for the Language, Thinking, and Vision parameters of the SS-QOL.

Conclusion

These results suggest that sensory therapies applied with conventional interventions increased upper extremity functions, activity daily living performance, participation and quality of life of the stroke survivors.

Registration

URL:https://clinicaltrials.gov/study/NCTxxxxxxUnique identifier: NCTxxxxx.
Measurement of doctor wellbeing prior to the Covid pandemic: a methodological systematic review
Authors: Simons Gemma , Opalinski Dominic , Jenkins John , Boxley Emma , Baldwin David
Published: October 2024

Objectives Attention has been focused on health professional during and after the Covid-19 pandemic, but relatively little is known about wellbeing before the pandemic struck. We therefore wised to describe which wellbeing outcomes had been measured in doctors and which wellbeing outcome measurement instruments had been used with doctors, prior to 2020. Design A methodological review of existing literature. Setting MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, and the International Bibliography of Social Science were searched for all study types, in all languages. Outcome measures Wellbeing outcomes were categorised as being defined/operationalised in the aims, the methods or the results, and by whether the outcome used to represent wellbeing included the word wellbeing, another positive concept, a pathological symptom, a pathology, and were work-specific or doctor-specific. The outcome measurement instruments used were then categorised as published or unpublished and the frequency of use was collected. Results A total of 218 studies were included in this review. The majority of studies were not interventional (83.9%). The total number of unique outcomes used to capture wellbeing in the eligible studies was 57, with 369 non-unique outcomes. The percentage of outcomes used that contained the word wellbeing, its components and other positive concepts, was 69.9% (258/369). The percentage of negative concept use such as negative work context outcomes, symptoms of pathologies, or pathologies, was 30.1% (111/369). For the outcome general wellbeing alone, 92 different measurement tools were used. The Maslach Burnout Inventory was the most frequently used measurement tool for all outcomes, used in 16.3% of studies. Conclusions Wellbeing has been measured heterogeneously in doctors in terms of the outcomes and the outcome measurement instruments used. In approximately one-third of the times it was measured, the best that could be achieved was an absence of pathological symptoms, as a negative concept was used to operationalise it.
CellStudio: a Modular, Tunable and Accessible Platform for Analysis of Growth Factors Secretions in Cell Cultures
Authors: Azuaje-Hualde Enrique , Lartitegui-Meneses Naiara , Alonso-Cabrera Juncal , Inchaurraga-Llamas Asier , Alvarez-Braña Yara , de Pancorbo Marian Martínez , Benito-Lopez Fernando , Basabe-Desmonts Lourdes
Published: October 2024

Traditional cell culture methods face significant limitations in monitoring cell secretions with spatial and temporal precision. Advanced microsystems incorporating biosensors have been developed to address these challenges, but they tend to lack versatility, and their complexity, along with the requirement for specialized equipment, limits their broader adoption. CellStudio offers an innovative, user-friendly solution that exploits the Printing and Vacuum Lithography combined with bead-based assays to create modular and tunable cell patterns surrounded by biosensors. This platform allows for high-resolution, spatially resolved analysis of secreted proteins, such as VEGF and FGF-2, while being easily implementable in standard laboratory settings. CellStudio’s design is compatible with conventional laboratory equipment, facilitating its integration into existing workflows without the need for extensive training or specialized tools. Validation experiments using mesenchymal stem cells (MSCs) and HeLa cells demonstrated that CellStudio can detect small secretion levels from small cell clusters with high sensitivity as well as analyze diffusion profiles, remarking the possibilities for studying cell behavior. By offering a standardized, cost-effective approach to detailed cellular analysis, CellStudio significantly enhances the capabilities of traditional cell culture techniques, with broad applications across biological and biomedical research.
An improved TEAD dominant-negative protein inhibitor to study Hippo YAP1/TAZ-dependent transcription
Authors: Branch Briana , Yuan Yao , Cascone Mariastella , Raimondi Francesco , Iglesias-Bartolome Ramiro
Published: October 2024

