Preclinical Evaluation of a Novel Series of Polyfluorinated Thalidomide Analogs in Drug-Resistant Multiple Myeloma.

Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.

Neurodevelopment in preschool children exposed and unexposed to Zika virus in utero in Nicaragua: a prospective cohort study.

BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Spectra without stories: reporting 94% dark and unidentified ancient proteomes.

Background: Data-dependent, bottom-up proteomics is widely used for identifying proteins and peptides. However, one key challenge is that 70% of fragment ion spectra consistently fail to be assigned by conventional database searching. This 'dark matter' of bottom-up proteomics seems to affect fields where non-model organisms, low-abundance proteins, non-tryptic peptides, and complex modifications may be present. While palaeoproteomics may appear as a niche field, understanding and reporting unidentified ancient spectra require collaborative innovation in bioinformatics strategies. This may advance the analysis of complex datasets. Methods: 14.97 million high-impact ancient spectra published in Nature and Science portfolios were mined from public repositories. Identification rates, defined as the proportion of assigned fragment ion spectra, were collected as part of deposited database search outputs or parsed using open-source python packages. Results and Conclusions: We report that typically 94% of the published ancient spectra remain unidentified. This phenomenon may be caused by multiple factors, notably the limitations of database searching and the selection of user-defined reference data with advanced modification patterns. These 'spectra without stories' highlight the need for widespread data sharing to facilitate methodological development and minimise the loss of often irreplaceable ancient materials. Testing and validating alternative search strategies, such as open searching and de novo sequencing, may also improve overall identification rates. Hence, lessons learnt in palaeoproteomics may benefit other fields grappling with challenging data.

Possible shift in controls of the tropical Pacific surface warming pattern.

Changes in the sea surface temperature (SST) pattern in the tropical Pacific modulate radiative feedbacks to greenhouse gas forcing, the pace of global warming and regional climate impacts. Therefore, elucidating the drivers of the pattern is critically important for reducing uncertainties in future projections. However, the causes of observed changes over recent decades, an enhancement of the zonal SST contrast coupled with a strengthening of the Walker circulation, are still debated. Here we focus on the role of external forcing and review existing mechanisms of the forced response categorized as either an energy perspective that adopts global and hemispheric energy budget constraints or a dynamical perspective that examines the atmosphere-ocean coupled processes. We then discuss their collective and relative contributions to the past and future SST pattern changes and propose a narrative that reconciles them. Although definitive evidence is not yet available, our assessment suggests that the zonal SST contrast has been dominated by strengthening mechanisms in the past, but will shift towards being dominated by weakening mechanisms in the future. Finally, we present opportunities to resolve the model-observations discrepancy regarding the recent trends.

Sequential trypsin and ProAlanase digestions unearth immunological protein biomarkers shrouded by skeletal collagen.

This study investigates the efficacy of proteomic analysis of human remains to identify active infections in the past through the detection of pathogens and the host response to infection. We advance leprosy as a case study due to the sequestering of sufferers in leprosaria and the suggestive skeletal lesions that can result from the disease. Here we present a sequential enzyme extraction protocol, using trypsin followed by ProAlanase, to reduce the abundance of collagen peptides and in so doing increase the detection of non-collagenous proteins. Through our study of five individuals from an 11th to 18th century leprosarium, as well as four from a contemporaneous non-leprosy associated cemetery in Barcelona, we show that samples from 2 out of 5 leprosarium individuals extracted with the sequential digestion methodology contain numerous host immune proteins associated with modern leprosy. In contrast, individuals from the non-leprosy associated cemetery and all samples extracted with a trypsin-only protocol did not. Through this study, we advance a palaeoproteomic methodology to gain insights into the health of archaeological individuals and take a step toward a proteomics-based method to study immune responses in past populations.

Evidence of Ongoing Transmission of Zika Virus in Mérida, Mexico.

