bluuebunny/crossref_metadata_2025 huggingface dataset:
Silicone cryogel skeletons enhance the survival and mechanical integrity of hydrogel-encapsulated cell therapies
Authors: Jeang William J. , Bochenek Matthew A. , Bose Suman , Zhao Yichao , Wong Bryan M. , Yang Jiawei , Jiang Alexis L. , Langer Robert , Anderson Daniel G.
Published: April 2024

The transplantation of engineered cells that secrete therapeutic proteins presents a promising method for addressing a range of chronic diseases. However, hydrogels used to encase and protect non-autologous cells from immune rejection often suffer from poor mechanical properties, insufficient oxygenation, and fibrotic encapsulation. Here, we introduce a composite encapsulation system comprising an oxygen-permeable silicone cryogel skeleton, a hydrogel matrix, and a fibrosis-resistant polymer coating. Cryogel skeletons enhance the fracture toughness of conventional alginate hydrogels by 23-fold and oxygen diffusion by 2.8-fold, effectively mitigating both implant fracture and hypoxia of encapsulated cells. Composite implants containing xenogeneic cells engineered to secrete erythropoietin significantly outperform unsupported alginate implants in therapeutic delivery over 8 weeks in immunocompetent mice. By improving mechanical resiliency and sustaining denser cell populations, silicone cryogel skeletons enable more durable and miniaturized therapeutic implants.
Human brain glycoform coregulation network and glycan modification alterations in Alzheimer’s disease
Authors: Zhang Qi , Ma Cheng , Chin Lih-Shen , Pan Sheng , Li Lian
Published: April 2024

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer’s disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain glycoproteome into networks of coregulated glycoforms and glycans and discovered glycoform and glycan modules associated with AD clinical phenotype, amyloid-β accumulation, and tau pathology. Our findings provide valuable insights into disease pathogenesis and a rich resource of glycoform and glycan changes in AD and pave the way forward for developing glycosylation-based therapies and biomarkers for AD.
Exceptional–point–enhanced phase sensing
Authors: Mao Wenbo , Fu Zhoutian , Li Yihang , Li Fu , Yang Lan
Published: April 2024

Optical sensors, crucial in diverse fields like gravitational wave detection, biomedical imaging, and structural health monitoring, rely on optical phase to convey valuable information. Enhancing sensitivity is important for detecting weak signals. Exceptional points (EPs), identified in non-Hermitian systems, offer great potential for advanced sensors, given their marked response to perturbations. However, strict physical requirements for operating a sensor at EPs limit broader applications. Here, we introduce an EP-enhanced sensing platform featuring plug-in external sensors separated from an EP control unit. EPs are achieved without modifying the sensor, solely through control-unit adjustments. This configuration converts and amplifies optical phase changes into quantifiable spectral features. By separating sensing and control functions, we expand the applicability of EP enhancement to various conventional sensors. As a proof-of-concept, we demonstrate a sixfold reduction in the detection limit of fiber-optic strain sensing using this configuration. This work establishes a universal platform for applying EP enhancement to diverse phase-dependent structures, promising ultrahigh-sensitivity sensing across various applications.
Biomimetic wafer-scale alignment of tellurium nanowires for high-mobility flexible and stretchable electronics
Authors: Zhao Yingtao , Zhao Sanchuan , Pang Xixi , Zhang Anni , Li Chenning , Lin Yuxuan , Du Xiaomeng , Cui Lei , Yang Zhenhua , Hao Tailang , Wang Chaopeng , Yin Jun , Xie Wei , Zhu Jian
Published: April 2024

Flexible and stretchable thin-film transistors (TFTs) are crucial in skin-like electronics for wearable and implantable applications. Such electronics are usually constrained in performance owing to a lack of high-mobility and stretchable semiconducting channels. Tellurium, a rising semiconductor with superior charge carrier mobilities, has been limited by its intrinsic brittleness and anisotropy. Here, we achieve highly oriented arrays of tellurium nanowires (TeNWs) on various substrates with wafer-scale scalability by a facile lock-and-shear strategy. Such an assembly approach mimics the alignment process of the trailing tentacles of a swimming jellyfish. We further apply these TeNW arrays in high-mobility TFTs and logic gates with improved flexibility and stretchability. More specifically, mobilities over 100 square centimeters per volt per second and on/off ratios of ~10
4
are achieved in TeNW-TFTs. The TeNW-TFTs on polyethylene terephthalate can sustain an omnidirectional bending strain of 1.3% for more than 1000 cycles. Furthermore, TeNW-TFTs on an elastomeric substrate can withstand a unidirectional strain of 40% with no performance degradation.
Direct synthesis of branched amines enabled by dual-catalyzed allylic C─H amination of alkenes with amines
Authors: Ren Yu-Feng , Chen Bi-Hong , Chen Xiao-Yi , Du Hai-Wu , Li Yu-Long , Shu Wei
Published: April 2024