Hippo signaling is one of the top pathways altered in human cancer, and intensive focus has been devoted to developing therapies targeting Hippo-dependent transcription mediated by YAP1 and TAZ interaction with TEAD proteins. However, a significant challenge in evaluating the efficacy of these approaches is the lack of models that can precisely characterize the consequences of TEAD inhibition. To address this gap, our laboratory developed a strategy that utilizes a fluorescently traceable, dominant-negative protein named TEADi. TEADi specifically blocks the nuclear interactions of TEAD with YAP1 and TAZ, enabling precise dissection of Hippo TEAD-dependent and independent effects on cell fate. In this study, we aimed to enhance TEADi effectiveness by altering post-transcriptional modification sites within its TEAD-binding domains (TBDs). We demonstrate that a D93E mutation in the YAP1 TBD significantly increases TEADi inhibitory capacity. Additionally, we find that TBDs derived from VGLL4 and YAP1 are insufficient to block TAZ-induced TEAD activity, revealing crucial differences in YAP1 and TAZ displacement mechanisms by dominant-negative TBDs. Structural differences in YAP1 and TAZ TBDs were also identified, which may contribute to the distinct binding of these proteins to TEAD. Our findings expand our understanding of TEAD regulation and highlight the potential of an optimized TEADi as a more potent, specific, and versatile tool for studying TEAD-transcriptional activity.
An effective method of measuring nanobody binding kinetics and competition-based epitope mapping using biolayer interferometry
Authors: Bates Timothy A. , Gurmesa Sintayehu K. , Weinstein Jules B. , Trank-Greene Mila , Wrynla Xammy Huu , Anastas Aidan , Anley Teketay Wassie , Hinchliff Audrey , Shinde Ujwal , Burke John E. , Tafesse Fikadu G.
Published: October 2024

Protein-protein interactions (PPI) underpin nearly all biological processes, and understanding the molecular mechanisms governing these interactions is crucial for the progress of biomedical sciences. The emergence of AI-driven computational tools can help reshape the methods in structural biology, however model data often quires empirical validation. The large scale of predictive modeling data will therefore benefit from optimized methodologies for the high-throughput biochemical characterization of PPIs. Biolayer interferometry (BLI) is one of very few approaches that can determine the rate of biomolecular interactions, called kinetics, and of the commonly available kinetic measurement techniques, it is the most suitable for high-throughput experimental designs. Here, we provide step-by-step instructions on how to perform kinetics experiments using BLI. We further describe the basis and execution of competition and epitope binning experiments, which are particularly useful for antibody and nanobody screening applications. The procedure requires 3 hours to complete and is suitable for users with minimal experience with biochemical techniques.
Purification of micrococcal nuclease (MNase) for use in ribosomal profiling of high-salinity extremophiles
Authors: Gregorova Pavlina , Isada Matthew , DiRuggiero Jocelyne , Sarin L. Peter
Published: October 2024

Nucleases, i.e. enzymes that catalyze the hydrolysis of phosphodiester bonds in nucleic acids, are essential tools in molecular biology and biotechnology.Staphylococcus aureus nuclease (MNase) is particularly interesting due to its thermostability and Ca2+-dependence, making it the prime choice for applications where nuclease modulation is critical, such as ribosome profiling in bacteria and halophilic archaea. The latter poses a technical and economical challenge: high salt reaction conditions are essential for maintaining ribosome integrity but negatively impact the MNase activity, necessitating using large amounts of nuclease to achieve efficient cleavage. Here, we set out to generate an optimized production protocol for two forms of MNase — fully processed MNaseA and the 19 amino acid propeptide-containing MNaseB — and to biochemically benchmark them against a commercial nuclease. Our results show that both MNases are highly active in normal reaction conditions, but MNaseA maintains higher enzymatic activity in high salt concentrations than MNaseB. MNaseA also retains >90% of its activity after multiple freeze-thaw cycles when stored at -80 °C in a buffer containing 5% glycerol. Importantly, ribosome profiling experiments in the haloarchaeonHaloferax volcanii demonstrated that MNaseA produces ribosome footprints and hallmarks of active translation highly comparable to those obtained with the commercial nuclease, making it a suitable alternative for high-salt ribosome profiling applications. In conclusion, our method can be easily implemented for efficient MNaseA production, thereby providing access to an effective, robust, and cost-efficient alternative to commercial nucleases, as well as facilitating future translation studies into halophilic organisms.