bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of adjuvant chemotherapy for patients who undergo radical cystectomy without neoadjuvant chemotherapy: A retrospective cohort study of 115 advanced bladder cancer patients with pathological lymph node classification
Authors: Sakura Yuma , Yamashita Ryo , Notsu Akifumi , Usui Kimitsugu , Shinsaka Hideo , Nakamura Masafumi , Matsuzaki Masato , Niwakawa Masashi
Published: April 2024

Objectives

We investigated the clinical outcomes of radical cystectomy without cisplatin‐based neoadjuvant chemotherapy (NAC) and identified factors affecting the effectiveness of cisplatin‐based adjuvant chemotherapy (AC).

Methods

Between September 2002 and February 2020, 288 bladder cancer patients who did not receive NAC underwent radical cystectomy. We retrospectively analyzed the recurrence rates, primary recurrence sites, recurrence‐free survival (RFS), and overall survival (OS) of 115 advanced bladder cancer patients (pT3–4 or pN1–3) who were divided into the AC and observation groups. Subgroup analysis was performed, focusing on pathological stage.

Results

In total, 51 patients received AC, and 64 patients were observed. The median follow‐up duration was 95 months. The recurrence rate was lower in the AC group than in the observation group (35.3% vs. 54.7%, p = 0.041). The rate of recurrences in the lymph node area (dissection site and proximal lymph nodes) was lower in the AC group (9.8% vs. 26.6%; p = 0.031). In the subgroup analysis of patients with pN1, the probability of RFS and OS was higher in the AC group than in the observation group. The hazard ratio for RFS and OS was 0.243 (95% confidence interval [CI]: 0.077–0.768) and 0.259 (95% CI: 0.082–0.816), respectively. The 5‐year RFS and OS were significantly higher in the AC group (80.0% and 79.4%) than in the observation group (35.7% and 42.9%; p < 0.008 and p < 0.012, respectively).

Conclusions

AC improved RFS and OS in patients with pN1 disease who did not receive NAC and should be considered for this population.
Wound healing rates in COPD patients undergoing traditional pulmonary rehabilitation versus tailored Wound‐Centric interventions
Authors: He Yan , Zhu He , Xu Wenjie , Wang Tao , Chen Ying
Published: April 2024

This comparative cross‐sectional study, conducted at Shanghai Pulmonary Hospital, aimed to evaluate the efficacy of tailored wound‐centric interventions (TWCI) versus traditional pulmonary rehabilitation (TPR) in enhancing wound healing in patients with chronic obstructive pulmonary disease (COPD). Enrolling 340 patients with confirmed COPD, the study randomly assigned participants to either the TWCI or TPR group for a 12‐week programme. The primary outcome measured was the rate of wound healing, with secondary outcomes including changes in pulmonary function tests (PFTs) and quality of life (QoL) scores. The TWCI group received a customized programme integrating standard pulmonary rehabilitation with specific wound care strategies, such as enhanced oxygen therapy, nutritional supplementation, and infection control measures. In contrast, the TPR group underwent a conventional pulmonary rehabilitation programme without targeted wound care interventions. Wound healing rates, PFTs, and QoL scores were assessed at the end of the intervention and 3 months post‐intervention. The TWCI group demonstrated a statistically significant improvement in wound healing rates compared with the TPR group. The TWCI group had a 15% higher rate of reduction in wound size, a 10% rise in complete healing rates, and a 20% drop in infection rates (p < 0.05). Specifically, TWCI group exhibited higher rates of wound size reduction, complete healing, and decreased infection rates. Additionally, long‐term pulmonary function and overall quality of life improvements were more pronounced in the tailored group, underscoring the benefits of a personalized approach to managing COPD and wound care. The study concluded that integrating wound‐specific care strategies with pulmonary rehabilitation significantly enhances health outcomes in COPD patients with wounds. These findings supported the adoption of customized, multidisciplinary care plans, suggesting that tailored interventions can offer a comprehensive solution to the complex needs of COPD patients, potentially redefining best practices in chronic disease management.
Surgical versus medical management of patients with primary hyperaldosteronism and indeterminate adrenal vein sampling: A 10‐year experience of the Cleveland Clinic
Authors: Onwubueke Chineme , Borgan Saif M , Xiao Huijun , Zhou Keren
Published: April 2024

