Shades of Gray: Internal Control Reporting by Chinese U.S.-listed Firms

Chinese firms listing in the U.S. via reverse mergers (CRMs) have dominated prior media, regulator and research attention. Yet CRMs have effectively ceased, leaving Chinese firms listing via initial public offerings (CIPOs) as the relevant remaining class of Chinese firms listing on U.S. exchanges. This study documents salient differences between CIPOs, CRMs and U.S.-domiciled U.S.-listed firms by examining Sarbanes-Oxley Act Section 302 and 404 ineffective internal control (IIC) and related disclosures that underlie financial reporting quality, with three main findings. First, both CIPOs and CRMs report significantly more IICs than U.S.-domiciled counterparts. Second, both CIPOs and CRMs under-report IICs to a greater degree than U.S.-domiciled counterparts (CIPO for only 302 disclosures). Third, CIPOs report and under-report IICs significantly less than CRMs. Collectively, our results clarify and recast prior characterizations of internal controls underlying the reporting quality of Chinese firms listed in the U.S. and elsewhere.preprin

Enabling the formation of native mAb, Fab ' and Fc-conjugates using a bis-disulfide bridging reagent to achieve tunable payload-to-antibody ratios (PARs)

Either as full IgGs or as fragments (Fabs, Fc, etc.), antibodies have received tremendous attention in the development of new therapeutics such as antibody-drug conjugates (ADCs). The production of ADCs involves the grafting of active payloads onto an antibody, which is generally enabled by the site-selective modification of native or engineered antibodies via chemical or enzymatic methods. Whatever method is employed, controlling the payload-antibody ratio (PAR) is a challenge in terms of multiple aspects including: (i) obtaining homogeneous protein conjugates; (ii) obtaining unusual PARs (PAR is rarely other than 2, 4 or 8); (iii) using a single method to access a range of different PARs; (iv) applicability to various antibody formats; and (v) flexibility for the production of heterofunctional antibody-conjugates (e.g. attachment of multiple types of payloads). In this article, we report a single pyridazinedione-based trifunctional dual bridging linker that enables, in a two-step procedure (re-bridging/click), the generation of either mAb-, Fab′-, or Fc-conjugates from native mAb, (Fab′)2 or Fc formats, respectively. Fc and (Fab′)2 formats were generated via enzymatic digestion of native mAbs. Whilst the same reduction and re-bridging protocols were applied to all three of the protein formats, the subsequent click reaction(s) employed to graft payload(s) drove the generation of a range of PARs, including heterofunctional PARs. As such, exploiting click reactivity and/or orthogonality afforded mAb-conjugates with PARs of 6, 4, 2 or 4 + 2, and Fab′- and Fc-conjugates with a PAR of 3, 2, 1 or 2 + 1 on-demand. We believe that the homogeneity, novelty and variety in accessible PARs, as well as the applicability to various antibody-conjugate formats enabled by our non-recombinant method could be a suitable tool for antibody-drug conjugates optimisation (optimal PAR value, optimal payloads combination) and boost the development of new antibody therapeutics (Fab′- and Fc-conjugates)

Exceptional sperm cooperation in the wood mouse

Spermatozoa from a single male will compete for fertilization of ova with spermatozoa from another male when present in the female reproductive tract at the same time. Close genetic relatedness predisposes individuals towards altruism, and as haploid germ cells of an ejaculate will have genotypic similarity of 50%, it is predicted that spermatozoa may display cooperation and altruism to gain an advantage when inter-male sperm competition is intense. We report here the probable altruistic behaviour of spermatozoa in an eutherian mammal. Spermatozoa of the common wood mouse, Apodemus sylvaticus, displayed a unique morphological transformation resulting in cooperation in distinctive aggregations or 'trains' of hundreds or thousands of cells, which significantly increased sperm progressive motility. Eventual dispersal of sperm trains was associated with most of the spermatozoa undergoing a premature acrosome reaction. Cells undergoing an acrosome reaction in aggregations remote from the egg are altruistic in that they help sperm transport to the egg but compromise their own fertilizing ability

Investigating changes in blood-cerebrospinal fluid barrier function in a rat model of chronic hypertension using non-invasive magnetic resonance imaging