Since the Zika virus (ZIKV) pandemic in 2015-2017, there has been a near absence of reported cases in the Americas outside of Brazil. However, the conditions for Aedes-borne transmission persist in Latin America, and the threat of ZIKV transmission is increasing as population immunity wanes. Mexico has reported only 70 cases of laboratory-confirmed ZIKV infection since 2020, with no cases recorded in the Yucatán peninsula. Here, we provide evidence of active ZIKV transmission, despite the absence of official case reports, in the city of Mérida, Mexico, the capital of the state of Yucatán. Capitalizing on an existing cohort, we detected cases in participants with symptoms consistent with flavivirus infection from 2021 to 2022. Serum samples from suspected cases were tested for ZIKV RNA by polymerase chain reaction or ZIKV-reactive IgM by ELISA. To provide more specific evidence of exposure, focus reduction neutralization tests were performed on ELISA-positive samples. Overall, we observed 25 suspected ZIKV infections for an estimated incidence of 2.8 symptomatic cases per 1,000 persons per year. Our findings emphasize the continuing threat of ZIKV transmission in the setting of decreased surveillance and reporting.

Human and animal skin identified by palaeoproteomics in Scythian leather objects from Ukraine.

Leather was one of the most important materials of nomadic Scythians, used for clothing, shoes, and quivers, amongst other objects. However, our knowledge regarding the specific animal species used in Scythian leather production remains limited. In this first systematic study, we used palaeoproteomics methods to analyse the species in 45 samples of leather and two fur objects recovered from 18 burials excavated at 14 different Scythian sites in southern Ukraine. Our results demonstrate that Scythians primarily used domesticated species such as sheep, goat, cattle, and horse for the production of leather, while the furs were made of wild animals such as fox, squirrel and feline species. The surprise discovery is the presence of two human skin samples, which for the first time provide direct evidence of the ancient Greek historian Herodotus' claim that Scythians used the skin of their dead enemies to manufacture leather trophy items, such as quiver covers. We argue that leather manufacture is not incompatible with a nomadic lifestyle and that Scythians possessed sophisticated leather production technologies that ensured stable supply of this essential material.

Long-term health care costs following COVID-19: implications for pandemic preparedness.

OBJECTIVES: To estimate excess health care costs in the 12 months following COVID-19 diagnosis. STUDY DESIGN: Retrospective cohort study using Blue Cross Blue Shield of Rhode Island claims incurred from January 1, 2019, to March 31, 2022, among commercial and Medicare Advantage members. METHODS: Difference-in-differences analyses were used to compare changes in health care spend between the 12 months before (baseline period) and the 12 months after (post period) COVID-19 diagnosis for COVID-19 cases and contemporaneous matched controls without COVID-19. RESULTS: Overall, there were 7224 commercial and 1630 Medicare Advantage members with a COVID-19 diagnosis on/before March 31, 2021, each with a matched control, yielding a sample of 14,448 commercial and 3260 Medicare Advantage members. Among commercial members, 51.9% were aged 25 to 54 years and 54.0% were female. Among Medicare Advantage members, 94.2% were 65 years or older and 62.0% were female. Among commercial members, from the baseline period to the post period, total health care spend increased $41.61 (7.7%) per member per month (PMPM) more among COVID-19 cases compared with their matched controls. Among Medicare Advantage members, the difference-in-differences was greater, with spend increasing $97.30 (13.1%) PMPM more among cases compared with controls. The difference-in-differences was greatest for outpatient and professional services (both populations) and prescription services (Medicare Advantage only). CONCLUSIONS: COVID-19 diagnosis was associated with excess health care spend PMPM over the subsequent 12 months, highlighting the importance of societal preparations to support individuals' long-term health care needs following COVID-19 and as a part of future pandemic preparedness.

Natural infection by Zika virus but not DNA vaccination consistently elicits antibodies that compete with two potently neutralising monoclonal antibodies targeting distinct epitopes.