In patients with primary hyperaldosteronism (PA), adrenal vein sampling (AVS) can identify patients suitable for unilateral adrenalectomy. However, in AVS with an indeterminate aldosterone‐to‐cortisol lateralization (ACL) ratio of 3.0–4.0, clinical guidance is unclear. The authors screened all patients undergoing AVS at the Cleveland Clinic from October 2010 to January 2021 and identified 18 patients with indeterminate ACL results. Ten underwent adrenalectomy and eight continued medical management. The surgical group was younger (58.5 vs. 68 years, p = .17), and more likely to have a unilateral imaging adrenal abnormality (90% vs. 38%, p = .043) and a lower contralateral suppression index (0.63 vs. 1.1, p = .14). Post‐treatment, the surgical group had a significant reduction in diastolic blood pressure (–5.5 mmHg, p = .043) and aldosterone (4.40 vs. 35.80 ng/mL, p = .035) and required fewer anti‐hypertensive medications (2 vs. 3, p = .015). These findings may support the benefit of adrenalectomy in a select group of patients with indeterminate ACL.
Sequential sampling plan for the adults of Conotrachelus psidii (Marshall, 1922) (Coleoptera: Curculionidae) in guava crop
Authors: Fernandes Marcos Gino , Costa Eduardo Neves , Valente Fabrício Iglesias
Published: April 2024

Understanding the spatial distribution and population fluctuations of insect pests facilitates the development of effective control strategies for a given crop. Conotrachelus psidii (Coleoptera: Curculionidae) is an important guava pest; however, no sampling plans are available for its management. Therefore, in this study, we aimed to (i) determine the spatial distribution pattern of C. psidii adults and (ii) develop a sequential sampling plan for pest control in guava crops. Evaluations began at 120 days after pruning and were performed weekly. To sample C. psidii adults, a white tarp was placed under the plants, covering the entire canopy. Plant branches were then shaken to dislodge the adult insects on the tarp, which were then identified and counted. Using the data obtained in each sampling, dispersion indices were determined and tests of adjustments to the theoretical Poisson and negative binomial frequency distributions were performed. The calculated dispersion indices revealed that the individuals in the studied populations exhibited aggregated dispersion. Notably, only four samples showed adjustment to the Poisson distribution, whereas 18 samples showed adjustment to the negative binomial distribution in the field, confirming the aggregated pattern of the population spatial arrangement. The sequential sampling plan developed for C. psidii revealed the maximum and minimum numbers of sample units expected for decision‐making as 45 and 15, respectively.
The asset growth return premium and anchoring on the 52‐week high
Authors: Blau Benjamin M. , Cannon Brad
Published: April 2024

Research shows that year‐over‐year growth in a firm's assets is associated with a negative stock return premium. A possible explanation for this premium is based on mispricing correction, due in part to investors' overvaluation related to investment. In this article, we argue that a correction of any type is more likely to occur when stock prices are further away from their 52‐week high. To the extent that the 52‐week high acts as a viable anchor, when stocks are closer to this anchor, investors might become less inclined to contribute to the typical downward correction for these types of growth firms. In several tests, we find that stocks that are furthest away exhibit the strongest return premium. The return premium, however, begins to disappear as stocks approach their 52‐week high. These results are robust to various risk factors and cross‐sectional tests that include several firm‐specific characteristics.
Zombie Credit and (Dis‐)Inflation: Evidence from Europe
Authors: ACHARYA VIRAL V. , CROSIGNANI MATTEO , EISERT TIM , EUFINGER CHRISTIAN
Published: April 2024

We show that “zombie credit”—subsidized credit to nonviable firms—has a disinflationary effect. By keeping these firms afloat, zombie credit creates excess aggregate supply, thereby putting downward pressure on prices. Granular European data on inflation, firms, and banks confirm this mechanism. Markets affected by a rise in zombie credit experience lower firm entry and exit, capacity utilization, markups, and inflation, as well as a misallocation of capital and labor, which results in lower productivity, investment, and value added. If weakly capitalized banks were recapitalized in 2009, inflation in Europe would have been up to 0.21 percentage points higher post‐2012.
The psychological and behavioral consequences of customer empowerment in new product development: Situational framework, review, and research agenda
Authors: Maier Lukas , Baccarella Christian V.
Published: April 2024