Chronic hypertension is a major risk factor for the development of neurodegenerative disease, yet the etiology of hypertension-driven neurodegeneration remains poorly understood. Forming a unique interface between the systemic circulation and the brain, the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus (CP) has been proposed as a key site of vulnerability to hypertension that may initiate downstream neurodegenerative processes. However, our ability to understand BCSFB’s role in pathological processes has, to date, been restricted by a lack of non-invasive functional measurement techniques. In this work, we apply a novel Blood-Cerebrospinal Fluid Barrier Arterial Spin Labeling (BCSFB-ASL) Magnetic resonance imaging (MRI) approach with the aim of detecting possible derangement of BCSFB function in the Spontaneous Hypertensive Rat (SHR) model using a non-invasive, translational technique. SHRs displayed a 36% reduction in BCSFB-mediated labeled arterial water delivery into ventricular cerebrospinal fluid (CSF), relative to normotensive controls, indicative of down-regulated choroid plexus function. This was concomitant with additional changes in brain fluid biomarkers, namely ventriculomegaly and changes in CSF composition, as measured by T1 lengthening. However, cortical cerebral blood flow (CBF) measurements, an imaging biomarker of cerebrovascular health, revealed no measurable change between the groups. Here, we provide the first demonstration of BCSFB-ASL in the rat brain, enabling non-invasive assessment of BCSFB function in healthy and hypertensive rats. Our data highlights the potential for BCSFB-ASL to serve as a sensitive early biomarker for hypertension-driven neurodegeneration, in addition to investigating the mechanisms relating hypertension to neurodegenerative outcomes

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of Intermediate Care Clinics for Diabetes (ICCD) : study protocol for a randomized controlled trial

Background World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. Methods/Design This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or Control group: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

&lt;p&gt;Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.&lt;/p&gt; &lt;p&gt;Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).&lt;/p&gt; &lt;p&gt;Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.&lt;/p&gt

Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony.

: Plasmodium parasites, the causative agents of malaria, have evolved a unique cell division cycle in the clinically relevant asexual blood stage of infection(1). DNA replication commences approximately halfway through the intracellular development following invasion and parasite growth. The schizont stage is associated with multiple rounds of DNA replication and nuclear division without cytokinesis, resulting in a multinucleated cell. Nuclei divide asynchronously through schizogony, with only the final round of DNA replication and segregation being synchronous and coordinated with daughter cell assembly(2,3). However, the control mechanisms for this divergent mode of replication are unknown. Here, we show that the Plasmodium-specific kinase PfCRK4 is a key cell-cycle regulator that orchestrates multiple rounds of DNA replication throughout schizogony in Plasmodium falciparum. PfCRK4 depletion led to a complete block in nuclear division and profoundly inhibited DNA replication. Quantitative phosphoproteomic profiling identified a set of PfCRK4-regulated phosphoproteins with greatest functional similarity to CDK2 substrates, particularly proteins involved in the origin of replication firing. PfCRK4 was required for initial and subsequent rounds of DNA replication during schizogony and, in addition, was essential for development in the mosquito vector. Our results identified an essential S-phase promoting factor of the unconventional P. falciparum cell cycle. PfCRK4 is required for both a prolonged period of the intraerythrocytic stage of Plasmodium infection, as well as for transmission, revealing a broad window for PfCRK4-targeted chemotherapeutics.<br/

Remote and Selective Control of Astrocytes by Magnetomechanical Stimulation

Astrocytes play crucial and diverse roles in brain health and disease. The ability to selectively control astrocytes provides a valuable tool for understanding their function and has the therapeutic potential to correct dysfunction. Existing technologies such as optogenetics and chemogenetics require the introduction of foreign proteins, which adds a layer of complication and hinders their clinical translation. A novel technique, magnetomechanical stimulation (MMS), that enables remote and selective control of astrocytes without genetic modification is described here. MMS exploits the mechanosensitivity of astrocytes and triggers mechanogated Ca2+ and adenosine triphosphate (ATP) signaling by applying a magnetic field to antibody-functionalized magnetic particles that are targeted to astrocytes. Using purpose-built magnetic devices, the mechanosensory threshold of astrocytes is determined, a sub-micrometer particle for effective MMS is identified, the in vivo fate of the particles is established, and cardiovascular responses are induced in rats after particles are delivered to specific brainstem astrocytes. By eliminating the need for device implantation and genetic modification, MMS is a method for controlling astroglial activity with an improved prospect for clinical application than existing technologies