Direct conversion of hydrocarbons into amines represents an important and atom-economic goal in chemistry for decades. However, intermolecular cross-coupling of terminal alkenes with amines to form branched amines remains extremely challenging. Here, a visible-light and Co-dual catalyzed direct allylic C─H amination of alkenes with free amines to afford branched amines has been developed. Notably, challenging aliphatic amines with strong coordinating effect can be directly used as C─N coupling partner to couple with allylic C─H bond to form advanced amines with molecular complexity. Moreover, the reaction proceeds with exclusive regio- and chemoselectivity at more steric hinder position to deliver primary, secondary, and tertiary aliphatic amines with diverse substitution patterns that are difficult to access otherwise.
Biomolecular dynamics with machine-learned quantum-mechanical force fields trained on diverse chemical fragments
Authors: Unke Oliver T. , Stöhr Martin , Ganscha Stefan , Unterthiner Thomas , Maennel Hartmut , Kashubin Sergii , Ahlin Daniel , Gastegger Michael , Medrano Sandonas Leonardo , Berryman Joshua T. , Tkatchenko Alexandre , Müller Klaus-Robert
Published: April 2024

The GEMS method enables molecular dynamics simulations of large heterogeneous systems at ab initio quality.
Regulation of BCR-mediated Ca
2+
mobilization by MIZ1-TMBIM4 safeguards IgG1
+
GC B cell–positive selection
Authors: Zhang Lingling , Toboso-Navasa Amparo , Gunawan Arief , Camara Abdouramane , Nakagawa Rinako , Finsterbusch Katja , Chakravarty Probir , Newman Rebecca , Zhang Yang , Eilers Martin , Wack Andreas , Tolar Pavel , Toellner Kai-Michael , Calado Dinis Pedro
Published: April 2024

The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG
+
B cells over IgM
+
B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1
+
GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1
+
GC B cell survival during positive selection, whereas IgM
+
GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)–mediated calcium (Ca
2+
) mobilization downstream of B cell receptor (BCR) signaling in IgG1
+
B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction–induced IgG1
+
GC cell death caused by excessive Ca
2+
accumulation. This study uncovers a unique Ig isotype–specific dependency on a hitherto unidentified mechanism in GC-positive selection.
The polyextremophile
Natranaerobius thermophilus
adopts a dual adaptive strategy to long-term salinity stress, simultaneously accumulating compatible solutes and K
+
Authors: Xing Qinghua , Zhang Shanshan , Tao Xinyi , Mesbah Noha M. , Mao Xinwei , Wang Haisheng , Wiegel Juergen , Zhao Baisuo
Published: April 2024

The bacterium
Natranaerobius thermophilus
is an extremely halophilic alkalithermophile that can thrive under conditions of high salinity (3.3–3.9 M Na
+
), alkaline pH (9.5), and elevated temperature (53°C). To understand the molecular mechanisms of salt adaptation in
N. thermophilus
, it is essential to investigate the protein, mRNA, and key metabolite levels on a molecular basis. Based on proteome profiling of
N. thermophilus
under 3.1, 3.7, and 4.3 M Na
+
conditions compared to 2.5 M Na
+
condition, we discovered that a hybrid strategy, combining the “compatible solute” and “salt-in” mechanisms, was utilized for osmotic adjustment dur ing the long-term salinity adaptation of
N. thermophilus
. The mRNA level of key proteins and the intracellular content of compatible solutes and K
+
support this conclusion. Specifically,
N. thermophilus
employs the glycine betaine ABC transporters (Opu and ProU families), Na
+
/solute symporters (SSS family), and glutamate and proline synthesis pathways to adapt to high salinity. The intracellular content of compatible solutes, including glycine betaine, glutamate, and proline, increases with rising salinity levels in
N. thermophilus
. Additionally, the upregulation of Na
+
/ K
+
/ H
+
transporters facilitates the maintenance of intracellular K
+
concentration, ensuring cellular ion homeostasis under varying salinities. Furthermore,
N. thermophilus
exhibits cytoplasmic acidification in response to high Na
+
concentrations. The median isoelectric points of the upregulated proteins decrease with increasing salinity. Amino acid metabolism, carbohydrate and energy metabolism, membrane transport, and bacterial chemotaxis activities contribute to the adaptability of
N. thermophilus
under high salt stress. This study provides new data that support further elucidating the complex adaptation mechanisms of
N. thermophilus
under multiple extremes.