In search of innovation and market success, firms have started to empower their customers in many ways, from customizing and self‐producing their own products (products made for one) to selecting and designing products for the broader marketplace (products made for many). This power shift has important behavioral and psychological consequences for customers and, hence, has attracted considerable interest from academics and practitioners alike. However, the literature is scattered, provides inconsistent findings, and lacks both a comprehensive conceptualization and empirical overview. Specifically, extant literature neglects the situational nature of customer empowerment, equalizing inherently different customer empowerment activities while failing to consider the divergent effects on participating versus observing customers (i.e., customers who do not participate in the new product development process themselves). This limits advancement of the field, and impedes integration with the related fields of innovation, marketing, and consumer research. To facilitate a better understanding of the psychological and behavioral consequences of customer empowerment, we systematically review literature in the field and develop a conceptual framework that integrates different customer empowerment situations and their respective psychological (e.g., firm perceptions and feelings of empowerment) and behavioral (e.g., product preferences and willingness‐to‐pay) consequences. Using this framework, we structure previous research, highlight similarities and differences across customer empowerment situations, and set the stage for future research. By taking a customer perspective, this research advances our understanding of why some customer empowerment strategies are more successful than others (and under which circumstances). On a broader level, we show that adopting a behavioral and psychological perspective may be a promising way to study innovation.
The complex, confusing and poorly understood immune responses to AAV‐mediated gene transfer in haemophilia—Is more or less immunosuppression required?
Authors: Tuddenham Edward G. D. , Foster Graham R.
Published: April 2024

Attempts to achieve a functional cure or amelioration of the severe X linked bleeding disorders haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) using AAV‐based vectors have been frustrated by immune responses that limit efficacy and durability. The immune responses include adaptive and innate pathways as well as cytokine mediated inflammation, especially of the target organ cells—hepatocytes. Immune suppression has only been partly effective in clinical trials at ameliorating the immune response and the lack of good animal models has delayed progress in identifying mechanisms and developing more effective approaches to controlling these effects of AAV gene transfer. Here we discuss the arguments for and against more potent immunosuppression to improve factor expression after AAV‐mediated gene therapy.
Global prevalence of onychomycosis in general and special populations: An updated perspective
Authors: Gupta Aditya K. , Wang Tong , Polla Ravi Shruthi , Mann Avantika , Bamimore Mary A.
Published: April 2024

Background

Onychomycosis is a chronic nail disorder commonly seen by healthcare providers; toenail involvement in particular presents a treatment challenge.

Objective

To provide an updated estimate on the prevalence of toenail onychomycosis.

Methods

We conducted a literature search using PubMed, Embase and Web of Science. Studies reporting mycology‐confirmed diagnoses were included and stratified into (a) populations‐based studies, and studies that included (b) clinically un‐suspected and (c) clinically suspected patients.

Results

A total of 108 studies were included. Based on studies that examined clinically un‐suspected patients (i.e., with or without clinical features suggestive of onychomycosis), the pooled prevalence rate of toenail onychomycosis caused by dermatophytes was 4% (95% CI: 3–5) among the general population; special populations with a heightened risk include knee osteoarthritis patients (RR: 14.6 [95% CI: 13.0–16.5]), chronic venous disease patients (RR: 5.6 [95% CI: 3.7–8.1]), renal transplant patients (RR: 4.7 [95% CI: 3.3–6.5]), geriatric patients (RR: 4.7 [95% CI: 4.4–4.9]), HIV‐positive patients (RR: 3.7 [95% CI: 2.9–4.7]), lupus erythematosus patients (RR: 3.1 [95% CI: 1.2–6.3]), diabetic patients (RR: 2.8 [95% CI: 2.4–3.3]) and hemodialysis patients (RR: 2.8 [95% CI: 1.9–4.0]). The prevalence of onychomycosis in clinically suspected patients was significantly higher likely due to sampling bias. A high degree of variability was found in a limited number of population‐based studies indicating that certain pockets of the population may be more predisposed to onychomycosis. The diagnosis of non‐dermatophyte mould onychomycosis requires repeat sampling to rule out contaminants or commensal organisms; a significant difference was found between studies that performed single sampling versus repeat sampling. The advent of PCR diagnosis results in improved detection rates for dermatophytes compared to culture.

Conclusion

Onychomycosis is an underrecognized healthcare burden. Further population‐based studies using standardized PCR methods are warranted.
Preoperative antibiotics are not indicated prior to closure of oroantral communication
Authors: Woo V. M. , Delpachitra S. N.
Published: April 2024

Objective

The aim of this paper was to determine whether the use of preoperative antibiotics improves surgical outcomes following oroantral communication (OAC) closure.

Materials and Methods

A single‐centre, retrospective study was conducted on all OAC repair procedures over a 24‐month period assessing a number of datapoints including the site of OAC occurrence, time to repair, local anaesthetic or general anaesthetic, and any complications noted. Patient follow‐up was up to 3 months post‐operative OAC closure. Data outputs primarily included descriptive statistics for demographic datasets included in the study. Fisher's exact test was used to determine non‐random associations between categorical variables (preoperative antibiotics vs. no preoperative antibiotics; successful closure vs. failed closure).