BACKGROUND: Autochthonous transmission of Zika virus (ZIKV) has been reported in 87 countries since 2015. Although most infections are mild, there is risk of Guillain-Barré syndrome and adverse pregnancy outcomes. Vaccines are urgently needed to prevent Zika, but sufficient understanding of humoral responses and tools to assess ZIKV-specific immunity are lacking. METHODS: We developed a blockade-of-binding (BOB) ELISA using A9E and G9E, two strongly neutralising ZIKV-specific monoclonal antibodies, which do not react with dengue virus. Receiver operating characteristic curve analysis assessed A9E and G9E BOB serodiagnostic performance. BOB was then applied to samples from a surveillance cohort in Risaralda, Colombia, and phase 1 ZIKV vaccine trial samples, comparing results against traditional serologic tests. FINDINGS: In the validation sample set (n = 120), A9E BOB has a sensitivity of 93.5% (95% CI: 79.3, 98.9) and specificity 97.8 (95% CI: 92.2, 99.6). G9E BOB had a sensitivity of 100% (95% CI: 89.0, 100.0) and specificity 100% (95% CI: 95.9, 100). Serum from natural infections consistently tested positive in these assays for up to one year, and reactivity tracks well with ZIKV infection status among sera from endemic areas with complicated flavivirus exposures. Interestingly, a leading ZIKV vaccine candidate elicited minimal BOB reactivity despite generating neutralising antibody responses. INTERPRETATION: In conclusion, A9E and G9E BOB assays are sensitive and specific assays for detecting antibodies elicited by recent or remote ZIKV infections. Given the additional ability of these BOB assays to detect immune responses that target different epitopes, further development of these assays is well justified for applications including flavivirus surveillance, translational vaccinology research and as potential serologic correlates of protective immunity against Zika. FUNDING: R21 AI129532 (PI: S. Becker-Dreps), CDCBAA 2017-N-18041 (PI: A. M. de Silva), Thrasher Fund (PI: M. H. Collins), K22 AI137306 (PI: M. H. Collins).

Grouping groupers in the Mediterranean: Ecological baselines revealed by ancient proteins.

Marine historical ecology provides a means to establish baselines to inform current fisheries management. Groupers (Epinephelidae) are key species for fisheries in the Mediterranean, which have been heavily overfished. Species abundance and distribution prior to the 20th century in the Mediterranean remains poorly known. To reconstruct the past biogeography of Mediterranean groupers, we investigated whether Zooarchaeology by Mass Spectrometry (ZooMS) can be used for identifying intra-genus grouper bones to species level. We discovered 22 novel, species-specific ZooMS biomarkers for groupers. Applying these biomarkers to Kinet Höyük, a Mediterranean archaeological site, demonstrated 4000 years of regional Epinephelus aeneus dominance and resiliency through millennia of fishing pressures, habitat degradation and climatic changes. Combining ZooMS identifications with catch size reconstructions revealed the Epinephelus aeneus capacity for growing 30 cm larger than hitherto documented, revising the maximum Total Length from 120 to 150 cm. Our results provide ecological baselines for a key Mediterranean fishery which could be leveraged to define and assess conservation targets.

Blockade Antibody Responses in Human Subjects Challenged with a New Snow Mountain Virus Inoculum.

Background: Noroviruses (NoVs) are a leading cause of non-bacterial gastroenteritis in young children and adults worldwide. Snow Mountain Virus (SMV) is the prototype of NoV GII genotype 2 (GII.2) that has been developed as a viral model for human challenge models, an important tool for studying pathogenesis and immune response of NoV infections and for evaluating NoV vaccine candidates. Previous studies have identified blockade antibodies that block the binding of NoV virus-like particles (VLPs) to histo-blood group antigens (HBGAs) as a surrogate for neutralization in human Norwalk virus and GII.4 infections but little is known about SMV blockade antibodies. Methods: In this secondary data analysis study, blockade antibodies were characterized in pre-challenge and post-challenge serum samples from human subjects challenged with a new SMV inoculum. The correlation between blockade antibody geometric mean antibody titers (GMTs) and SMV-specific serum IgG/IgA GMTs were examined after stratifying the subjects by infection status. A linear mixed model was applied to test the association between HBGA blockade antibody concentrations and post-challenge days accounting for covariates and random effects. Results: Laboratory results from 33 SMV inoculated individuals were analyzed and 75.7% (25/33) participants became infected. Serum SMV-specific blockade antibodies, IgA, and IgG were all significantly different between infected and uninfected individuals beginning day 15 post-challenge. Within infected individuals, a significant correlation was observed between both IgG and IgA and blockade antibody concentration as early as day 6 post-challenge. Analysis of blockade antibody using the linear mixed model showed that infected individuals, when compared to uninfected individuals, had a statistically significant increase in blockade antibody concentrations across the post-challenge days. Among the post-challenge days, blockade antibody concentrations on days 15, 30, and 45 were significantly higher than those observed pre-challenge. The intraclass correlation coefficient (ICC) analysis indicated that the variability of blockade antibody titers is more observed between individuals rather than observations within subjects. Conclusions: These results indicate that HBGA-blockade antibody GMTs are generated after SMV challenge and the blockade antibodies were still detectable at day 45 post-challenge. These data indicate that the second generation of SMV inoculum is highly effective.