IMPORTANCE

This study represents the first report of simultaneous utilization of two salt adaptation mechanisms within the
Clostridia
class in response to long-term salinity stress.
Indirect CD4
+
T cell protection against mouse gamma-herpesvirus infection via interferon gamma
Authors: Xie Wanxiaojie , Bruce Kimberley , Belz Gabrielle T. , Farrell Helen E. , Stevenson Philip G.
Published: April 2024

CD4
+
T cells play a key role in γ-herpesvirus infection control. However, the mechanisms involved are unclear. Murine herpesvirus type 4 (MuHV-4) allows relevant immune pathways to be dissected experimentally in mice. In the lungs, it colonizes myeloid cells, which can express MHC class II (MHCII), and type 1 alveolar epithelial cells (AEC1), which lack it. Nevertheless, CD4
+
T cells can control AEC1 infection, and this control depends on MHCII expression in myeloid cells. Interferon-gamma (IFNγ) is a major component of CD4
+
T cell-dependent MuHV-4 control. Here, we show that the action of IFNγ is also indirect, as CD4
+
T cell-mediated control of AEC1 infection depended on IFNγ receptor (IFNγR1) expression in CD11c
+
cells. Indirect control also depended on natural killer (NK) cells. Together, the data suggest that the activation of MHCII
+
CD11c
+
antigen-presenting cells is key to the CD4
+
T cell/NK cell protection axis. By contrast, CD8
+
T cell control of AEC1 infection appeared to operate independently.

IMPORTANCE

CD4
+
T cells are critical for the control of gamma-herpesvirus infection; they act indirectly, by recruiting natural killer (NK) cells to attack infected target cells. Here, we report that the CD4
+
T cell/NK cell axis of gamma-herpesvirus control requires interferon-γ engagement of CD11c
+
dendritic cells. This mechanism of CD4
+
T cell control releases the need for the direct engagement of CD4
+
T cells with virus-infected cells and may be a common strategy for host control of immune-evasive pathogens.
Tracking
Vibrio
: population dynamics and ecology of
Vibrio parahaemolyticus
and
V. vulnificus
in an Alabama estuary
Authors: Morrison Blair H. , Jones Jessica L. , Dzwonkowski Brian , Krause Jeffrey W.
Published: April 2024

Vibrio
is a genus of halophilic, gram-negative bacteria found in estuaries around the globe. Integral parts of coastal cultures often involve contact with vectors of pathogenic
Vibrio
spp. (e.g., consuming raw shellfish). High rates of mortality from certain
Vibrio
spp. infections demonstrate the need for an improved understanding of
Vibrio
spp. dynamics in estuarine regions. Our study assessed meteorological, hydrographic, and biological correlates of
Vibrio parahaemolyticus
and
V. vulnificus
at 10 sites in the Eastern Mississippi Sound System (EMSS) from April to October 2019. During the sampling period, median abundances of
V. parahaemolyticus
and
V. vulnificus
were 2.31 log MPN/L and 2.90 log MPN/L, respectively.
Vibrio
spp. dynamics were largely driven by site-based variation, with sites closest to freshwater inputs having the highest abundances. The E-W wind scalar, which affects Ekman transport, was a novel
Vibrio
spp. correlate observed. A potential salinity effect on bacterial-particle associations was identified, where
V. vulnificus
was associated with larger particles in conditions outside of their optimal salinity. Additionally,
V. vulnificus
abundances were correlated to those of harmful algal species that did not dominate community chlorophyll. Correlates from this study may be used to inform the next iteration of regionally predictive
Vibrio
models and may lend additional insight to
Vibrio
spp. ecology in similar systems.

IMPORTANCE

Vibrio
spp. are bacteria found in estuaries worldwide; some species can cause illness and infections in humans. Relationships between
Vibrio
spp. abundance, salinity, and temperature are well documented, but correlations to other environmental parameters are less understood. This study identifies unique correlates (e.g., E-W wind scalar and harmful algal species) that could potentially inform the next iteration of predictive
Vibrio
models for the EMSS region. Additionally, these correlates may allow existing environmental monitoring efforts to be leveraged in providing data inputs for future Vibrio risk models. An observed correlation between salinity and
V. vulnificus
/particle-size associations suggests that predicted environmental changes may affect the abundance of
Vibrio
spp. in certain reservoirs, which may alter which vectors present the greatest vibrio risk.
The Permian Cornubian granite batholith, SW England; Part 2: Gravity anomalies, structure, and state of isostasy
Authors: Watts A.B. , Xu C. , Searle M.P. , Jurkowski C. , Shail R.K.
Published: April 2024