Results

Thirty‐one patients met the inclusion criteria and timeframe of this study. All OACs were a result of dental extraction. For patients who had an OAC visualised immediately after extraction, 18 had an OAC repair completed on the same day. Fifteen patients had a delayed closure, defined as a closure over 48 h following the development of OAC. Thirteen patients had their procedure completed under local anaesthetic; none had preoperative antibiotics prior to surgery. Only one patient with delayed closure of an OAC who had a procedure completed under local anaesthetic had a prophylactic dose 1 h prior to surgery. Patients who underwent OAC closure under general anaesthetic received an intra‐operative dose of antibiotics. Using Fisher's exact test, there was no significant difference between the two groups (preoperative antibiotics given vs. no preoperative antibiotics given) with regard to the likelihood of success following OAC closure (p = 0.1419).

Conclusion

This study demonstrates that the routine use of preoperative antibiotics may not improve surgical outcomes following the closure of oroantral communication.
Plasma biomarkers for predicting the development of dementia in a community‐dwelling older Japanese population
Authors: Ohara Tomoyuki , Tatebe Harutsugu , Hata Jun , Honda Takanori , Shibata Mao , Matsuura Sayo , Mikami Tatsuya , Maeda Tetsuya , Ono Kenjiro , Mimura Masaru , Nakashima Kenji , Iga Jun‐ichi , Takebayashi Minoru , Tokuda Takahiko , Ninomiya Toshiharu ,   JPSC‐AD (Japan Prospective Studies Collaboration for Aging and Dementia) study group
Published: April 2024

Aim

To assess the association between plasma amyloid β (Aβ) 42/40, phosphorylated tau (p‐τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population.

Methods

A total of 1346 Japanese community‐dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD‐X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia.

Results

During the follow‐up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non–Alzheimer dementia (non‐AD). Lower plasma Aβ42/40 levels and higher plasma p‐τ181 levels were significantly associated with developing AD but not non‐AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non‐AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia.

Conclusion

Our findings suggest that plasma Aβ42/40 and p‐τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all‐cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low‐invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.
Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low‐density lipoprotein receptor knockout mice
Authors: Hoekstra Menno , Snip Olga S. C. , Janusz Philip , Bernabé Kleijn Mireia N. A. , Truitt Edward R. , Sullivan Benjamin D. , Schmidt Tannin A. , Jay Gregory D. , Van Eck Miranda
Published: April 2024

Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin‐like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti‐atherogenic potential of chronic rhPRG4 treatment. Female low‐density lipoprotein receptor knockout mice were fed an atherogenic Western‐type diet for 6 weeks and injected three times per week intraperitoneally with 0.5 mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma‐free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4‐treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 103 μm2 compared with 339 ± 15 × 103 μm2 in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti‐inflammatory M2‐like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro‐inflammatory/pro‐atherogenic cytokine TNF‐alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti‐inflammatory agent.

image

Key points

Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility.

In this study we investigated the anti‐atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low‐density lipoprotein receptor knockout mice.

We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro‐inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF‐alpha levels and a lowered atherosclerosis susceptibility.

Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions.
Catalytic atomic layer deposition of amorphous alumina–silica thin films on carbon microfibers
Authors: des Ligneris Elise , Samélor Diane , Sekkat Abderrahime , Josse Claudie , Hungria Teresa , Pugliara Alessandro , Vahlas Constantin , Caussat Brigitte
Published: April 2024

Deposition of silica-based thin films on carbon microfibers has long been considered a challenge. Indeed, the oxidation-sensitive nature of carbon microfibers over 550 K and their submicron-textured surface does not bode well with the required conformity of deposition best obtained by atomic layer deposition (ALD) and the thermal oxidative conditions associated with common protocols of silica ALD. Nonetheless, the use of a catalytic ALD process allowed for the deposition of amorphous alumina–silica bilayers from 445 K using trimethylaluminium and tris(tert-pentoxy)silanol (TPS). In this study, first undertaken on flat silicon wafers to make use of optical spectroscopies, the interplay between kinetics leading to a dense silica film growth was investigated in relation to the applied operation parameters. A threshold between the film catalyzed growth and the complete outgassing of pentoxy-derived compounds from TPS was found, resulting in a deposition of equivalent growth per cycle of 1.1 nm c−1, at a common ALD rate of 0.3 nm  min−1, with a flat thickness gradient. The deposition on carbon microfiber fabrics was found conformal, albeit with a thickness growth capped below 20 nm, imparted by the microfiber surface texture. STEM-EDX showed a sharp interface of the bilayer with limited carbon diffusion. The conformal and dense deposition of alumina–silica thin films on carbon microfibers holds great potential for further use as refractory oxygen barrier layers.
Multi-Ingredient Preworkout Supplementation Compared With Caffeine and a Placebo Does Not Improve Repetitions to Failure in Resistance-Trained Women
Authors: Snyder Mariah , Brewer Christi , Taylor Katrina
Published: April 2024