The prelude to industrial whaling: identifying the targets of ancient European whaling using zooarchaeology and collagen mass-peptide fingerprinting.

Taxonomic identification of whale bones found during archaeological excavations is problematic due to their typically fragmented state. This difficulty limits understanding of both the past spatio-temporal distributions of whale populations and of possible early whaling activities. To overcome this challenge, we performed zooarchaeology by mass spectrometry on an unprecedented 719 archaeological and palaeontological specimens of probable whale bone from Atlantic European contexts, predominantly dating from ca 3500 BCE to the eighteenth century CE. The results show high numbers of Balaenidae (many probably North Atlantic right whale (Eubalaena glacialis)) and grey whale (Eschrichtius robustus) specimens, two taxa no longer present in the eastern North Atlantic. This discovery matches expectations regarding the past utilization of North Atlantic right whales, but was unanticipated for grey whales, which have hitherto rarely been identified in the European zooarchaeological record. Many of these specimens derive from contexts associated with mediaeval cultures frequently linked to whaling: the Basques, northern Spaniards, Normans, Flemish, Frisians, Anglo-Saxons and Scandinavians. This association raises the likelihood that early whaling impacted these taxa, contributing to their extirpation and extinction. Much lower numbers of other large cetacean taxa were identified, suggesting that what are now the most depleted whales were once those most frequently used.

Threads of memory: Reviving the ornament of a dead child at the Neolithic village of Ba`ja (Jordan).

In 2018, a well-constructed cist-type grave was discovered at Ba`ja, a Neolithic village (7,400-6,800 BCE) in Southern Jordan. Underneath multiple grave layers, an 8-year-old child was buried in a fetal position. Over 2,500 beads were found on the chest and neck, along with a double perforated stone pendant and a delicately engraved mother-of-pearl ring discovered among the concentration of beads. The first was found behind the neck, and the second on the chest. The meticulous documentation of the bead distribution indicated that the assemblage was a composite ornament that had gradually collapsed, partly due to the burying position. Our aim was to challenge time degradation and to reimagine the initial composition in order to best explore the significance of this symbolic category of material culture, not as mere group of beads, but as an ornamental creation with further aesthetic, artisanal and socioeconomic implications. The reconstruction results exceeded our expectations as it revealed an imposing multi-row necklace of complex structure and attractive design. Through multiple lines of evidence, we suggest that the necklace was created at Ba`ja, although significant parts of beads were made from exotic shells and stones, including fossil amber, an unprecedented material never attested before for this period. The retrieval of such an ornament from life and its attribution to a young dead child highlights the significant social status of this individual. Beyond the symbolic functions related to identity, the necklace is believed to have played a key role in performing the inhumation rituals, understood as a public event gathering families, relatives, and people from other villages. In this sense, the necklace is not seen as belonging completely to the realm of death but rather to the world of the living, materializing a collective memory and shared moments of emotions and social cohesion.

North and South: Exploring isotopic analysis of bone carbonates and collagen to understand post-medieval diets in London and northern England.