A new compilation of Bouguer gravity anomaly data has been used, together with forward and inverse modeling, to reappraise the structure, volume, and state of isostasy of the Cornubian batholith of SW England. We show the individual plutons that comprise the batholith are, on average, ~10–11 km thick, are outward-sloping in their upper 2–3 km, and are underlain by roots which protrude downward into the middle crust. The batholith volume is estimated within the range of 76,367 ± 17,286 km3, significantly larger than previous estimates. Granite outcrops correlate with elevated topography, and mass balance calculations show that the mass deficiency of the granites relative to their host metasedimentary rocks is approximately equal to the mass excess of the topography relative to air. The existence of roots beneath individual plutons is in general agreement with predictions of an Airy model of isostasy and a depth of compensation that is within the crust rather than at the Moho. In addition, a middle crust compensation depth is compatible with the origin of the granites by heating and melting of metasedimentary rocks and with data from experimental rock mechanics which suggest that at the melting temperature and pressure of granite formation, deformation is likely to be plastic and controlled by glide along dislocations. During pluton emplacement the middle crust would, therefore, have acted as a mechanically weak layer, effectively decoupling the topography from any support it might otherwise have received from the lower crust and/or upper mantle.
Reference ranges for ambulatory heart rate measurements in a middle-aged population
Authors: Persson Anders Paul , Måneheim Alexandra , Economou Lundeberg Johan , Fedorowski Artur , Healey Jeff S , Sundström Johan , Engström Gunnar , Johnson Linda S B
Published: April 2024

Background

Elevated heart rate (HR) predicts cardiovascular disease and mortality, but there are no established normal limits for ambulatory HR. We used data from the Swedish CArdioPulmonary Imaging Study to determine reference ranges for ambulatory HR in a middle-aged population. We also studied clinical correlates of ambulatory HR.

Methods

A 24-hour ECG was registered in 5809 atrial fibrillation-free individuals, aged 50–65 years. A healthy subset (n=3942) was used to establish reference values (excluding persons with beta-blockers, cardiovascular disease, hypertension, heart failure, anaemia, diabetes, sleep apnoea or chronic obstructive pulmonary disease).

Minimum HR was defined as the lowest 1-minute HR. Reference ranges are reported as means±SDs and 2.5th–97.5th percentiles. Clinical correlates of ambulatory HR were analysed with multivariable linear regression.

Results

The average mean and minimum HRs were 73±9 and 48±7 beats per minute (bpm) in men and 76±8 and 51±7 bpm in women; the reference range for mean ambulatory HR was 57–90 bpm in men and 61–92 bpm in women. Average daytime and night-time HRs are also reported. Clinical correlates, including age, sex, height, body mass index, physical activity, smoking, alcohol intake, diabetes, hypertension, haemoglobin level, use of beta-blockers, estimated glomerular filtration rate, per cent of predicted forced expiratory volume in 1 s and coronary artery calcium score, explained <15% of the interindividual differences in HR.

Conclusion

Ambulatory HR varies widely in healthy middle-aged individuals, a finding with relevance for the management of patients with a perception of tachycardia. Differences in ambulatory HR between individuals are largely independent of common clinical correlates.
Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer
Authors: Martincuks Antons , Zhang Chunyan , Austria Theresa , Li Yi-Jia , Huang Rui , Lugo Santiago Nicole , Kohut Adrian , Zhao Qianqian , Borrero Rosemarie Martinez , Shen Binghui , Cristea Mihaela , Wang Edward W , Song Mihae , Rodriguez-Rodriguez Lorna , Yu Hua
Published: April 2024

Background

Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment.

Methods

By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG’s catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, andBrca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetentBrca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition.

Results

Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors.

Conclusions

We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.
Blocking senescence and tolerogenic function of dendritic cells induced by γδ Treg cells enhances tumor-specific immunity for cancer immunotherapy
Authors: Si Fusheng , Liu Xia , Tao Yan , Zhang Yuanqin , Ma Feiya , Hsueh Eddy C , Puram Sidharth V , Peng Guangyong
Published: April 2024

Background

Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy.

Methods

Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence and dysfunction induced by Treg cells. Impaired tumor antigen HER2-specific recognition and immune response of senescent DCs induced by γδ Treg cells were explored in vitro and in vivo in humanized mouse models. In addition, the DC-based HER2 tumor vaccine immunotherapy in breast cancer models was performed to explore the enhanced antitumor immunity via prevention of DC senescence through blockages of STAT3 and programmed death-ligand 1 (PD-L1) signaling.

Results

We showed that tumor-derived γδ Treg cells promote the development of senescence in DCs with tolerogenic functions in breast cancer. Senescent DCs induced by γδ Treg cells suppress Th1 and Th17 cell differentiation but promote the development of Treg cells. In addition, we demonstrated that PD-L1 and STAT3 signaling pathways are critical and involved in senescence induction in DCs mediated by tumor-derived γδ Treg cells. Importantly, our complementary in vivo studies further demonstrated that blockages of PD-L1 and/or STAT3 signaling can prevent γδ Treg-induced senescence and reverse tolerogenic functions in DCs, resulting in enhanced HER2 tumor-specific immune responses and immunotherapy efficacy in human breast cancer models.