There has been an increase in the use of commercially available multi-ingredient preworkout supplements (MIPS); however, there are inconsistencies regarding the efficacy of MIPS in resistance-trained women. Purpose: To determine the effect of varying doses of MIPS compared with caffeine only (C) and a placebo (PL) on resistance-training performance in trained women. Methods: Ten women (21.5 [2.3] y) completed 1-repetition-maximum tests at baseline for leg press and bench press. A within-group, double-blind, and randomized design was used to assign supplement drinks (ie, PL, C, MIPS half scoop [MIPS-H], and MIPS full scoop [MIPS-F]). Repetitions to failure were assessed at 75% and 80% to 85% of 1-repetition maximum for bench and leg press, respectively. Total performance volume was calculated as load × sets × repetitions for each session. Data were analyzed using a 1-way repeated-measures analysis of variance and reported as means and SDs. Results: There were no differences in repetitions to failure for bench press (PL: 14.4 [3.2] repetitions, C: 14.4 [2.9] repetitions, MIPS-H: 14.2 [2.6] repetitions, MIPS-F: 15.1 [3.1] repetitions; P = .54) or leg press (PL: 13.9 [7.8] repetitions, C: 10.8 [5.9] repetitions, MIPS-H: 13.1 [7.1] repetitions, MIPS-F: 12.4 [10.7] repetitions; P = .44). Furthermore, there were no differences in total performance volume across supplements for bench press (PL: 911.2 [212.8] kg, C: 910.7 [205.5] kg, MIPS-H: 913.6 [249.3] kg, MIPS-F: 951.6 [289.6] kg; P = .39) or leg press (PL: 4318.4 [1633.6] kg, C: 3730.0 [1032.5] kg, MIPS-H: 4223.0 [1630.0] kg, MIPS-F: 4085.5 [2098.3] kg; P = .34). Conclusions: Overall, our findings suggest that caffeine and MIPS do not provide ergogenic benefits for resistance-trained women in delaying muscular failure.
Managing Challenging Situations in the Coach–Athlete Dyad: Introducing the Grey Zone Model From the Coach Perspective
Authors: Slade Katelynn , Jowett Sophia , Rhind Daniel
Published: April 2024

Challenging situations and interactions are necessary and unavoidable in sport. From deselection to injury, burnout, and mental health issues, coaches and athletes will face challenging situations throughout their sporting career. The aims of this research study were to (a) introduce a conceptual model of challenging situations and subsequently to (b) explore a range of challenging situations that occur in high-performance sport, and (c) discover how such challenging situations are managed and perceived by high-performance coaches. In this study, challenging situations in coach–athlete dyads are defined as organisational, performance, interpersonal, and personal stressors that can push or pull one or both the coach and athlete, and subsequently their relationship into a state of indeterminacy (i.e., the Grey Zone) that may cause stress, strain, conflict, or resolution and understanding depending on how the challenging situations are managed. A total of 11 current high-performance and World Class Performance coaches (M = 41.64 years old, SD = 10.69 years; female = 4, male = 7), took part in a semistructured interview aided by vignettes to explore and discover the process by which coaches deal with challenging situations. Using a pragmatism approach, a content analysis guided by the conceptual Grey Zone Model was utilised to analyse the obtained qualitative data. Results indicated that coaches regularly experience challenging situations and use a variety of techniques to manage them. The Grey Zone Model is proposed as a practical tool to help coaches, athletes, and other practitioners, such as sport psychology consultants and coach developers to analyse the various phases of challenging situations.
Mechanisms used for cDNA synthesis and site-specific integration of RNA into DNA genomes by a reverse transcriptase–Cas1 fusion protein
Authors: Mohr Georg , Yao Jun , Park Seung Kuk , Markham Laura , Lambowitz Alan M.
Published: April 2024