OBJECTIVES: We evaluate the potential of paired isotopic analysis of bone carbonate and collagen to examine the diet of post-medieval human and animal populations from England (17th-19th c.), including, for the first time, manufacturing towns in northern England. The potential for identifying C4 crop consumption is explored alongside regional and local patterning in diet by sex and socioeconomic status. MATERIALS AND METHODS: Humans (n = 216) and animals (n = 168) were analyzed from sites in London and northern England for both carbon and nitrogen isotopes of bone collagen (𝛿13 Ccoll , 𝛿15 Ncoll ). Isotopic analysis of bone carbonates (𝛿13 Ccarb , 𝛿18 Ocarb ) was carried out on all humans and 27 animals, using Fourier transform infrared spectroscopy-attenuated total reflectance to assess diagenesis. RESULTS: Variations in diet were observed between and within different populations by geographical location and socioeconomic status. Three pigs and one cow consumed C4 resources, indicating the availability of C4 -fed animal protein. Londoners consumed more animal and marine protein and C4 resources. Middle- and upper-class populations from both London and northern populations also had greater access to these foods compared to those of lower status in the same regions. DISCUSSION: This substantial multi-isotope dataset deriving from bone carbonate and collagen combined from diverse post-medieval urban communities enabled, for the first time, the biomolecular identification of the dynamics of C4 consumption (cane sugar/maize) in England, providing insight into the dynamics of food globalization during this period. We also add substantially to the animal dataset for post-medieval England, providing further insight into animal management during a key moment of agricultural change.

Bioarchaeological and paleogenomic profiling of the unusual Neolithic burial from Grotta di Pietra Sant'Angelo (Calabria, Italy).

The Neolithic burial of Grotta di Pietra Sant'Angelo (CS) represents a unique archaeological finding for the prehistory of Southern Italy. The unusual placement of the inhumation at a rather high altitude and far from inhabited areas, the lack of funerary equipment and the prone deposition of the body find limited similarities in coeval Italian sites. These elements have prompted wider questions on mortuary customs during the prehistory of Southern Italy. This atypical case requires an interdisciplinary approach aimed to build an integrated bioarchaeological profile of the individual. The paleopathological investigation of the skeletal remains revealed the presence of numerous markers that could be associated with craft activities, suggesting possible interpretations of the individual's lifestyle. CT analyses, carried out on the maxillary bones, showed the presence of a peculiar type of dental wear, but also a good density of the bone matrix. Biomolecular and micromorphological analyses of dental calculus highlight the presence of a rich Neolithic-like oral microbiome, the composition of which is consistent with the presence pathologies. Finally, paleogenomic data obtained from the individual were compared with ancient and modern Mediterranean populations, including unpublished high-resolution genome-wide data for 20 modern inhabitants of the nearby village of San Lorenzo Bellizzi, which provided interesting insights into the biodemographic landscape of the Neolithic in Southern Italy.

Visual findings in children exposed to Zika in utero in Nicaragua.

Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in children exposed to Zika virus (ZIKV) in utero but born without congenital Zika syndrome (CZS) is limited. We hypothesized that children exposed to ZIKV in utero born without CZS may have visual impairments in early childhood. We performed ophthalmic examination between 16 and 21 months of age and neurodevelopment assessment at 24 months of age with the Mullen Scales of Early Learning test (MSEL) on children enrolled in a cohort born to women pregnant during and shortly after the ZIKV epidemic in Nicaragua (2016-2017). ZIKV exposure status was defined based on maternal and infant serological testing. Visual impairment was defined as abnormal if the child had an abnormal ophthalmic exam and/or low visual reception score in the MSEL assessment. Of 124 children included in the analysis, 24 (19.4%) were classified as ZIKV-exposed and 100 (80.6%) unexposed according to maternal or cord blood serology. Ophthalmic examination showed that visual acuity did not differ significantly between groups, thus, 17.4% of ZIKV-exposed and 5.2% of unexposed had abnormal visual function (p = 0.07) and 12.5% of the ZIKV-exposed and 2% of the unexposed had abnormal contrast testing (p = 0.05). Low MSEL visual reception score was 3.2-fold higher in ZIKV-exposed than unexposed children, but not statistically significant (OR 3.2, CI: 0.8-14.0; p = 0.10). Visual impairment (a composite measure of visual function or low MESL visual reception score) was present in more ZIKV-exposed than in unexposed children (OR 3.7, CI: 1.2, 11.0; p = 0.02). However, the limited sample size warrants future investigations to fully assess the impact of in utero ZIKV exposure on ocular structures and visual function in early childhood, even in apparently healthy children.