Conclusions

These studies not only dissect the suppressive mechanism mediated by tumor-derived γδ Treg cells on DCs in the tumor microenvironment but also provide novel strategies to prevent senescence and dysfunction in DCs and enhance antitumor efficacy mediated by tumor-specific T cells for cancer immunotherapy.
Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers
Authors: Zhang You , Cao Min , Wu Yanfei , Malih Sara , Xu Dong , Yang Erpeng , Younis Muhsin H , Lin Wilson , Zhao Haitao , Wang Cheng , Liu Qiufang , Engle Jonathan W , Rasaee Mohammad J , Guan Yihui , Huang Gang , Liu Jianjun , Cai Weibo , Xie Fang , Wei Weijun
Published: April 2024

Background

The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape.

Methods

By immunizing an alpaca with recombinant human PD-L1, three clones of thevariable domain of theheavy chain ofheavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).

Results

While RW102 has a high binding affinity to PD-L1 with an excellent KDvalue of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KDvalue of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have differentin vivocirculation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.

Conclusions

We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.

Trial registration number

NCT06165874.
Incomplete sensorimotor paresis after upper abdominal surgery with TEA and spinal epidural lipomatosis: a case report
Authors: Zugaj Marco Richard , Gutzeit Oliver , Mayer Victoria Louise , Ishak Basem , Gumbinger Christoph , Weigand Markus Alexander , Keßler Jens
Published: April 2024

Introduction

This case report documents a postoperative, incomplete sensorimotor paraparesis from thoracic vertebral body 6 (Th6) after combined anesthesia for upper abdominal surgery in a patient who had a thoracic localization of spinal epidural lipomatosis (SEL).

Case presentation

The patient was treated in our clinic with a thoracic epidural catheter (TEA) for perioperative analgesia during a partial duodenopancreatectomy. Paraparetic symptoms occurred 20 hours after surgery. Initial MRI did not show bleeding, infection or spinal cord damage and the neurosurgeon consultants recommended observation. The neurological examination and the third follow-up MRI on 15th postoperative day showed ventrolateral damage of the spinal cord at level Th6. It is possible that local anesthetic compressed the spinal cord in addition to the existing lipomatosis and the thoracic kyphosis. The paraparesis improved during follow-up paraplegiologic treatment.

Conclusion

So far, only two uncomplicated lumbar epidural catheter anesthesias have been described in patients who had a lumbar SEL. Epidural catheter anesthesia is a safe and effective method of pain control. But it is important to carefully identify and stratify patients with risk factors during the premedication visit. In patients who had kyphosis and thoracic localization of SEL, TEA may only be used after a risk–benefit assessment.
Fluoroscopy-guided high-intensity focused ultrasound neurotomy of the lumbar zygapophyseal joints: a prospective, open-label study
Authors: Gofeld Michael , Smith Kevin J , Bhatia Anuj , Djuric Vladimir , Leblang Suzanne , Rebhun Niv , Aginsky Ron , Miller Eric , Skoglind Brian , Hananel Arik
Published: April 2024

Objective

The objective of this study is to investigate safety and effectiveness of a fluoroscopy-guided high-intensity focused ultrasound (HIFU) system for thermal ablation of the lumbar medial branch nerves.

Methods

This dual center prospective cohort study enrolled 30 participants with lumbar zygapophyseal joint syndrome. Each participant previously had a positive response to either a single diagnostic analgesic block or radiofrequency ablation (RFA). The primary effectiveness outcome was individual responder rate, defined as a reduction of two points or more on the pain intensity numerical rating scale without an increase in opioid intake, or a reduction in opioid intake without an increase in pain at 6 months after the intervention. The primary safety outcome was procedure-related or device-related adverse events (AEs). Secondary outcome variables included MRI evidence of tissue ablation, Oswestry Disability Index, 12-Item Short Form Health Survey, Brief Pain Inventory, and Patient Global Impression of Change.

Results

The individual responder rate was 89.7% at 2 days, 89.7% at 7 days, 72.4% at 14 days, 82.1% at 30 days, 59.3% at 90 days and 82.6% at 180 days. The average Numeric Rating Scale for pain severity decreased from 7.1 at baseline to 3.0 (N=29) after 2 days, 3.0 (N=29) after 7 days, 3.1 (N=29) after 14 days, 3.2 (N=28) after 30 days, 4.3 (N=27) after 90 days, and 3.3 (N=23) after 180 days. All participants tolerated the procedure well with no significant side effects or complications.

Conclusions

Fluoroscopy-guided HIFU neurotomy achieved clinical responses comparable with RFA, and there were no significant device-related or procedure-related AEs.