Reverse transcriptase–Cas1 (RT-Cas1) fusion proteins found in some CRISPR systems enable spacer acquisition from both RNA and DNA, but the mechanism of RNA spacer acquisition has remained unclear. Here, we found that
Marinomonas mediterranea
RT-Cas1/Cas2 adds short 3′-DNA (dN) tails to RNA protospacers, enabling their direct integration into CRISPR arrays as 3′-dN-RNAs or 3′-dN-RNA/cDNA duplexes at rates comparable to similarly configured DNAs. Reverse transcription of RNA protospacers is initiated at 3′ proximal sites by multiple mechanisms, including recently described de novo initiation, protein priming with any dNTP, and use of short exogenous or synthesized DNA oligomer primers, enabling synthesis of near full-length cDNAs of diverse RNAs without fixed sequence requirements. The integration of 3′-dN-RNAs or single-stranded DNAs (ssDNAs) is favored over duplexes at higher protospacer concentrations, potentially relevant to spacer acquisition from abundant pathogen RNAs or ssDNA fragments generated by phage defense nucleases. Our findings reveal mechanisms for site-specifically integrating RNA into DNA genomes with potential biotechnological applications.
Miniature battery-free epidural cortical stimulators
Authors: Woods Joshua E. , Singer Amanda L. , Alrashdan Fatima , Tan Wendy , Tan Chunfeng , Sheth Sunil A. , Sheth Sameer A. , Robinson Jacob T.
Published: April 2024

Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power and reliability for real-world operation by showing acute motor cortex activation in human patients and reliable chronic motor cortex activation for 30 days in a porcine model. This platform opens the possibility of simple surgical procedures for precise neuromodulation.
Merging total synthesis and NMR technology for deciphering the realistic structure of natural 2,6-dideoxyglycosides
Authors: Zhang Zhaolun , Wu Renjie , Cao Shen , Li Jiaji , Huang Guangen , Wang Haoyu , Yang Tao , Tang Wei , Xu Peng , Yu Biao
Published: April 2024

The structural identification and efficient synthesis of bioactive 2,6-dideoxyglycosides are daunting challenges. Here, we report the total synthesis and structural revision of a series of 2,6-dideoxyglycosides from folk medicinal plants
Ecdysanthera rosea
and
Chonemorpha megacalyx
, which feature pregnane steroidal aglycones bearing an 18,20-lactone and glycans consisting of 2,6-dideoxy-3-
O
-methyl-β-pyranose residues, including ecdysosides A, B, and F and ecdysantheroside A. All the eight possible 2,6-dideoxy-3-
O
-methyl-β-pyranoside stereoisomers (of the proposed ecdysantheroside A) have been synthesized that testify the effective gold(I)-catalyzed glycosylation methods for the synthesis of various 2-deoxy-β-pyranosidic linkages and lays a foundation via nuclear magnetic resonance data mapping to identify these sugar units which occur promiscuously in the present and other natural glycosides. Moreover, some synthetic natural compounds and their isomers have shown promising anticancer, immunosuppressive, anti-inflammatory, and anti-Zika virus activities.
Supplemental Material: Stratigraphic and U-Pb zircon age constraints on the timing of the Yanliao Biota in northern China
Authors: Zou Zu-Yang , et al.
Published: April 2024

Figure S1 (sampling horizons and outcrops), Figure S2 (cathodoluminescence images of all zircons dated in this study), Figure S3 (weighted average age graphs as supplements to Figure 7), and Table S1 (results of SIMS U-Pb zircon dating).
Storylines of family medicine V: ways of thinking—honing the therapeutic self
Authors: Ventres William B , Stone Leslie A , Shapiro Johanna F , Haq Cynthia , Leão Jéssica R B , Nease Donald E , Grant Liz , Mercer Stewart W , Gillies John C M , Blasco Pablo González , De Benedetto Maria Auxiliadora C , Moreto Graziela , Levites Marcelo R , DeVoe Jennifer E , Phillips William R , Uygur Jane M , Egnew Thomas R , Stanley Colette S
Published: April 2024

Storylines of Family Medicineis a 12-part series of thematically linked essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In ‘V: ways of thinking—honing the therapeutic self’, authors present the following sections: ‘Reflective practice in action’, ‘The doctor as drug—Balint groups’, ‘Cultivating compassion’, ‘Towards a humanistic approach to doctoring’, ‘Intimacy in family medicine’, ‘The many faces of suffering’, ‘Transcending suffering’ and ‘The power of listening to stories.’ May readers feel a deeper sense of their own therapeutic agency by reflecting on these essays.
Storylines of family medicine VIII: clinical approaches
Authors: Ventres William B , Stone Leslie A , Gibson-Oliver Lauren E , Meehan Elizabeth Kyle , Ricker Mari A , Loxterkamp David , Ogbeide Stacy A , deGruy Frank V , Mahoney Megan R , Lin Steven , MacRae Clare , Mercer Stewart W
Published: April 2024