The most at-risk regions in the world for high-impact heatwaves.

Heatwaves are becoming more frequent under climate change and can lead to thousands of excess deaths. Adaptation to extreme weather events often occurs in response to an event, with communities learning fast following unexpectedly impactful events. Using extreme value statistics, here we show where regional temperature records are statistically likely to be exceeded, and therefore communities might be more at-risk. In 31% of regions examined, the observed daily maximum temperature record is exceptional. Climate models suggest that similar behaviour can occur in any region. In some regions, such as Afghanistan and parts of Central America, this is a particular problem - not only have they the potential for far more extreme heatwaves than experienced, but their population is growing and increasingly exposed because of limited healthcare and energy resources. We urge policy makers in vulnerable regions to consider if heat action plans are sufficient for what might come.

Ultrasound Manipulation and Extrusion of Active Nanorods.

Synthetic self-propelled nano and microparticles have a growing appeal for targeted drug delivery, collective functionality, and manipulation at the nanoscale. However, it is challenging to control their positions and orientations under confinement, e.g., in microchannels, nozzles, and microcapillaries. This study reports on the synergistic effect of acoustic and flow-induced focusing in microfluidic nozzles. In a microchannel with a nozzle, the balance between the acoustophoretic forces and the fluid drag due to streaming flows generated by the acoustic field controls the microparticle's dynamics. This study manipulates the positions and orientations of dispersed particles and dense clusters inside the channel at a fixed frequency by tuning the acoustic intensity. The main findings are: first, this study successfully manipulates the positions and orientations of individual particles and dense clusters inside the channel at a fixed frequency by tuning the acoustic intensity. Second, when an external flow is applied, the acoustic field separates and selectively extrudes shape-anisotropic passive particles and self-propelled active nanorods. Finally, the observed phenomena are explained by multiphysics finite-element modeling. The results shed light on the control and extrusion of active particles in confined geometries and enable applications for acoustic cargo (e.g., drug) delivery, particle injection, and additive manufacturing via printed self-propelled active particles.

A biological reading of a palimpsest.

In the Middle Ages, texts were recorded and preserved on parchment, an animal-derived material. When this resource was scarce, older manuscripts were sometimes recycled to write new manuscripts. In the process, the ancient text was erased, creating what is known as a palimpsest. Here, we explore the potential of peptide mass fingerprinting (PMF), widely applied to identify species, to help reconnect the dispersed leaves of a manuscript and reveal differences in parchment manufacturing. In combination with visual methods, we analyzed a whole palimpsest, the codex AM 795 4to from the Arnamagnæan Collection (Copenhagen, Denmark). We find that both sheep and goat skins were used in this manuscript, and that parchment differed in quality. Notably, the PMF analysis distinguished five groups of folios which match the visual groupings. We conclude that this detailed interrogation of a single mass spectrum can be a promising tool to understand how palimpsest manuscripts were constructed.

Epidemiologic and Clinical Features of Mpox-Associated Deaths - United States, May 10, 2022-March 7, 2023.

As of March 7, 2023, a total of 30,235 confirmed and probable monkeypox (mpox) cases were reported in the United States,† predominantly among cisgender men§ who reported recent sexual contact with another man (1). Although most mpox cases during the current outbreak have been self-limited, cases of severe illness and death have been reported (2-4). During May 10, 2022-March 7, 2023, 38 deaths among persons with probable or confirmed mpox¶ (1.3 per 1,000 mpox cases) were reported to CDC and classified as mpox-associated (i.e., mpox was listed as a contributing or causal factor). Among the 38 mpox-associated deaths, 94.7% occurred in cisgender men (median age = 34 years); 86.8% occurred in non-Hispanic Black or African American (Black) persons. The median interval from symptom onset to death was 68 days (IQR = 50-86 days). Among 33 decedents with available information, 93.9% were immunocompromised because of HIV. Public health actions to prevent mpox deaths include integrated testing, diagnosis, and early treatment for mpox and HIV, and ensuring equitable access to both mpox and HIV prevention and treatment, such as antiretroviral therapy (ART) (5).