Trial registration number

NCT04129034.
Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1–phase 2a study
Authors: Barde François , Lorenzon Roberta , Vicaut Eric , Rivière Sébastien , Cacoub Patrice , Cacciatore Carlotta , Rosenzwajg Michelle , Daguenel-Nguyen Anne , Fain Olivier , Klatzmann David , Mekinian Arsène
Published: April 2024

Background

Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc.

Objective

We aimed to assess the safety and biological efficacy of IL-2LDin patients with SSc.

Methods

As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6.

Results

At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LDwas well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period.

Conclusion

IL-2LDat a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LDtherapeutic efficacy in SSc.
Diagnostic accuracy in axial spondyloarthritis: a systematic evaluation of the role of clinical information in the interpretation of sacroiliac joint imaging
Authors: Pohlner Tim , Deppe Dominik , Ziegeler Katharina , Proft Fabian , Protopopov Mikhail , Rademacher Judith , Rios Rodriguez Valeria , Torgutalp Murat , Braun Jürgen , Diekhoff Torsten , Poddubnyy Denis
Published: April 2024

Objectives

Radiography and MRI of the sacroiliac joints (SIJ) are relevant for the diagnosis and classification of patients with axial spondyloarthritis (axSpA). This study aimed to evaluate the impact of clinical information (CI) on the accuracy of imaging interpretation.

Methods

Out of 109 patients referred because of suspicion of axSpA with complete imaging sets (radiographs and MRI of SIJ), 61 were diagnosed with axSpA (56%). Images were independently evaluated by three radiologists in four consecutive reading campaigns: radiographs and radiographs+MRI without and with CI including demographic data, SpA features, physical activity and pregnancy. Radiographs were scored according to the modified New York criteria, and MRIs for inflammatory and structural changes compatible with axSpA (yes/no). The clinical diagnosis was taken as reference standard. The compatibility of imaging findings with a diagnosis of axSpA (precision) before and after the provision of CI and radiologists’ confidence with their findings (0–10) were evaluated.

Results

The precision of radiographs evaluation without versus with CI increased from 70% to 78% (p=0.008), and for radiographs+MRI from 81% to 82% (p=1.0), respectively. For CR alone, the sensitivity and specificity of radiologic findings were 51% and 94% without and 60% and 100% with CI, while, for radiographs+MRI, they were 74% and 90% vs 71% and 98%, respectively. The diagnostic confidence of radiologists increased from 5.2±1.9 to 6.0±1.7 with CI for radiographs, and from 6.7±1.6 to 7.2±1.6 for radiographs+MRI, respectively.

Conclusion

The precision, specificity and diagnostic confidence of radiologic evaluation increased when CI was provided.
Recommendations for physical activity and exercise in persons living with Systemic Lupus Erythematosus (SLE): consensus by an international task force
Authors: Blaess Julien , Geneton Sophie , Goepfert Thibaut , Appenzeller Simone , Bordier Gabriel , Davergne Thomas , Fuentes Yurilis , Haglo Håvard , Hambly Karen , Kinnett-Hopkins Dominique , Su Kuei-Ying , Legge Alexandra , Li Linda , Mak Anselm , Padjen Ivan , Sciascia Savino , Sheikh Saira Z , Soriano-Maldonado Alberto , Ugarte-Gil Manuel F , Md Yusof Md Yuzaiful , Parodis Ioannis , Arnaud Laurent
Published: April 2024

Objective

This international task force aimed to provide healthcare professionals and persons living with systemic lupus erythematosus (SLE) with consensus-based recommendations for physical activity and exercise in SLE.

Methods

Based on evidence from a systematic literature review and expert opinion, 3 overarching principles and 15 recommendations were agreed on by Delphi consensus.

Results

The overarching principles highlight the importance of shared decision-making and the need to explain the benefits of physical activity to persons living with SLE and other healthcare providers. The 15 specific recommendations state that physical activity is generally recommended for all people with SLE, but in some instances, a medical evaluation may be needed to rule out contraindications. Pertaining to outdoor activity, photoprotection is necessary. Both aerobic and resistance training programmes are recommended, with a gradual increase in frequency and intensity, which should be adapted for each individual, and ideally supervised by qualified professionals.