Storylines of Family Medicineis a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In ‘VIII: clinical approaches’, authors address the following themes: ‘Evaluation, diagnosis and management I—toward a working diagnosis’, ‘Evaluation, diagnosis and management II—process steps’, ‘Interweaving integrative medicine and family medicine’, ‘Halfway—the art of clinical judgment’, ‘Seamless integration in family medicine—team-based care’, ‘Technology—uncovering stories from noise’ and ‘Caring for patients with multiple long-term conditions’. May readers recognise in these essays the uniqueness of a family medicine approach to care.
Storylines of family medicine IX: people and places—diverse populations and locations of care
Authors: Ventres William B , Stone Leslie A , Abou-Arab Emad R , Meza Julio , Buck David S , Crowder Jerome W , Edgoose Jennifer Y C , Brown Alexander , Plumb Ellen J , Norris Amber K , Allen Jay J , Giammar Lauren E , Wood John E , Dickson Scott M , Brown G Austin
Published: April 2024

Storylines of Family Medicineis a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In ‘IX: people and places—diverse populations and locations of care’, authors address the following themes: ‘LGBTQIA+health in family medicine’, ‘A family medicine approach to substance use disorders’, ‘Shameless medicine for people experiencing homelessness’, ‘‘‘Difficult” encounters—finding the person behind the patient’, ‘Attending to patients with medically unexplained symptoms’, ‘Making house calls and home visits’, ‘Family physicians in the procedure room’, ‘Robust rural family medicine’ and ‘Full-spectrum family medicine’. May readers appreciate the breadth of family medicine in these essays.
Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells
Authors: Ducellier Sarah , Demeules Mélanie , Letribot Boris , Gaetani Massimiliano , Michaudel Chloé , Sokol Harry , Hamze Abdallah , Alami Mouad , Nascimento Mégane , Apcher Sébastien
Published: April 2024

Background

Despite the current therapeutic treatments including surgery, chemotherapy, radiotherapy and more recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered that a molecule called QAPHA ((E)−3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)−2-methoxyphenyl)-N-hydroxyacrylamide) has a dual function as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the immune response to lung cancer.

Methods

To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterized by flow cytometry.

Results

In this study, we first showed that QAPHA effectively inhibited histone deacetylase 6, leading to upregulation of HSP90, cytochrome C and caspases, as revealed by proteomic analysis. We confirmed that QAPHA induces immunogenic cell death (ICD) by expressing calreticulin at cell surface in vitro and demonstrated its efficacy as a vaccine in vivo. Remarkably, even at a low concentration (0.5 mg/kg), QAPHA achieved complete tumor regression in approximately 60% of mice treated intratumorally, establishing a long-lasting anticancer immune response. Additionally, QAPHA treatment promoted the infiltration of M1-polarized macrophages in treated mice, indicating the induction of a pro-inflammatory environment within the tumor. Very interestingly, our findings also revealed that QAPHA upregulated major histocompatibility complex class II (MHC-II) expression on TC-1 tumor cells both in vitro and in vivo, facilitating the recruitment of cytotoxic CD4+T cells (CD4+CTL) expressing CD4+, NKG2D+, CRTAM+, and Perforin+. Finally, we showed that tumor regression strongly correlates to MHC-II expression level on tumor cell and CD4+CTL infiltrate.

Conclusion

Collectively, our findings shed light on the discovery of a new multitarget inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate in enhancing a specific CD4+cytotoxic T cell-mediated antitumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising agent for cancer treatment.
Efficient CAR T cell targeting of the CA125 extracellular repeat domain of MUC16
Authors: Casey Nicholas P , Kleinmanns Katrin , Forcados Christopher , Gelebart Pascal F , Joaquina Sandy , Lode Martine , Benard Emmanuelle , Kaveh Fatemeh , Caulier Benjamin , Helgestad Gjerde Christiane , García de Jalón Elvira , Warren David J , Lindemann Kristina , Rokkones Erik , Davidson Ben , Myhre Marit Renee , Kvalheim Gunnar , Bjørge Line , McCormack Emmet , Inderberg Else Marit , Wälchli Sébastien
Published: April 2024

Background

Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients’ own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy.

Methods

We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct.

Results

We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain.