Conclusion

In summary, the consensus reached by the international task force provides a valuable framework for the integration of physical activity and exercise into the management of SLE, offering a tailored evidence-based and eminence-based approach to enhance the well-being of individuals living with this challenging autoimmune condition.
Development of a novel empirical approach to control overbreak, surface quality, and slope angle of benches following blasting
Authors: Soltanalinejad Sina , Moomivand Hassan
Published: April 2024

Overbreak, slope angle, and quality of a bench behind the boundary of excavation as attractive subjects for mining and civil engineers are the most crucial consequences of the post-blast. But the breakage mechanism of blasting has not originally been well clarified how a desirable slope angle and quality of a bench can be obtained by common drilling and blasting operations and what parameters can quantitatively affect such blasting consequences? The slope angle of the remained bench face ( β ) can be influenced by the overbreak zone between the last row of holes and the remained bench face after blasting. The breakage mechanism and influence of the blasthole parameters, such as hole diameters ( ϕ h), explosive weight per hole ( Q), burden ( B), spacing ( S), stemming ( St), bench height ( K), powder factor ( q), and blastability index (BI) on the width of overbreak zone ( LOZ), and the difference between hole and bench slope angles ( α ° − β °) and the width of damaged zone (LDZ) in 15 zones of Sun gun open pit copper mine, Golgohar open pit iron ore mine, Khoy limestone, Rashakan limestone, Bonab silica mine, and Evoghli gypsum mine were investigated. Several parameters were measured in each of 15 drilling and blasting operations. The blasthole parameters varied in a wide range for different mines. Both the inclined and horizontal faces of a bench as two free faces, which are subjected to the shock waves' reflection by blasting, can affect the overbreak and damaged zones. Impact of shock waves' reflection, breakage potential, and overbreak increases from the foot of the bench to the top. LOZ, ( α ° − β °), and LDZ of the results increased by power functions with increasing ϕ h, Q, B, S, St, and K. But acceptable correlations between each of LOZ, ( α ° − β °) and LDZ with q and BI were not achieved. New multivariable nonlinear relations between each of LOZ, ( α ° − β °), and LDZ with the combination of six blasthole parameters ϕ h, Q, B, S, St, and K were developed with good correlations. In some cases, with lower values of ϕ h, Q, B, S, St, and K, both the LOZ and ( α ° − β °) approached to zero value. The new achievements in this study can be important new guides to obtain the desirable bench slope angle and bench faces.
Genomic regions associated with coat color in Gir cattle
Authors: Maciel Silel Vinicius Simões Andrade , Oliveira Ingrid Pereira Pinto , Senes Beatriz Bastos , Silva Josineudson Augusto II de Vasconcelos , Feitosa Fabieli Loise Braga , Alves Jackeline Santos , Costa Raphael Bermal , de Camargo Gregório Miguel Ferreira
Published: April 2024

Indicine cattle breeds are adapted to the tropical climate, and their coat plays an important role in this process. Coat color influences thermoregulation and the adhesion of ectoparasites and may be associated with productive and reproductive traits. Furthermore, coat color is used for breed qualification, with breeders preferring certain colors. The Gir cattle is characterized by a wide variety of coat colors. Therefore, we performed genome-wide association studies to identify candidate genes for coat color in Gir cattle. Different phenotype scenarios were considered in the analyses and regions were identified on eight chromosomes. Some regions and many candidate genes are influencing coat color in the Gir cattle, which was found to be a polygenic trait. The candidate genes identified have been associated with white spotting patterns and base coat color in cattle and other species. In addition, a possible epistatic effect on coat color determination in the Gir cattle was suggested. This is the first published study that identified genomic regions and listed candidate genes associated with coat color in Gir cattle. The findings provided a better understanding of the genetic architecture of the trait in the breed and will allow to guide future fine-mapping studies for the development of genetic markers for selection.
New bound-state solutions and statistical properties of the IMK-GIQYP and IMSK-IQYP models in 3D-NRNCPS symmetries
Authors: Maireche Abdelmadjid
Published: April 2024

Within the framework of three-dimensional non-relativistic noncommutative quantum phase-space (3D-NRNCPS) symmetries, we study the three-dimensional deformed Schrödinger equation (3D-DSE) using the improved modified Kratzer plus generalized inverse quadratic Yukawa potential (IMK-GIQYP) and the improved modified screened Kratzer plus inversely quadratic Yukawa potential (IMSK-IQYP) models. For this consideration, the well-known generalized Bopp’s shifts method and standard perturbation theory are used to solve the DSE in the 3D-NRNCPS regime. For the homogeneous (H2, N2 and I2) and heterogeneous (CO, CH and NO) diatomic molecules, the new non-relativistic energy equation and eigenfunction for the IMK-GIQYP and the IMSK-IQYP models in the presence of deformation phase-space are obtained to be sensitive to the atomic quantum numbers ([Formula: see text] and m), the mixed potential depths ([Formula: see text] and V) and ([Formula: see text] and [Formula: see text]), the screening parameters ([Formula: see text] and [Formula: see text]), and non-commutativity parameters ([Formula: see text] and [Formula: see text]) for the IMK-GIQYP and the IMSK-IQYP, respectively. We investigate the newly obtained bound state eigenvalues of the DSE in 3D-NRNCPS symmetries using the IMK-GIQYP and the IMSK-IQYP, with appropriate adjustments made to the improved modified Kratzer potential, improved modified screened Kratzer potential, improved generalized inverse quadratic Yukawa potential model and improved inversely quadratic Yukawa potential model. Additionally, in 3D-NRNCPS symmetries, the thermal properties of the IMK-GIQYP and the IMSK-IQYP, including their partition function, mean energy, free energy, specific heat and entropy, are thoroughly examined. Significant areas, including atomic and molecular physics, find many uses for this study.
Localized wave solutions to coupled variable-coefficient fourth-order nonlinear Schrödinger equations
Authors: Song N. , Guo M. M. , Liu R. , Ma W. X.
Published: April 2024