Conclusions

Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies.
A, B, C of three-qubit entanglement: three vectors to control it all
Authors: Uskov Dmitry B. , Alsing Paul M.
Published: April 2024

In this paper, we are focusing on entanglement control problem in a three-qubit system. We demonstrate that vector representation of entanglement, associated with SO(6) representation of SU(4) two-qubit group, can be used to solve various control problems analytically including ( i) the transformation between a W-type states and GHZ state, and ( ii) manipulating bipartite concurrences and three-tangle under a restricted access to only two qubits, and ( iii) designing USp(4)-type quaternionic operations and quantum states.
Exact phonon quasibound states around an optical black hole
Authors: Senjaya David
Published: April 2024

In this work, we present an exact solution of phonon quasibound states in a vortex photon flow that creates an analogous black hole background. We worked out and successfully solve the governing differential equation of the systen that is similar with the relativistic Klein–Gordon equation. The exact radial solutions are discovered in terms of the confluent Heun functions that behaves as ingoing waves near the black hole’s horizon and decaying far away from the black hole’s horizon. The polynomial condition of the confluent Heun function leads to the discovery of the the complex valued quantized energy levels expression of the quasibound state of which depends on the phonon mass $$\Omega _0$$

Ω
0

, the photon vortex horizon’s spin $$\Omega _H$$

Ω
H

and the azimuthal and the main quantum number (m, n). In the last section, by using the Damour–Ruffini method, the Hawking radiation of the analog black hole’s horizon is investigated to derive the phononic radiation distribution function from where, the Hawking temberature is obtained.
eZNS: Elastic Zoned Namespace for Enhanced Performance Isolation and Device Utilization
Authors: Min Jaehong , Zhao Chenxingyu , Liu Ming , Krishnamurthy Arvind
Published: April 2024

Emerging Zoned Namespace (ZNS) SSDs, providing the coarse-grained zone abstraction, hold the potential to significantly enhance the cost efficiency of future storage infrastructure and mitigate performance unpredictability. However, existing ZNS SSDs have a static zoned interface, making them in-adaptable to workload runtime behavior, unscalable to underlying hardware capabilities, and interfering with co-located zones. Applications either under-provision the zone resources yielding unsatisfied throughput, create over-provisioned zones and incur costs, or experience unexpected I/O latencies.

We propose eZNS, an elastic-ZNS interface that exposes an adaptive zone with predictable characteristics. eZNS comprises two major components: a zone arbiter that manages zone allocation and active resources on the control plane, and a hierarchical I/O scheduler with read congestion control and write admission control on the data plane. Together, eZNS enables the transparent use of a ZNS SSD and closes the gap between application requirements and zone interface properties. Our evaluations over RocksDB demonstrate that eZNS outperforms a static zoned interface by 17.7% and 80.3% in throughput and tail latency, respectively, at most.
From Detection to Application: Recent Advances in Understanding Scientific Tables and Figures
Authors: Huang Jiani , Chen Haihua , Yu Fengchang , Lu Wei
Published: April 2024

Tables and figures are usually used to present information in a structured and visual way in scientific documents. Understanding the tables and figures in scientific documents is significant for a series of downstream tasks, such as academic search, scientific knowledge graphs, and so on. Existing studies mainly focus on detecting figures and tables from scientific documents, interpreting their semantics, and integrating them into downstream tasks. However, a systematic and comprehensive literature review on the mining and application of tables and figures in academic papers is still missing. In this article, we introduce the research framework and the whole pipeline for understanding tables and figures, including detection, structural analysis, interpretation, and application. We deliver a thorough analysis of benchmark datasets, recent techniques, and their pros and cons. Additionally, a quantitative analysis of the effectiveness of different models on popular benchmarks is presented. We further outline several important applications that exploit the semantics of scientific tables and figures. Finally, we highlight the challenges and some potential directions for future research. We believe this is the first comprehensive survey in understanding scientific tables and figures that covers the landscape from detection to application.
BatFix: Repairing language model-based transpilation
Authors: Ramos Daniel , Lynce Inês , Manquinho Vasco , Martins Ruben , Le Goues Claire
Published: April 2024

To keep up with changes in requirements, frameworks, and coding practices, software organizations might need to migrate code from one language to another. Source-to-source migration, or transpilation, is often a complex, manual process. Transpilation requires expertise both in the source and target language, making it highly laborious and costly. Languages models for code generation and transpilation are becoming increasingly popular. However, despite capturing code-structure well, code generated by language models is often spurious and contains subtle problems. We propose
BatFix
, a novel approach that augments language models for transpilation by leveraging program repair and synthesis to fix the code generated by these models.
BatFix
takes as input both the original program, the target program generated by the machine translation model, and a set of test cases and outputs a repaired program that passes all test cases. Experimental results show that our approach is agnostic to language models and programming languages.
BatFix
can locate bugs spawning multiple lines and synthesize patches for syntax and semantic bugs for programs migrated from
Java
to
C++
and
Python
to
C++
from multiple language models, including, OpenAI’s
Codex
.