This study investigates higher-order localized waves for coupled variable-coefficient fourth-order nonlinear Schrödinger equations, which are used to describe the simultaneous propagation of optical pulses in an inhomogeneous optical fiber. Based on the seed solutions and Lax pair, the Nth-order localized wave solutions are constructed. The interactions of rogue waves with dark–bright solitons are graphically analyzed via numerical simulation. The results are helpful for studying localized wave phenomena in nonlinear optics.
Harald Fritzsch and the early days of quantum chromodynamics
Authors: ’t Hooft Gerard
Published: April 2024

Shortly after his escape, in 1968, from the DDR to the Western world, Harald Fritzsch made a fast career in physics while investigating the strong force in elementary particles. Inspired by Gell-Mann, Yang and Mills and many others, he contributed to the rise of the Standard Model, and in particular the developments of theories for the color confinement mechanism.
Color symmetry and confinement as an underlying superconformal structure in holographic QCD
Authors: de Téramond Guy F. , Brodsky Stanley J.
Published: April 2024

Dedicated to the memory of our colleague, Harald Fritzsch, who, together with Murray Gell-Mann, introduced the color quantum number as the exact symmetry responsible for the strong interaction, thus establishing quantum chromodynamics (QCD) as a fundamental non-Abelian gauge theory. A basic understanding of hadron properties, however, such as confinement and the emergence of a mass scale, from first principles QCD has remained elusive: Hadronic characteristics are not explicit properties of the QCD Lagrangian and perturbative QCD, so successful in the large transverse momentum domain, is not applicable at large distances. In this article, we shall examine how this daunting obstacle is overcome in holographic QCD with the introduction of a superconformal symmetry in anti de Sitter (AdS) space which is responsible for confinement and the introduction of a mass scale within the superconformal group. When mapped to light-front coordinates in physical spacetime, this approach incorporates supersymmetric relations between the Regge trajectories of meson, baryon and tetraquark states which can be visualized in terms of specific [Formula: see text] color representations of quarks. We will also briefly discuss here the implications of holographic models for QCD color transparency in view of the present experimental interest.
Towards understanding fermion masses and mixings
Authors: Berezhiani Zurab , Belfatto Benedetta
Published: April 2024

The Standard Model does not constrain the form of the Yukawa matrices and thus the origin of fermion mass hierarchies and mixing pattern remains puzzling. On the other hand, there are intriguing relations between the quark masses and their weak mixing angles, such as the well-known relationship [Formula: see text] for the Cabibbo angle, which may point towards specific textures of Yukawa matrices hypothesized by Harald Fritzsch at the end of the 70s. Though the original ansatz of Fritzsch is excluded by the experimental data, one can consider its minimal modification which consists in introducing an asymmetry between the 23 and 32 entries in the down-quark Yukawa matrix. We show that this structure is perfectly compatible with the present precision data on quark masses and CKM mixing matrix, and theoretically it can be obtained in the context of [Formula: see text] model with inter-family [Formula: see text] symmetry. We also discuss some alternative approaches which could give a natural description of the fermion mass spectrum and weak mixing pattern.
Testing Poincare invariance with QED
Authors: Spannowsky Michael
Published: April 2024

The principles of time and space translation invariance, which result in energy and momentum conservation, are among the most fundamental and widely accepted symmetry assumptions in physics. However, it is judicious to subject such assumptions to experimental and observational scrutiny. Thus, we initiate this process by specifying a simple periodic time dependence that contravenes time translation invariance in QED, and establishing phenomenological constraints on it. Besides observational and experimental constraints on time-varying couplings, we emphasise probes of energy conservation violation such as spontaneous photon and electron pair production and the [Formula: see text] process.
Harald Fritzsch in Singapore
Authors: Chan A. H.
Published: April 2024

This article is a reflection and reminiscence of Harald Fritzsch’s contributions to the High Energy Particle Physics scene in Singapore, namely in 1978, 2008 to 2022. It also captures rare moments of Harald’s fun, light-hearted times and conversations beneath his stoic demeanor.